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Sample records for abnormal cytokine secretion

  1. Abnormal Growth Factor/Cytokine Network in Gastric Cancer

    PubMed Central

    2008-01-01

    Gastric cancer cells express a broad spectrum of the growth factor/cytokine receptor systems that organize the complex interaction between cancer cells and stromal cells in tumor microenvironment, which confers cell growth, apoptosis, morphogenesis, angiogenesis, progression and metastasis. However, these abnormal growth factor/cytokine networks differ in the two histological types of gastric cancer. Importantly, activation of nuclear factor-kB pathway by Helicobacter pylori infection may act as a key player for induction of growth factor/cytokine networks in gastritis and pathogenesis of gastric cancer. Better understanding of these events will no doubt provide new approaches for biomarkers of diagnosis and effective therapeutic targeting of gastric cancer. PMID:19308687

  2. Adiponectin stimulates proliferation and cytokine secretion in colonic epithelial cells.

    PubMed

    Ogunwobi, Olorunseun Olatunji; Beales, Ian L P

    2006-05-15

    Adiponectin is a recently described mediator secreted by adipose tissue. Here we report the growth promoting and pro-inflammatory actions of adiponectin on colonic epithelial cancer cells. Full-length and globular adiponectin produced an identical stimulation of HT-29 cell growth that was blocked by inhibition of adenylate cyclase and protein kinase A and partially inhibited by a pan-specific protein kinase C inhibitor, but was unaffected by specific inhibition of extracellular signal-related kinase (ERK) or p38 MAP kinase. Globular adiponectin but not full-length adiponectin significantly increased the secretion and mRNA levels of IL-8, GM-CSF and MCP-1. Globular adiponectin doubled IL-1beta-stimulated IL-8 and GM-CSF secretion. Adiponectin-stimulated cytokine secretion was blocked by pharmacological inhibitors of NF-kappaB, ERK and p38 MAP kinase. Globular adiponectin increased phosphorylation of both ERK and p38 MAP kinase and increased the nuclear translocation of active NF-kappaB. Adiponectin has pro-proliferative and pro-inflammatory actions on colonic epithelial cells; these appear to be differentially activated by the adiponectin isoforms. Adiponectin may have a role in the regulation of gastrointestinal mucosal function, inflammation and colon carcinogenesis.

  3. Immunomodulation of Skin Cytokine Secretion by House Dust Mite Extracts

    PubMed Central

    Arlian, Larry G.; Morgan, Marjorie S.

    2011-01-01

    Background Skin contact with house dust mites may contribute to atopic dermatitis and other skin diseases. We sought to determine if molecules from house dust mites could influence the release of proinflammatory cytokines and chemokines from epidermal keratinocytes and dermal fibroblasts grown in a human skin equivalent (HSE) model. Methods HSEs consisting of an epidermis of keratinocytes with stratum corneum over a dermis of fibroblasts in a collagen matrix were challenged with Dermatophagoides farinae, D. pteronyssinus and Euroglyphus maynei mite extracts. Results HSEs secreted interleukin (IL)-1α, IL-1 receptor antagonist, IL-6, IL-8, cutaneous T cell-attracting chemokine, transforming growth factor-α, granulocyte/macrophage and macrophage colony-stimulating factors and vascular endothelial cell growth factor in response to at least 1 mite extract. Extracts of different mite species stimulated HSEs to release different cytokines. Therefore, extracts of different species contained different molecules or different concentrations of similar molecules. The cytokine release profiles of cells in the HSEs were not the same as for monocultured keratinocytes and fibroblasts. Conclusions Molecules from house dust mites are capable of inducing the release of multiple proinflammatory cytokines and chemokines from epidermal keratinocytes and dermal fibroblasts. Avoiding skin contact with house dust mites would reduce the possibility of mite-induced inflammation in the skin. Therefore, measures to reduce contact with mite molecules such as frequent vacuuming of upholstered furniture and carpets and laundering of clothing and bedding to remove mite molecules and allergens could reduce skin contact with mite molecules and diminish exacerbations of skin inflammation in patients with atopic dermatitis and other skin diseases. PMID:21576987

  4. Mechanisms of abnormal lamellar body secretion and the dysfunctional skin barrier in patients with atopic dermatitis.

    PubMed

    Elias, Peter M; Wakefield, Joan S

    2014-10-01

    I review how diverse inherited and acquired abnormalities in epidermal structural and enzymatic proteins converge to produce defective permeability barrier function and antimicrobial defense in patients with atopic dermatitis (AD). Although best known are mutations in filaggrin (FLG), mutations in other member of the fused S-100 family of proteins (ie, hornerin [hrn] and filaggrin 2 [flg-2]); the cornified envelope precursor (ie, SPRR3); mattrin, which is encoded by TMEM79 and regulates the assembly of lamellar bodies; SPINK5, which encodes the serine protease inhibitor lymphoepithelial Kazal-type trypsin inhibitor type 1; and the fatty acid transporter fatty acid transport protein 4 have all been linked to AD. Yet these abnormalities often only predispose to AD; additional acquired stressors that further compromise barrier function, such as psychological stress, low ambient humidity, or high-pH surfactants, often are required to trigger disease. T(H)2 cytokines can also compromise barrier function by downregulating expression of multiple epidermal structural proteins, lipid synthetic enzymes, and antimicrobial peptides. All of these inherited and acquired abnormalities converge on the lamellar body secretory system, producing abnormalities in lipid composition, secretion, and/or extracellular lamellar membrane organization, as well as antimicrobial defense. Finally, I briefly review therapeutic options that address this new pathogenic paradigm.

  5. Mechanisms of abnormal lamellar body secretion and the dysfunctional skin barrier in atopic dermatitis

    PubMed Central

    Elias, Peter M.; Wakefield, Joan

    2014-01-01

    We review here how diverse inherited and acquired abnormalities in epidermal structural and enzymatic proteins converge to produce defective permeability barrier function and antimicrobial defense in AD. Although best known are mutations in filaggrin (FLG), mutations in other member of the fused S-100 family of proteins (i.e., hornerin [hrn] and filaggrin 2 [flg-2]); the cornified envelope precursor (e.g., SPRR3); mattrin, encoded by Tmem79, which regulates the assembly of lamellar bodies; SPINK5, which encodes the serine protease inhibitor, LEKTI1; and the fatty acid transporter, FATP4, have all been linked to AD. Yet, these abnormalities often only predispose to AD; additional acquired stressors that further compromise barrier function; e.g., psychological stress, a low ambient humidity, or high pH surfactants, often are required to trigger disease. Th2 cytokines can also compromise barrier function by downregulating expression of multiple epidermal structural proteins, lipid synthetic enzymes and antimicrobial peptides. All of these inherited and acquired abnormalities converge on the lamellar body secretory system, producing abnormalities in lipid composition, secretion and/or extracellular lamellar membrane organization, as well as in antimicrobial defense. Finally, we briefly review therapeutic options that address this new pathogenic paradigm. PMID:25131691

  6. Secretion of cytokines by natural killer cells primed with interleukin-2 and stimulated with different lipoproteins.

    PubMed Central

    De Sanctis, J B; Blanca, I; Bianco, N E

    1997-01-01

    Natural killer (NK) cells were shown to secrete differentially interleukins (IL), IL-1 alpha, IL-1 beta, IL-2, IL-8, interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha), granulocyte-macrophage colony-stimulating factor (GM-CSF), and leukaemia inhibitory factor (LIF) upon stimulation with optimal concentrations of chylomicrons (CM), very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), high-density lipoprotein (HDL) or acetyl-modified low-density lipoprotein (AcLDL). CM, VLDL, LDL and AcLDL induced LIF secretion which was absent in nonstimulated cells. CM, VLDL, and LDL did not affect IL-1 alpha secretion. CM stimulated IL-8 > TNF-alpha > IL-1 alpha > IL-2 = IFN-gamma, and decreased seventeen-fold GM-CSF secretion. VLDL stimulated IL-8 secretion > IL-1 alpha = IL-2 > IFN-gamma > TNF-alpha and decreased fivefold GM-CSF secretion. LDL stimulated IL-8 secretion > IL-1 alpha > IL-2 = IFN-gamma, it did not modify TNF-alpha and inhibited five hundred-fold GM-CSF secretion. HDL stimulated IL-2 secretion = IFN-gamma > IL-8, it decreased GM-CSF secretion > IL-1 alpha > IL-1 beta > TNF-alpha without affecting LIF. AcLDL stimulated IL-8 secretion > TNF-alpha > IL-1 alpha > IL-2 = IFN-gamma = IL-1 beta, and decreased GM-CSF secretion eightfold. When NK cells were primed with 10, 100 or 500 IU/ml of IL-2 before the addition of lipoproteins, a decrease in the secretion of cytokines was observed as compared with cells primed with IL-2 only. Differences in cytokine secretion were observed among the diverse type of lipoproteins used for cell stimulus. Thus, lipoproteins may condition NK cytokine secretion and cell activation. Images Figure 1 PMID:9176105

  7. Neuroinflammation and cytokine abnormality in major depression: Cause or consequence in that illness?

    PubMed

    Jeon, Sang Won; Kim, Yong Ku

    2016-09-22

    Depression results from changes in the central nervous system (CNS) that may result from immunological abnormalities. The immune system affects the CNS through cytokines, which regulate brain activities and emotions. Cytokines affect two biological systems that are most associated with the pathophysiology of depression: The hypothalamic-pituitary-adrenal axis and the catecholamine/sympathetic nervous system. Neuroinflammation and cytokines affect the brain signal patterns involved in the psychopathology of depression and the mechanisms of antidepressants, and they are associated with neurogenesis and neural plasticity. These observations suggest that neuroinflammation and cytokines might cause and/or maintain depression, and that they might be useful in the diagnosis and prognosis of depression. This psychoneuroimmunologic perspective might compensate for some of the limitations of the monoamine theory by suggesting that depression is a result of a failure to adapt to stress and that inflammatory responses and cytokines are involved in this process. In this review, the interactions of cytokines with the CNS, neuroendocrine system, neurotransmitters, neurodegeneration/neurogenesis, and antidepressants are discussed. The roles of cytokines in the etiology and psychopathology of depression are examined. The use of cytokine inhibitors or anti-inflammatory drugs in depression treatment is explored. Finally, the significance and limitations of the cytokine hypothesis are discussed. PMID:27679767

  8. Neuroinflammation and cytokine abnormality in major depression: Cause or consequence in that illness?

    PubMed Central

    Jeon, Sang Won; Kim, Yong Ku

    2016-01-01

    Depression results from changes in the central nervous system (CNS) that may result from immunological abnormalities. The immune system affects the CNS through cytokines, which regulate brain activities and emotions. Cytokines affect two biological systems that are most associated with the pathophysiology of depression: The hypothalamic-pituitary-adrenal axis and the catecholamine/sympathetic nervous system. Neuroinflammation and cytokines affect the brain signal patterns involved in the psychopathology of depression and the mechanisms of antidepressants, and they are associated with neurogenesis and neural plasticity. These observations suggest that neuroinflammation and cytokines might cause and/or maintain depression, and that they might be useful in the diagnosis and prognosis of depression. This psychoneuroimmunologic perspective might compensate for some of the limitations of the monoamine theory by suggesting that depression is a result of a failure to adapt to stress and that inflammatory responses and cytokines are involved in this process. In this review, the interactions of cytokines with the CNS, neuroendocrine system, neurotransmitters, neurodegeneration/neurogenesis, and antidepressants are discussed. The roles of cytokines in the etiology and psychopathology of depression are examined. The use of cytokine inhibitors or anti-inflammatory drugs in depression treatment is explored. Finally, the significance and limitations of the cytokine hypothesis are discussed. PMID:27679767

  9. Neuroinflammation and cytokine abnormality in major depression: Cause or consequence in that illness?

    PubMed Central

    Jeon, Sang Won; Kim, Yong Ku

    2016-01-01

    Depression results from changes in the central nervous system (CNS) that may result from immunological abnormalities. The immune system affects the CNS through cytokines, which regulate brain activities and emotions. Cytokines affect two biological systems that are most associated with the pathophysiology of depression: The hypothalamic-pituitary-adrenal axis and the catecholamine/sympathetic nervous system. Neuroinflammation and cytokines affect the brain signal patterns involved in the psychopathology of depression and the mechanisms of antidepressants, and they are associated with neurogenesis and neural plasticity. These observations suggest that neuroinflammation and cytokines might cause and/or maintain depression, and that they might be useful in the diagnosis and prognosis of depression. This psychoneuroimmunologic perspective might compensate for some of the limitations of the monoamine theory by suggesting that depression is a result of a failure to adapt to stress and that inflammatory responses and cytokines are involved in this process. In this review, the interactions of cytokines with the CNS, neuroendocrine system, neurotransmitters, neurodegeneration/neurogenesis, and antidepressants are discussed. The roles of cytokines in the etiology and psychopathology of depression are examined. The use of cytokine inhibitors or anti-inflammatory drugs in depression treatment is explored. Finally, the significance and limitations of the cytokine hypothesis are discussed.

  10. Regulation of Neutrophil Degranulation and Cytokine Secretion: A Novel Model Approach Based on Linear Fitting

    PubMed Central

    Naegelen, Isabelle; Beaume, Nicolas; Plançon, Sébastien; Schenten, Véronique; Tschirhart, Eric J.; Bréchard, Sabrina

    2015-01-01

    Neutrophils participate in the maintenance of host integrity by releasing various cytotoxic proteins during degranulation. Due to recent advances, a major role has been attributed to neutrophil-derived cytokine secretion in the initiation, exacerbation, and resolution of inflammatory responses. Because the release of neutrophil-derived products orchestrates the action of other immune cells at the infection site and, thus, can contribute to the development of chronic inflammatory diseases, we aimed to investigate in more detail the spatiotemporal regulation of neutrophil-mediated release mechanisms of proinflammatory mediators. Purified human neutrophils were stimulated for different time points with lipopolysaccharide. Cells and supernatants were analyzed by flow cytometry techniques and used to establish secretion profiles of granules and cytokines. To analyze the link between cytokine release and degranulation time series, we propose an original strategy based on linear fitting, which may be used as a guideline, to (i) define the relationship of granule proteins and cytokines secreted to the inflammatory site and (ii) investigate the spatial regulation of neutrophil cytokine release. The model approach presented here aims to predict the correlation between neutrophil-derived cytokine secretion and degranulation and may easily be extrapolated to investigate the relationship between other types of time series of functional processes. PMID:26579547

  11. Dietary gluten increases natural killer cell cytotoxicity and cytokine secretion.

    PubMed

    Larsen, Jesper; Dall, Morten; Antvorskov, Julie Christine; Weile, Christian; Engkilde, Kåre; Josefsen, Knud; Buschard, Karsten

    2014-10-01

    Dietary gluten influences the development of type 1 diabetes in nonobese diabetic (NOD) mice and biobreeding rats, and has been shown to influence a wide range of immunological factors in the pancreas and gut. In the present study, the effects of gluten on NK cells were studied in vitro and in vivo. We demonstrated that gliadin increased direct cytotoxicity and IFN-γ secretion from murine splenocytes and NK cells toward the pancreatic beta-cell line MIN6 cells. Additionally, stimulation of MIN6 cells led to a significantly increased proportion of degranulating C57BL/6 CD107a(+) NK cells. Stimulation of C57BL/6 pancreatic islets with gliadin significantly increased secretion of IL-6 more than ninefold. In vivo, the gluten-containing diet led to a higher expression of NKG2D and CD71 on NKp46(+) cells in all lymphoid organs in BALB/c and NOD mice compared with the gluten-free diet. Collectively, our data suggest that dietary gluten increases murine NK-cell activity against pancreatic beta cells. This mechanism may contribute to development of type 1 diabetes and explain the higher disease incidence associated with gluten intake in NOD mice.

  12. Correlation between TLR9 Expression and Cytokine Secretion in the Clinical Diagnosis of Systemic Lupus Erythematosus

    PubMed Central

    Rao, Hui; Zeng, Qinghua; Liang, Yumei; Xiao, Changjuan; Xie, Shuoshan; Xu, Xiangyu

    2015-01-01

    To investigate the correlation between TLR9 and cytokine secretion in SLE diagnosis and treatment. A total of 66 cases (39 SLE and 27 healthy donors) were enrolled in this study. The CD20+ labeled B cells were isolated from SLE patients. TLR9 mRNA expression from SLE tissues and B cells was detected using RT-PCR. The cytokine secretion in B cells were measured using ELISA. Correlation between TLR9 expression and cytokines secretion was analyzed using gene silencing method. Compared with the controls, TLR9 expression was significantly high in SLE patients tissues, as well as in B cells. Expressions of IL-6 and ds-DNA antibody were high in SLE patients serum and were positively correlated with TLR9 level in SLE patients (IL-6, R2 = 0.768; ds-DNA antibody, R2 = 0.730). The IL-6 and ds-DNA expression were significantly decreased by silencing TLR9 compared to the controls. Moreover, silencing TLR9 significantly decreased cytokines secretion including IL-6, IL-10, and IL-1rα, as well as the pathway-associated protein expression, including ICOS and Foxp3. The successful application of TLR9 silencing method in human SLE B cells may loan theatrical basis for the possibility of TLR9 genetic therapy in SLE diagnosis and treatment. PMID:26457008

  13. [Effect of gallic acid derivatives on secretion of Th1 cytokines and Th2 cytokines from anti CD3-stimulated spleen cells].

    PubMed

    Kato, K; Yamashita, S; Kitanaka, S; Toyoshima, S

    2001-06-01

    As reported previously (Kosuge et al., Yakugaku Zasshi, 120, 408 (2000)), methyl gallate, a gallic acid derivative, which has been one of compounds isolated from extracts of Psidium geneus Myrtaceae, selectively suppresses Th2 cytokine secretion. In the present study, to examine more effective compounds than methyl gallate, the effects of various gallic acid derivatives on the secretion of helper T cell subtype specific cytokines from anti CD3-stimulated spleen cells were investigated. Ten micrograms/ml of methyl gallate and ethyl gallate remarkably suppressed the secretion of IL-4 and IL-5, Th2 cytokines, but did not suppress meaningfully the secretion of IFN-gamma, a Th1 cytokine. On the other hand, the other gallic acid derivatives suppressed the secretion of both IL-4 and IFN-gamma. Ten micrograms/ml of methyl gallate suppressed the secretion of IL-2, a Th1 cytokine, but the same concentration of ethyl gallate did not suppress it. In conclusion, it seemed that ethyl gallate was the most selective inhibitor for the secretion of Th2 cytokines among gallic acid derivatives used in this study.

  14. Detecting multiple cell-secreted cytokines from the same aptamer-functionalized electrode.

    PubMed

    Liu, Ying; Liu, Ying; Matharu, Zimple; Rahimian, Ali; Revzin, Alexander

    2015-02-15

    Inflammatory cytokines are secreted by immune cells in response to infection or injury. Quantification of multiple cytokines in parallel may help with disease diagnosis by illuminating inflammatory pathways related to disease onset and progression. This paper describes development of an electrochemical aptasensor for simultaneous detection of two important inflammatory cytokines, interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α). To enable multiplexing, IFN-γ and TNF-α aptamers were labeled with anthraquinone (AQ) and methylene blue (MB) redox reporters respectively. Random immobilization of two aptamer on gold exhibited redox peaks at -0.37 V (AQ) and -0.15 V (MB) vs. Ag/AgCl reference. When challenged with either IFN-γ or TNF-α, redox signal of the appropriate reporter changed in concentration dependent manner. To demonstrate one possible application of this sensing approach, electrodes were integrated into microfluidic devices and used to dynamically monitor cytokine release from immune cells. Two cell types, primary human CD4 T-cells and U937 monocytic cells, were used to compare differences in cytokine secretions upon stimulation. These cells were infused into the microfluidic devices and stimulated to commence cytokine production. Release of IFN-γ and TNF-α was monitored concurrently from the same small group of cells over the course of 2h. The strategy of encoding specific aptamer types with unique redox reporters allows sensitive and specific detection of multiple protein biomarkers from the same electrode. PMID:25189099

  15. Mesangial cell-matrix interactions. Effects on mesangial cell growth and cytokine secretion.

    PubMed Central

    Ruef, C.; Kashgarian, M.; Coleman, D. L.

    1992-01-01

    Glomerulonephritis (GN) results in proliferation of mesangial cells (MC), infiltration of inflammatory cells, and accumulation of extracellular matrix (ECM) proteins in the mesangium. Locally secreted cytokines may stimulate MC growth or the secretion of inflammatory mediators by MC. Interleukin-6 (IL-6) may be an autocrine cofactor in the pathogenesis of mesangioproliferative GN. We studied the regulation of IL-6 secretion by MC in response to MC-derived cytokines and ECM proteins. IL-6 secretion is stimulated in a dose-dependent manner by IL-1 alpha, TNF-alpha, and PDGF. Constitutive and LPS-induced release of IL-6 by MCs is reduced on collagen type I (coll I) compared-with uncoated surfaces. IL-6 release on collagen type IV (coll IV), however, is enhanced. In addition, MC on coll I exhibit a sixfold higher growth rate than cells on uncoated surfaces. The reduction of cytokine secretion in parallel with the stimulation of MC growth by coll I suggests that exposure to coll I may result in a change from secretory to proliferative phenotype in vitro. PMID:1323220

  16. The effect of sodium bicarbonate on cytokine secretion in CKD patients with metabolic acidosis.

    PubMed

    Ori, Yaacov; Zingerman, Boris; Bergman, Michael; Bessler, Hanna; Salman, Hertzel

    2015-04-01

    The incidence of acidosis increases with the progression of chronic kidney disease (CKD). Correction of acidosis by sodium bicarbonate may slow CKD deterioration. Inflammation, which is common in CKD, may be related to acidosis. Whether the slower rate of GFR decline following the correction of acidosis is related to changes in inflammatory markers is unknown. The current study examined whether correcting CKD-acidosis affected inflammatory cytokines secretion. Thirteen patients with CKD 4-5 and acidosis were tested for cytokines secretion from peripheral-blood mononuclear cells at baseline and after one month of oral sodium bicarbonate. Following treatment with sodium bicarbonate there was no change in weight, blood pressure, serum creatinine, albumin, sodium, calcium, phosphate, PTH, hemoglobin and CRP. Serum urea decreased (134±10-116±8 mg/dl, P=0.002), potassium decreased (5.1±0.4-4.8±0.1 mequiv./l, P=0.064), pH increased (7.29±0.01-7.33±0.01, P=0.008), and serum bicarbonate increased (18.6±0.4 mequiv./l to 21.3±0.3 mequiv./l, P=0.001). The secretion of the anti-inflammatory cytokine IL-10 decreased (2.75±0.25 ng/ml to 2.29±0.21 ng/ml, P=0.041). There was no significant change in the secretion of the other pro-inflammatory and anti-inflammatory cytokines, including IL-1β, IL-2, IL-6, TNFα, IFNγ, IL-1ra. Thus, correcting acidosis in CKD with bicarbonate decreases IL-10 secretion. Its significance needs to be further investigated.

  17. Human Parainfluenza Virus Serotypes Differ in Their Kinetics of Replication and Cytokine Secretion in Human Tracheobronchial Airway Epithelium

    PubMed Central

    Schaap-Nutt, Anne; Liesman, Rachael; Bartlett, Emmalene J.; Scull, Margaret A.; Collins, Peter L.; Pickles, Raymond J.; Schmidt, Alexander C.

    2012-01-01

    Human parainfluenza viruses (PIVs) cause acute respiratory illness in children, the elderly, and immunocompromised patients. PIV3 is a common cause of bronchiolitis and pneumonia, whereas PIV1 and 2 are frequent causes of upper respiratory tract illness and croup. To assess how PIV1, 2, and 3 differ with regard to replication and induction of type I interferons, interleukin-6, and relevant chemokines, we infected primary human airway epithelium (HAE) cultures from the same tissue donors and examined replication kinetics and cytokine secretion. PIV1 replicated to high titer yet did not induce cytokine secretion until late in infection, while PIV2 replicated less efficiently but induced an early cytokine peak. PIV3 replicated to high titer but induced a slower rise in cytokine secretion. The T cell chemoattractants CXCL10 and CXCL11 were the most abundant chemokines induced. Differences in replication and cytokine secretion might explain some of the differences in PIV serotype-specific pathogenesis and epidemiology. PMID:22959894

  18. Mometasone and desloratadine additive effect on eosinophil survival and cytokine secretion from epithelial cells

    PubMed Central

    2011-01-01

    Background Although antihistamines and topical corticosteroids are used in combination to treat allergic rhinitis, their additive effect has not been yet demonstrated. The aim was investigate the antiinflammatory additive effect of mometasone and desloratadine on cytokine and sICAM-1 secretion by epithelial cells, and on eosinophil survival stimulated by human epithelial cells secretions from nasal mucosa and polyps. Methods Epithelial cells obtained from nasal mucosa or polyps were stimulated with 10% fetal bovine serum in presence of mometasone (10-11M-10-5M) with/without desloratadine (10-5M). Cytokine and sICAM-1 concentrations in supernatants were measured by ELISA. Peripheral blood eosinophils were incubated during 4 days with epithelial cell secretions with (10-11M-10-5M) and/or desloratadine (10-5M) and survival assessed by Trypan blue. Results are expressed as percentage (mean ± SEM) compared to control. Results Fetal bovine serum stimulated IL-6, IL-8, GM-CSF and sICAM-1 secretion. In mucosa and polyp epithelial cells, mometasone inhibited this induced secretion while desloratadine inhibited IL-6 and IL-8. The combination of 10-5M desloratadine and 10-9M mometasone reduced IL-6 secretion (48 ± 11%, p < 0.05) greater extent than mometasone alone (68 ± 10%) compared to control (100%). Epithelial cell secretions induced eosinophil survival from day 1 to 4, this effect being inhibited by mometasone. At day 4, the combination of mometasone (10-11M) and desloratadine (10-5M) provoked an increased inhibition of eosinophil survival induced by cell secretions (27 ± 5%, p < 0.01) than mometasone (44 ± 7%) or desloratadine (46 ± 7%) alone. Conclusions These results suggest that the combination of desloratadine and mometasone furoate have a greater antinflammatory effect in an in vitro model of eosinophil inflammation than those drugs administered alone. PMID:21352574

  19. Impact of fexofenadine, osthole and histamine on peripheral blood mononuclear cell proliferation and cytokine secretion.

    PubMed

    Karolina Kordulewska, Natalia; Kostyra, Elżbieta; Matysiewicz, Michał; Cieślińska, Anna; Jarmołowska, Beata

    2015-08-15

    This paper compares results of peripheral blood mononuclear cell (PBMC) incubation with fexofenadine (FXF) and osthole. FXF is a third-generation antihistamine drug and osthole is assumed a natural antihistamine alternative. To our best knowledge, this is the first comparative study on FXF, osthole and histamine cytokine secretion and cytotoxicity in PBMC in vitro cultures using cell proliferation ELISA BrdU. The cultures were treated 12, 42, 48 and 72h with FXF and osthole at 150, 300 and 450ng/ml concentrations and histamine at 50, 100 and 200ng/ml. Our study results confirm that FXF, osthole and histamine exert no cytotoxic effect on PBMCs and that IL-6, IL-10 and TNF-α cytokine secretion following osthole cell stimulation was similar to that by FXF stimulation.This confirms our hypothesis that osthole is a natural histamine antagonist, and can therefore be beneficially applied in antihistamine treatment.

  20. Cytokines secreted by macrophages isolated from tumor microenvironment of inflammatory breast cancer patients possess chemotactic properties.

    PubMed

    Mohamed, Mona M; El-Ghonaimy, Eslam A; Nouh, Mohamed A; Schneider, Robert J; Sloane, Bonnie F; El-Shinawi, Mohamed

    2014-01-01

    Although there is a growing literature describing the role of macrophages in breast cancer, the role of macrophages in inflammatory breast cancer (IBC) is unclear. The aim of present study was to isolate and characterize tumor associated macrophages of IBC and non-IBC patients and define their role in IBC. Tumor infiltrating monocytes/macrophages (CD14+ and CD68+) were measured by immunohistochemistry using specific monoclonal antibodies. Blood drained from axillary vein tributaries was collected during breast cancer surgery and the percentage of CD14+ in the total isolated leukocytes was assessed by flow cytometric analysis. CD14+ cells were separated from total leukocytes by immuno-magnetic beads technique and were cultured overnight. Media conditioned by CD14+ were collected and subjected to cytokine profiling using cytokine antibody array. Wound healing and invasion assays were used to test whether cytokines highly secreted by tumor drained macrophages induce motility and invasion of breast cancer cells. We found that macrophages highly infiltrate into carcinoma tissues of IBC patients. In addition blood collected from axillary tributaries of IBC patients is highly enriched with CD14+ cells as compared to blood collected from non-IBC patients. Cytokine profiling of CD14+ cells isolated from IBC patients revealed a significant increase in secretion of tumor necrosis factor-α; monocyte chemoattractant protein-1/CC-chemokine ligand 2; interleukin-8 and interleukin-10 as compared to CD14+ cells isolated from non-IBC patients. Tumor necrosis factor-α, interleukin-8 and interleukin-10 significantly increased motility and invasion of IBC cells in vitro. In conclusion, macrophages isolated from the tumor microenvironment of IBC patients secrete chemotactic cytokines that may augment dissemination and metastasis of IBC carcinoma cells.

  1. Cytokines secreted by macrophages isolated from tumor microenvironment of inflammatory breast cancer patients possess chemotactic properties

    PubMed Central

    Mohamed, Mona M.; El-Ghonaimy, Eslam A.; Nouh, Mohamed A.; Schneider, Robert J.; Sloane, Bonnie F.; El-Shinawi, Mohamed

    2014-01-01

    Although there is a growing literature describing the role of macrophages in breast cancer, the role of macrophages in inflammatory breast cancer (IBC) is unclear. The aim of present study was to isolate and characterize tumor associated macrophages of IBC and non-IBC patients and define their role in IBC. Tumor infiltrating monocytes/macrophages (CD14+ and CD68+) were measured by immunohistochem-istry using specific monoclonal antibodies. Blood drained from axillary vein tributaries was collected during breast cancer surgery and the percentage of CD14+ in the total isolated leukocytes was assessed by flow cytometric analysis. CD14+ cells were separated from total leukocytes by immuno-magnetic beads technique and were cultured overnight. Media conditioned by CD14+ were collected and subjected to cytokine profiling using cytokine antibody array. Wound healing and invasion assays were used to test whether cytokines highly secreted by tumor drained macrophages induce motility and invasion of breast cancer cells. We found that macrophages highly infiltrate into carcinoma tissues of IBC patients. In addition blood collected from axillary tributaries of IBC patients is highly enriched with CD14+ cells as compared to blood collected from non-IBC patients. Cytokine profiling of CD14+ cells isolated from IBC patients revealed a significant increase in secretion of tumor necrosis factor-α; monocyte chemoat-tractant protein-1/CC-chemokine ligand 2; interleukin-8 and interleukin-10 as compared to CD14+ cells isolated from non-IBC patients. Tumor necrosis factor-a, interleukin-8 and interleukin-10 significantly increased motility and invasion of IBC cells in vitro. In conclusion, macrophages isolated from the tumor microenvironment of IBC patients secrete chemotactic cytokines that may augment dissemination and metastasis of IBC carcinoma cells. PMID:24291763

  2. TREK-1 Regulates Cytokine Secretion from Cultured Human Alveolar Epithelial Cells Independently of Cytoskeletal Rearrangements

    PubMed Central

    Schwingshackl, Andreas; Roan, Esra; Teng, Bin; Waters, Christopher M.

    2015-01-01

    Background TREK-1 deficient alveolar epithelial cells (AECs) secrete less IL-6, more MCP-1, and contain less F-actin. Whether these alterations in cytokine secretion and F-actin content are related remains unknown. We now hypothesized that cytokine secretion from TREK-1-deficient AECs was regulated by cytoskeletal rearrangements. Methods We determined F-actin and α-tubulin contents of control, TREK-1-deficient and TREK-1-overexpressing human A549 cells by confocal microscopy and western blotting, and measured IL-6 and MCP-1 levels using real-time PCR and ELISA. Results Cytochalasin D decreased the F-actin content of control cells. Jasplakinolide increased the F-actin content of TREK-1 deficient cells, similar to the effect of TREK-1 overexpression in control cells. Treatment of control and TREK-1 deficient cells with TNF-α, a strong stimulus for IL-6 and MCP-1 secretion, had no effect on F-actin structures. The combination of TNF-α+cytochalasin D or TNF-α+jasplakinolide had no additional effect on the F-actin content or architecture when compared to cytochalasin D or jasplakinolide alone. Although TREK-1 deficient AECs contained less F-actin at baseline, quantified biochemically, they contained more α-tubulin. Exposure to nocodazole disrupted α-tubulin filaments in control and TREK-1 deficient cells, but left the overall amount of α-tubulin unchanged. Although TNF-α had no effect on the F-actin or α-tubulin contents, it increased IL-6 and MCP-1 production and secretion from control and TREK-1 deficient cells. IL-6 and MCP-1 secretions from control and TREK-1 deficient cells after TNF-α+jasplakinolide or TNF-α+nocodazole treatment was similar to the effect of TNF-α alone. Interestingly, cytochalasin D decreased TNF-α-induced IL-6 but not MCP-1 secretion from control but not TREK-1 deficient cells. Conclusion Although cytochalasin D, jasplakinolide and nocodazole altered the F-actin and α-tubulin structures of control and TREK-1 deficient AEC, the

  3. Cytokine secretion by decidual lymphocytes in transient hypertension of pregnancy and pre-eclampsia.

    PubMed Central

    Wilczyński, Jacek R; Tchórzewski, Henryk; Głowacka, Ewa; Banasik, Małgorzata; Lewkowicz, Przemyslaw; Szpakowski, Marian; Zeman, Krzysztof; Wilczyński, Jan

    2002-01-01

    BACKGROUND: Transient hypertension (TH) and preeclampsia (PE) are believed to have different pathophysiology. However, 15-25% of pregnant women initially diagnosed as having TH develop PE. To clarify the immuno-pathogenetical connections between the two syndromes, we studied the pattern of T helper cell (Th)1/Th2 cytokine balance disturbances existing inside maternal decidua in normal pregnancy (NP) and pregnancies complicated with TH and PE. METHODS: Third-trimester decidual tissue was obtained by curettage of uterine cavity during elective caesarean sections in NP (n = 11), TH (n = 17) and PE (n = 21) patients. Cell suspensions were prepared by an electromechanical dispersal method and centrifugated using a standard gradient sedimentation technique. Isolated lymphocytes were placed in medium (RPMI 1640, 10% fetal calf serum, L-glutamine, penicillin, streptomycin) and cultured for 72 h with or without mitogen phytohaemaglutinine (PHA). The enzyme-linked immunosorbent assay method was used for estimation of interleukin (IL)-2, IL-4, IL-6, IL-10, IL-12 and interferon-gamma (IFN-gamma) in culture supernatant. STATISTICAL ANALYSIS: The Kruskal-Wallis and the Mann-Whitney U tests were used (p < 0.05). RESULTS: Both spontaneous and PHA-stimulated secretion of Th2-type cytokines IL-6 and IL-10 was decreased in PE patients compared with TH and NP patients. The concentration of Th1-type cytokine IFN-gamma was increased in patients suffering both from TH and PE. CONCLUSION: On the base of decidual cytokine secretion, both PE and TH are syndromes of local Th1/Th2 cytokine balance disturbances as compared with NP, and TH seems to be an intermediate step to PE. PMID:12061422

  4. Human dendritic cell maturation and cytokine secretion upon stimulation with Bordetella pertussis filamentous haemagglutinin.

    PubMed

    Dirix, Violette; Mielcarek, Nathalie; Debrie, Anne-Sophie; Willery, Eve; Alonso, Sylvie; Versheure, Virginie; Mascart, Françoise; Locht, Camille

    2014-07-01

    In addition to antibodies, Th1-type T cell responses are also important for long-lasting protection against pertussis. However, upon immunization with the current acellular vaccines, many children fail to induce Th1-type responses, potentially due to immunomodulatory effects of some vaccine antigens, such as filamentous haemagglutinin (FHA). We therefore analysed the ability of FHA to modulate immune functions of human monocyte-derived dendritic cells (MDDC). FHA was purified from pertussis toxin (PTX)-deficient or from PTX- and adenylate cyclase-deficient Bordetella pertussis strains, and residual endotoxin was neutralized with polymyxin B. FHA from both strains induced phenotypic maturation of human MDDC and cytokine secretion (IL-10, IL-12p40, IL-12p70, IL-23 and IL-6). To identify the FHA domains responsible for MDDC immunomodulation, MDDC were stimulated with FHA containing a Gly→Ala substitution at its RGD site (FHA-RAD) or with an 80-kDa N-terminal moiety of FHA (Fha44), containing its heparin-binding site. Whereas FHA-RAD induced maturation and cytokine production comparable to those of FHA, Fha44 did not induce IL-10 production, but maturated MDDC at least partially. Nevertheless, Fha44 induced the secretion of IL-12p40, IL-12p70, IL-23 and IL-6 by MDDC, albeit at lower levels than FHA. Thus, FHA can modulate MDDC responses in multiple ways, and IL-10 induction can be dissociated from the induction of other cytokines.

  5. Vesicular Trafficking and Signaling for Cytokine and Chemokine Secretion in Mast Cells

    PubMed Central

    Blank, Ulrich; Madera-Salcedo, Iris Karina; Danelli, Luca; Claver, Julien; Tiwari, Neeraj; Sánchez-Miranda, Elizabeth; Vázquez-Victorio, Genaro; Ramírez-Valadez, Karla Alina; Macias-Silva, Marina; González-Espinosa, Claudia

    2014-01-01

    Upon activation mast cells (MCs) secrete numerous inflammatory compounds stored in their cytoplasmic secretory granules by a process called anaphylactic degranulation, which is responsible for type I hypersensitivity responses. Prestored mediators include histamine and MC proteases but also some cytokines and growth factors making them available within minutes for a maximal biological effect. Degranulation is followed by the de novo synthesis of lipid mediators such as prostaglandins and leukotrienes as well as a vast array of cytokines, chemokines, and growth factors, which are responsible for late phase inflammatory responses. While lipid mediators diffuse freely out of the cell through lipid bilayers, both anaphylactic degranulation and secretion of cytokines, chemokines, and growth factors depends on highly regulated vesicular trafficking steps that occur along the secretory pathway starting with the translocation of proteins to the endoplasmic reticulum. Vesicular trafficking in MCs also intersects with endocytic routes, notably to form specialized cytoplasmic granules called secretory lysosomes. Some of the mediators like histamine reach granules via specific vesicular monoamine transporters directly from the cytoplasm. In this review, we try to summarize the available data on granule biogenesis and signaling events that coordinate the complex steps that lead to the release of the inflammatory mediators from the various vesicular carriers in MCs. PMID:25295038

  6. Yeast Modulation of Human Dendritic Cell Cytokine Secretion: An In Vitro Study

    PubMed Central

    Smith, Ida M.; Christensen, Jeffrey E.; Arneborg, Nils; Jespersen, Lene

    2014-01-01

    Probiotics are live microorganisms which when administered in adequate amounts confer a health benefit on the host. The concept of individual microorganisms influencing the makeup of T cell subsets via interactions with intestinal dendritic cells (DCs) appears to constitute the foundation for immunoregulatory effects of probiotics, and several studies have reported probiotic strains resulting in reduction of intestinal inflammation through modulation of DC function. Consequent to a focus on Saccharomyces boulardii as the fundamental probiotic yeast, very little is known about hundreds of non-Saccharomyces yeasts in terms of their interaction with the human gastrointestinal immune system. The aim of the present study was to evaluate 170 yeast strains representing 75 diverse species for modulation of inflammatory cytokine secretion by human DCs in vitro, as compared to cytokine responses induced by a S. boulardii reference strain with probiotic properties documented in clinical trials. Furthermore, we investigated whether cytokine inducing interactions between yeasts and human DCs are dependent upon yeast viability or rather a product of membrane interactions regardless of yeast metabolic function. We demonstrate high diversity in yeast induced cytokine profiles and employ multivariate data analysis to reveal distinct clustering of yeasts inducing similar cytokine profiles in DCs, highlighting clear species distinction within specific yeast genera. The observed differences in induced DC cytokine profiles add to the currently very limited knowledge of the cross-talk between yeasts and human immune cells and provide a foundation for selecting yeast strains for further characterization and development toward potentially novel yeast probiotics. Additionally, we present data to support a hypothesis that the interaction between yeasts and human DCs does not solely depend on yeast viability, a concept which may suggest a need for further classifications beyond the current

  7. Type III secretion needle proteins induce cell signaling and cytokine secretion via Toll-like receptors.

    PubMed

    Jessen, Danielle L; Osei-Owusu, Patrick; Toosky, Melody; Roughead, William; Bradley, David S; Nilles, Matthew L

    2014-06-01

    Pathogens are recognized by hosts by use of various receptors, including the Toll-like receptor (TLR) and Nod-like receptor (NLR) families. Ligands for these varied receptors, including bacterial products, are identified by the immune system, resulting in development of innate immune responses. Only a couple of components from type III secretion (T3S) systems are known to be recognized by TLR or NLR family members. Known T3S components that are detected by pattern recognition receptors (PRRs) are (i) flagellin, detected by TLR5 and NLRC4 (Ipaf); and (ii) T3S rod proteins (PrgJ and homologs) and needle proteins (PrgI and homologs), detected by NAIP and the NLRC4 inflammasome. In this report, we characterize the induction of proinflammatory responses through TLRs by the Yersinia pestis T3S needle protein, YscF, the Salmonella enterica needle proteins PrgI and SsaG, and the Shigella needle protein, MxiH. More specifically, we determine that the proinflammatory responses occur through TLR2 and -4. These data support the hypothesis that T3S needles have an unrecognized role in bacterial pathogenesis by modulating immune responses. PMID:24643544

  8. Type III Secretion Needle Proteins Induce Cell Signaling and Cytokine Secretion via Toll-Like Receptors

    PubMed Central

    Jessen, Danielle L.; Osei-Owusu, Patrick; Toosky, Melody; Roughead, William; Bradley, David S.

    2014-01-01

    Pathogens are recognized by hosts by use of various receptors, including the Toll-like receptor (TLR) and Nod-like receptor (NLR) families. Ligands for these varied receptors, including bacterial products, are identified by the immune system, resulting in development of innate immune responses. Only a couple of components from type III secretion (T3S) systems are known to be recognized by TLR or NLR family members. Known T3S components that are detected by pattern recognition receptors (PRRs) are (i) flagellin, detected by TLR5 and NLRC4 (Ipaf); and (ii) T3S rod proteins (PrgJ and homologs) and needle proteins (PrgI and homologs), detected by NAIP and the NLRC4 inflammasome. In this report, we characterize the induction of proinflammatory responses through TLRs by the Yersinia pestis T3S needle protein, YscF, the Salmonella enterica needle proteins PrgI and SsaG, and the Shigella needle protein, MxiH. More specifically, we determine that the proinflammatory responses occur through TLR2 and -4. These data support the hypothesis that T3S needles have an unrecognized role in bacterial pathogenesis by modulating immune responses. PMID:24643544

  9. Differential gene expression profile and altered cytokine secretion of thyroid cancer cells in space.

    PubMed

    Ma, Xiao; Pietsch, Jessica; Wehland, Markus; Schulz, Herbert; Saar, Katrin; Hübner, Norbert; Bauer, Johann; Braun, Markus; Schwarzwälder, Achim; Segerer, Jürgen; Birlem, Maria; Horn, Astrid; Hemmersbach, Ruth; Waßer, Kai; Grosse, Jirka; Infanger, Manfred; Grimm, Daniela

    2014-02-01

    This study focuses on the effects of short-term [22 s, parabolic flight campaign (PFC)] and long-term (10 d, Shenzhou 8 space mission) real microgravity on changes in cytokine secretion and gene expression patterns in poorly differentiated thyroid cancer cells. FTC-133 cells were cultured in space and on a random positioning machine (RPM) for 10 d, to evaluate differences between real and simulated microgravity. Multianalyte profiling was used to evaluate 128 secreted cytokines. Microarray analysis revealed 63 significantly regulated transcripts after 22 s of microgravity during a PFC and 2881 after 10 d on the RPM or in space. Genes in several biological processes, including apoptosis (n=182), cytoskeleton (n=80), adhesion/extracellular matrix (n=98), proliferation (n=184), stress response (n=268), migration (n=63), angiogenesis (n=39), and signal transduction (n=429), were differentially expressed. Genes and proteins involved in the regulation of cancer cell proliferation and metastasis, such as IL6, IL8, IL15, OPN, VEGFA, VEGFD, FGF17, MMP2, MMP3, TIMP1, PRKAA, and PRKACA, were similarly regulated under RPM and spaceflight conditions. The resulting effect was mostly antiproliferative. Gene expression during the PFC was often regulated in the opposite direction. In summary, microgravity is an invaluable tool for exploring new targets in anticancer therapy and can be simulated in some aspects in ground-based facilities.

  10. Analysis of T-cell proliferation and cytokine secretion in the individuals exposed to arsenic.

    PubMed

    Biswas, R; Ghosh, P; Banerjee, N; Das, J K; Sau, T; Banerjee, A; Roy, S; Ganguly, S; Chatterjee, M; Mukherjee, A; Giri, A K

    2008-05-01

    Over six million people in nine districts of West Bengal, India are exposed to very high levels of arsenic primarily through their drinking water. More than 300,000 people showed arsenic-induced skin lesions in these districts. This is regarded as the greatest arsenic calamity in the world. Chronic arsenicosis causes varied dermatological signs ranging from pigmentation changes, hyperkeratosis to non-melanocytic cancer of skin, and also malignancies in different internal organs. Higher incidences of opportunistic infections are found in the arsenic-exposed individuals, indicating that their immune systems may be impaired somehow. We have thus investigated the effect of arsenic on T-cell proliferation and cytokine secretion in 20 individuals with arsenic-induced skin lesions and compared the results with 18 arsenic-unexposed individuals. A marked dose-dependent suppression of Concanavalin A (Con A) induced T-cell proliferation was observed in the arsenic-exposed individuals compared with the unexposed (P < 0.001) individuals. This correlated with a significant decrease in the levels of secreted cytokines by the T cells (TNF-alpha, IFN-gamma, IL2, IL10, IL5, and IL4) in the exposed individuals (P < 0.001). Thus it can be inferred that arsenic exposure can cause immunosuppression in humans.

  11. Suppressed cytokine and immunoglobulin secretions by murine splenic lymphocytes infected in vitro with Toxoplasma gondii tachyzoites.

    PubMed

    Guk, S M; Kook, J; Jeon, Y H; Choi, J H; Han, E T; Shin, E H; Chai, J Y

    2005-04-01

    Mechanisms of host immunosuppression after infection with Toxoplasma gondii are unclear. This study was performed to observe cytokine and immunoglobulin secretions by murine splenic lymphocytes infected in vitro with live, nonreplicating (irradiated) RH tachyzoites on stimulation with concanavalin A (Con A) or lipopolysaccharide (LPS). For lymphocyte cultivation, 3 groups were prepared: coculture with live nonirradiated tachyzoites separated by a transwell (group T), live irradiated tachyzoites without a transwell (group R), and no tachyzoites (group C). Compared with group T, groups R and C, on stimulation with Con A, revealed significantly (P < 0.05) lower levels of interleukin-2 (IL-2) and IFN-gamma, but not IL-10. The levels of IgG1, IgG2a, IgG2b, IgG3, IgA, and IgM were also significantly (P < 0.05) lower in groups R and C than in group T after stimulation with LPS. The results suggest that intracellular infection of murine splenic lymphocytes with T. gondii tachyzoites could impair their capacity to produce cytokine and immunoglobulin secretions.

  12. Pathogenic Lifestyles of E. coli Pathotypes in a Standardized Epithelial Cell Model Influence Inflammatory Signaling Pathways and Cytokines Secretion

    PubMed Central

    Sanchez-Villamil, Javier; Tapia-Pastrana, Gabriela; Navarro-Garcia, Fernando

    2016-01-01

    Inflammatory response is key for the host defense against diarrheagenic Escherichia coli and contributes to the pathogenesis of the disease but there is not a comparative study among different diarrheagenic pathotypes. We analyzed the inflammatory response induced by five diarrheagenic pathotypes in a HT-29 cell infection model. The model was unified to reproduce the pathogenesis of each pathotype. To compare the inflammatory responses we evaluated: (i) nuclear NF-κB and ERK1/2 translocation by confocal microscopy; (ii) kinetics of activation by each pathway detecting p65 and ERK1/2 phosphorylation by Western blotting; (iii) pathways modulation through bacterial infections with or without co-stimulation with TNF-α or EGF; (iv) cytokine profile induced by each pathotype with and without inhibitors of each pathway. EHEC but mainly EPEC inhibited translocation and activation of p65 and ERK1/2 pathways, as well as cytokines secretion; inhibition of p65 and ERK1/2 phosphorylation prevailed in the presence of TNF-α and EGF, respectively. Intracellular strains, EIEC/Shigella flexneri, caused a strong translocation, activation, and cytokines secretion but they could not inhibit TNF-α and EGF stimulation. ETEC and mainly EAEC caused a moderate translocation, but a differential activation, and high cytokines secretion; interestingly TNF-α and EGF stimulation did no modify p65 and ERK1/2 activation. The use of inhibitors of NF-κB and/or ERK1/2 showed that NF-κB is crucial for cytokine induction by the different pathotypes; only partially depended on ERK1/2 activation. Thus, in spite of their differences, the pathotypes can also be divided in three groups according to their inflammatory response as those (i) that inject effectors to cause A/E lesion, which are able to inhibit NF-κB and ERK1/2 pathways, and cytokine secretion; (ii) with fimbrial adherence and toxin secretion with a moderate inhibition of both pathways but high cytokines secretion through autocrine

  13. Optineurin deficiency in mice contributes to impaired cytokine secretion and neutrophil recruitment in bacteria-driven colitis.

    PubMed

    Chew, Thean S; O'Shea, Nuala R; Sewell, Gavin W; Oehlers, Stefan H; Mulvey, Claire M; Crosier, Philip S; Godovac-Zimmermann, Jasminka; Bloom, Stuart L; Smith, Andrew M; Segal, Anthony W

    2015-08-01

    Crohn's disease (CD) is associated with delayed neutrophil recruitment and bacterial clearance at sites of acute inflammation as a result of impaired secretion of proinflammatory cytokines by macrophages. To investigate the impaired cytokine secretion and confirm our previous findings, we performed transcriptomic analysis in macrophages and identified a subgroup of individuals with CD who had low expression of the autophagy receptor optineurin (OPTN). We then clarified the role of OPTN deficiency in: macrophage cytokine secretion; mouse models of bacteria-driven colitis and peritonitis; and zebrafish Salmonella infection. OPTN-deficient bone-marrow-derived macrophages (BMDMs) stimulated with heat-killed Escherichia coli secreted less proinflammatory TNFα and IL6 cytokines despite similar gene transcription, which normalised with lysosomal and autophagy inhibitors, suggesting that TNFα is mis-trafficked to lysosomes via bafilomycin-A-dependent pathways in the absence of OPTN. OPTN-deficient mice were more susceptible to Citrobacter colitis and E. coli peritonitis, and showed reduced levels of proinflammatory TNFα in serum, diminished neutrophil recruitment to sites of acute inflammation and greater mortality, compared with wild-type mice. Optn-knockdown zebrafish infected with Salmonella also had higher mortality. OPTN plays a role in acute inflammation and neutrophil recruitment, potentially via defective macrophage proinflammatory cytokine secretion, which suggests that diminished OPTN expression in humans might increase the risk of developing CD. PMID:26044960

  14. Optineurin deficiency in mice contributes to impaired cytokine secretion and neutrophil recruitment in bacteria-driven colitis

    PubMed Central

    Chew, Thean S.; O'Shea, Nuala R.; Sewell, Gavin W.; Oehlers, Stefan H.; Mulvey, Claire M.; Crosier, Philip S.; Godovac-Zimmermann, Jasminka; Bloom, Stuart L.; Smith, Andrew M.; Segal, Anthony W.

    2015-01-01

    ABSTRACT Crohn's disease (CD) is associated with delayed neutrophil recruitment and bacterial clearance at sites of acute inflammation as a result of impaired secretion of proinflammatory cytokines by macrophages. To investigate the impaired cytokine secretion and confirm our previous findings, we performed transcriptomic analysis in macrophages and identified a subgroup of individuals with CD who had low expression of the autophagy receptor optineurin (OPTN). We then clarified the role of OPTN deficiency in: macrophage cytokine secretion; mouse models of bacteria-driven colitis and peritonitis; and zebrafish Salmonella infection. OPTN-deficient bone-marrow-derived macrophages (BMDMs) stimulated with heat-killed Escherichia coli secreted less proinflammatory TNFα and IL6 cytokines despite similar gene transcription, which normalised with lysosomal and autophagy inhibitors, suggesting that TNFα is mis-trafficked to lysosomes via bafilomycin-A-dependent pathways in the absence of OPTN. OPTN-deficient mice were more susceptible to Citrobacter colitis and E. coli peritonitis, and showed reduced levels of proinflammatory TNFα in serum, diminished neutrophil recruitment to sites of acute inflammation and greater mortality, compared with wild-type mice. Optn-knockdown zebrafish infected with Salmonella also had higher mortality. OPTN plays a role in acute inflammation and neutrophil recruitment, potentially via defective macrophage proinflammatory cytokine secretion, which suggests that diminished OPTN expression in humans might increase the risk of developing CD. PMID:26044960

  15. Modulation of Cytokine Secretion Allows CD4 T Cells Secreting IL-10 and IL-17 to Simultaneously Participate in Maintaining Tolerance and Immunity.

    PubMed

    Saito, Kanako; Pignon, Pascale; Ayyoub, Maha; Valmori, Danila

    2015-01-01

    CD4 T cells secreting IL-10 or IL-17 are frequent at mucosal sites, where their equilibrium is important for simultaneously maintaining tolerance and immunity to the resident microbiota. The mode of action of these cells, however, is as yet incompletely understood. In this study, we have combined ex vivo analysis of CD4 T cells producing IL-10 or/and IL-17 with assessment of clonal populations isolated ex vivo using a cytokine catch assay. We found that circulating CD4 T cells secreting IL-10 or/and IL-17 ex vivo include both conventional FOXP3- CD4 T cells and FOXP3+ Helios- Treg. Upon assessment of clonal populations derived from single ex vivo isolated cytokine secreting cells, we found that IL-10 or/and IL-17 secreting cells prevalently secrete one or the other cytokine depending on the type of stimulation, the time after stimulation and the presence of microbial products. Namely, IL-10 secretion by clonal cells was prevalent at early time points after TCR mediated stimulation, was independent of co-stimulation and was increased in the presence of the microbial fermentation product butyrate. In contrast, IL-17 secretion was higher at later time points after TCR mediated stimulation and in the presence of co-stimulatory signals. Taken together, these results provide insights into the mechanisms that, through modulation of cytokine secretion depending on conditions, allow IL-10 and IL-17 producing CD4 T cells to contribute to maintain tolerance to microbes locally, while retaining the ability to participate in protective immune responses at distant sites.

  16. The splenocyte proliferative response and cytokine secretion in mice after oral administration of commercial gold nanocolloid.

    PubMed

    Małaczewska, J

    2015-01-01

    Owing to their unique physicochemical properties, gold nanoparticles find numerous biomedical applications. Experiments on rodents prove that the main target organs of gold nanoparticles entering an organism are the liver and spleen, whose reticuloendothelial system removes foreign particles from the bloodstream. Through interactions with resident tissue macrophages, nanoparticles can evoke a systemic immunological response. The aim of this study has been to determine the effect of oral administration of commercial gold nanocolloid, recommended by the producer inter alia as a dietary supplement, on the proliferative activity and cytokine secretion by murine splenocytes. The colloid was given to the animals in three different doses (0.25, 2.5, 25 ppm), for three different time periods (7, 14, 28 days). The influence of nanogold on splenocyte functions was time-dependent and the various doses were distinguished by distinct modes of action. The lowest dose had a pro-inflammatory or immunostimulating effect, enhancing the synthesis of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). The effect of the highest dose can be considered as a pro-inflammatory, or immunotoxic one, because the stimulated cytokine synthesis was accompanied by a drastic decline in the proliferative activity of lymphocytes. The medium dose, while inhibiting the synthesis of pro-inflammatory cytokines of macrophages, simultaneously stimulated the proliferation of lymphocytes. All the doses also modulated the synthesis of IL-2, which may implicate their effect on the immunoregulatory mechanisms of an organism. The effect of alimentary administration of gold nanocolloid on the immune system seems to be difficult to predict, hence a risk that this type of dietary supplements might have some adverse impact on the immunity cannot be excluded, especially after their chronic administration.

  17. Subfractions of enamel matrix derivative differentially influence cytokine secretion from human oral fibroblasts

    PubMed Central

    Villa, Oscar; Brookes, Steven J; Thiede, Bernd; Heijl, Lars; Lyngstadaas, Staale P

    2015-01-01

    Enamel matrix derivative is used to promote periodontal regeneration during the corrective phase of the treatment of periodontal defects. Our main goal was to analyze the bioactivity of different molecular weight fractions of enamel matrix derivative. Enamel matrix derivative, a complex mixture of proteins, was separated into 13 fractions using size-exclusion chromatography and characterized by sodium dodecyl sulfate–polyacrylamide gel electrophoresis and liquid chromatography–electrospray ionization–tandem mass spectrometry. Human periodontal ligament fibroblasts were treated with either enamel matrix derivative or the different fractions. Proliferation and cytokine secretion to the cell culture medium were measured and compared to untreated cells. The liquid chromatography–electrospray ionization–tandem mass spectrometry analyses revealed that the most abundant peptides were amelogenin and leucine-rich amelogenin peptide related. The fractions containing proteins above 20 kDa induced an increase in vascular endothelial growth factor and interleukin-6 secretion, whereas lower molecular weight fractions enhanced proliferation and secretion of interleukin-8 and monocyte chemoattractant protein-1 and reduced interleukin-4 release. The various molecular components in the enamel matrix derivative formulation might contribute to reported effects on tissue regeneration through their influence on vascularization, the immune response, and chemotaxis. PMID:26090085

  18. Subfractions of enamel matrix derivative differentially influence cytokine secretion from human oral fibroblasts.

    PubMed

    Villa, Oscar; Brookes, Steven J; Thiede, Bernd; Heijl, Lars; Lyngstadaas, Staale P; Reseland, Janne E

    2015-01-01

    Enamel matrix derivative is used to promote periodontal regeneration during the corrective phase of the treatment of periodontal defects. Our main goal was to analyze the bioactivity of different molecular weight fractions of enamel matrix derivative. Enamel matrix derivative, a complex mixture of proteins, was separated into 13 fractions using size-exclusion chromatography and characterized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and liquid chromatography-electrospray ionization-tandem mass spectrometry. Human periodontal ligament fibroblasts were treated with either enamel matrix derivative or the different fractions. Proliferation and cytokine secretion to the cell culture medium were measured and compared to untreated cells. The liquid chromatography-electrospray ionization-tandem mass spectrometry analyses revealed that the most abundant peptides were amelogenin and leucine-rich amelogenin peptide related. The fractions containing proteins above 20 kDa induced an increase in vascular endothelial growth factor and interleukin-6 secretion, whereas lower molecular weight fractions enhanced proliferation and secretion of interleukin-8 and monocyte chemoattractant protein-1 and reduced interleukin-4 release. The various molecular components in the enamel matrix derivative formulation might contribute to reported effects on tissue regeneration through their influence on vascularization, the immune response, and chemotaxis. PMID:26090085

  19. Silicon photonic microring resonators for quantitative cytokine detection and T-cell secretion analysis.

    PubMed

    Luchansky, Matthew S; Bailey, Ryan C

    2010-03-01

    The ability to perform multiple simultaneous protein biomarker measurements in complex media with picomolar sensitivity presents a large challenge to disease diagnostics and fundamental biological studies. Silicon photonic microring resonators represent a promising platform for real-time detection of biomolecules on account of their spectral sensitivity toward surface binding events between a target and antibody-modified microrings. For all refractive index-based sensing schemes, the mass of bound analytes, in combination with other factors such as antibody affinity and surface density, contributes to the observed signal and measurement sensitivity. Therefore, proteins that are simultaneously low in abundance and have a lower molecular weight are often challenging to detect. By employing a more massive secondary antibody to amplify the signal arising from the initial binding event, it is possible to improve both the sensitivity and the specificity of protein assays, allowing for quantitative sensing in complex sample matrices. Herein, a sandwich assay is used to detect the 15.5 kDa human cytokine interleukin-2 (IL-2) at concentrations down to 100 pg/mL (6.5 pM) and to quantitate unknown solution concentrations over a dynamic range spanning 2.5 orders of magnitude. This same sandwich assay is then used to monitor the temporal secretion profile of IL-2 from Jurkat T lymphocytes in serum-containing cell culture media in the presence of the entire Jurkat secretome. The same temporal secretion analysis is performed in parallel using a commercial ELISA, revealing similar IL-2 concentration profiles but superior precision for the microring resonator sensing platform. Furthermore, we demonstrate the generality of the sandwich assay methodology on the microring resonator platform for the analysis of any biomolecular target for which two high-affinity antibodies exist by detecting the approximately 8 kDa cytokine interleukin-8 (IL-8) with a limit of detection and dynamic

  20. Nanoelectronic detection of triggered secretion of pro-inflammatory cytokines using CMOS compatible silicon nanowires.

    PubMed

    Pui, Tze-Sian; Agarwal, Ajay; Ye, Feng; Huang, Yinxi; Chen, Peng

    2011-01-15

    Nanotechnology, such as nanoelectronic biosensors, is bringing new opportunities and tools to the studies of cell biology, clinical applications, and drug discovery. In this study, crystalline silicon nanowire based field-effect transistors fabricated using top-down approach were employed to parallelly detect pro-inflammatory cytokines in the complex biological fluids (cell culture medium and blood samples) with high specificity and femtomolar sensitivity. Using this technique, the dynamic secretion of TNF-alpha and IL6 was revealed during the immune response of macrophages and rats to the stimulation of bacteria endotoxin. This technique could provide a unique platform to examine the profile of complex immune responses for fundamental studies and diagnosis. PMID:20977978

  1. Nanoelectronic detection of triggered secretion of pro-inflammatory cytokines using CMOS compatible silicon nanowires.

    PubMed

    Pui, Tze-Sian; Agarwal, Ajay; Ye, Feng; Huang, Yinxi; Chen, Peng

    2011-01-15

    Nanotechnology, such as nanoelectronic biosensors, is bringing new opportunities and tools to the studies of cell biology, clinical applications, and drug discovery. In this study, crystalline silicon nanowire based field-effect transistors fabricated using top-down approach were employed to parallelly detect pro-inflammatory cytokines in the complex biological fluids (cell culture medium and blood samples) with high specificity and femtomolar sensitivity. Using this technique, the dynamic secretion of TNF-alpha and IL6 was revealed during the immune response of macrophages and rats to the stimulation of bacteria endotoxin. This technique could provide a unique platform to examine the profile of complex immune responses for fundamental studies and diagnosis.

  2. Histamine H3 receptor in primary mouse microglia inhibits chemotaxis, phagocytosis, and cytokine secretion.

    PubMed

    Iida, Tomomitsu; Yoshikawa, Takeo; Matsuzawa, Takuro; Naganuma, Fumito; Nakamura, Tadaho; Miura, Yamato; Mohsen, Attayeb S; Harada, Ryuichi; Iwata, Ren; Yanai, Kazuhiko

    2015-07-01

    Histamine is a physiological amine which initiates a multitude of physiological responses by binding to four known G-protein coupled histamine receptor subtypes as follows: histamine H1 receptor (H1 R), H2 R, H3 R, and H4 R. Brain histamine elicits neuronal excitation and regulates a variety of physiological processes such as learning and memory, sleep-awake cycle and appetite regulation. Microglia, the resident macrophages in the brain, express histamine receptors; however, the effects of histamine on critical microglial functions such as chemotaxis, phagocytosis, and cytokine secretion have not been examined in primary cells. We demonstrated that mouse primary microglia express H2 R, H3 R, histidine decarboxylase, a histamine synthase, and histamine N-methyltransferase, a histamine metabolizing enzyme. Both forskolin-induced cAMP accumulation and ATP-induced intracellular Ca(2+) transients were reduced by the H3 R agonist imetit but not the H2 R agonist amthamine. H3 R activation on two ubiquitous second messenger signalling pathways suggests that H3 R can regulate various microglial functions. In fact, histamine and imetit dose-dependently inhibited microglial chemotaxis, phagocytosis, and lipopolysaccharide (LPS)-induced cytokine production. Furthermore, we confirmed that microglia produced histamine in the presence of LPS, suggesting that H3 R activation regulate microglial function by autocrine and/or paracrine signalling. In conclusion, we demonstrate the involvement of histamine in primary microglial functions, providing the novel insight into physiological roles of brain histamine.

  3. [Intestinal dysbacteriosis promotes intestinal intraepithelial T lymphocyte activation and proinflammatory cytokine secretion in mice].

    PubMed

    Luo, Xia; Luo, Shuang; Zheng, Yanyi; Wen, Ruyan; Deng, Xiangliang; Zhou, Lian

    2016-08-01

    Objective To study the effect of intestinal dysbacteriosis on mouse intestinal intraepithelial T lymphocytes (iIELs). Methods The intestinal dysbacteriosis was induced in mice by oral administration of ceftriaxone sodium. The iIELs were digested with ethylene diaminetetraacetic acid (EDTA) and DL-dithiothreitol (DTT). The phenotype of iIELs and the proportions of subsets of T cells were detected by flow cytometry; the concentrations of cytokines (IL-2, IL-6, IFN-γ) in the intestine were examined by ELISA; the intestinal bacteria were analyzed with selective medium and PCR. Results Compared with the control group, intestinal commensal bacteria in mice were significantly reduced after the administration of ceftriaxone sodium, but fungi and yeasts increased. The proportions of T cell subgroups in ilELs changed, in which the proportion of TCR γδ(+)T cells significantly increased, and the activated CD3(+)T, CD8(+)T and TCR γδ(+)T cells increased. The concentrations of IL-2, IL-6 and IFN-γ were significantly raised in the intestine. Conclusion The dysbacteriosis results in the decrease of commensal bacteria, the increase of the fungus, the damage of microbial barrier, the more activated T cells in ilELs and the promotion of proinflammatory cytokine secretion in the gut. This is probably one of the reasons for inflammatory bowel disease caused by dysbacteriosis. PMID:27412931

  4. Selective suppression of cytokine secretion in whole blood cell cultures of patients with colorectal cancer.

    PubMed Central

    Lahm, H.; Schindel, M.; Frikart, L.; Cerottini, J. P.; Yilmaz, A.; Givel, J. C.; Fischer, J. R.

    1998-01-01

    We have investigated the secretion of interferon alpha (IFN-alpha), IFN-gamma, interleukin-1alpha (IL-1alpha), IL-1beta, IL-2 and tumour necrosis factor alpha (TNF-alpha) in whole blood cell cultures (WBCCs) of colorectal cancer patients upon mitogen stimulation. Whereas the values for IL-1beta and TNF-alpha remained virtually unchanged in comparison with healthy control subjects, WBCCs of colorectal cancer patients secreted significantly lower amounts of IFN-alpha (P < 0.005), IFN-gamma (P < 0.0001), IL-1alpha (P < 0.0001) and IL-2 (P < 0.05). This reduction correlated with the progression of the disease. The total leucocyte and monocyte population were almost identical in both groups. In contrast, a dramatic depletion of lymphocytes was observed in colorectal cancer patients, which affected both lymphocyte counts (P < 0.0005) and their distribution (P < 0.0001). Our results suggest a selective suppression of cytokines in colorectal cancer patients that is related to tumour burden. Several mechanisms might account for this phenomenon, one of which might be lymphocyte depletion. PMID:9792144

  5. Vitamin D Regulates Cytokine Patterns Secreted by Dendritic Cells to Promote Differentiation of IL-22-Producing T Cells

    PubMed Central

    Sommer, Andrea; Fabri, Mario

    2015-01-01

    One central mechanism, by which vitamin D regulates human immune responses, is the direct modulation of dendritic cells (DCs). However, the effect of vitamin D on several key DC functions, such as the secretion of central inflammatory cytokines, remains controversial. Moreover, whether vitamin D treatment of DCs regulates their ability to promote differentiation of IL-17-/IL-22-producing T cell subsets, such as Th17 and Th22 cell, is not known. Here, we report that vitamin D treatment during differentiation of monocytes into DCs markedly enhanced their ability to secrete TNF-α, IL-6, IL-1β and IL-23. Cytokines secreted by vitamin D-treated DC were significantly more potent in driving differentiation of IL-22-producing T cells, but not IL-17-producing T cells, as compared to secreted cytokines of not-vitamin D-treated DCs. Finally, we found that the differentiation of IL-22-producing T cells mediated by supernatants of vitamin D-treated DCs was dependent on TNF-α IL-6 and IL-23. In summary, our study suggests a novel role of vitamin D in regulating DC-mediated immune responses in humans. PMID:26107738

  6. Protection against endotoxic shock and lipopolysaccharide-induced local inflammation by tetracycline: correlation with inhibition of cytokine secretion.

    PubMed Central

    Shapira, L; Soskolne, W A; Houri, Y; Barak, V; Halabi, A; Stabholz, A

    1996-01-01

    Septic shock results from excessive stimulation of host immune cells, particularly monocytes and macrophages, by lipopolysaccharide (LPS) released from gram-negative bacteria. Macrophage-derived cytokines, such as tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1 beta), have been identified as central mediators in the pathogenesis of septic shock and the resultant mortality. Therefore, these cytokines were targets for experimental therapy for septic shock. Because of tetracycline's ability to intervene in cellular mechanisms involved in cytokine secretion, we tested the effect of tetracycline on LPS-induced septic shock and inflammatory lesions in mice. Tetracycline was found to protect mice against LPS-induced lethality and to abolish clinical signs of LPS-induced inflammatory lesions. This protection correlates with tetracycline's ability to reduce LPS-induced TNF-alpha levels in serum. Furthermore, tetracycline was found to inhibit LPS-induced TNF-alpha and IL-1 beta secretion, but not cytokine mRNA accumulation, in human monocytes in vitro. The results presented here suggest that tetracycline is a potent drug for LPS-induced pathology and that its mechanism of action involves blockage of posttranscriptional events of cytokine production. PMID:8641787

  7. Role of 5 Saponins in Secretion of Cytokines by PRRSV-induced Endothelial Cells.

    PubMed

    Hu, Y; Mao, A; Tan, Y; Zhao, Y; He, K

    2016-07-01

    The aim of the research presented here was to investigate the immunoloregulatory effects of 5 saponins: Saikosaponins A (SSA) and D (SSD) from Bupleurum chinese DC (Umbelliferae), Panax Notoginseng Saponin (PNS) and Notoginsenoside R1 from Panax notoginseng (Araliaceae) (SR1), and Anemoside B4 from Pulsatilla chinensis Regel (Ranunculaceae) (AB4). To achieve this, endothelial cells were challenged with 10(5) TCID50/mL PRRSV for 24 h then treated respectively with 5 saponins at 3 concentrations (1, 5 and 10 μg/mL). The cells were incubated at 37°C in a cell incubator for 24 h. The supernatants were collected and analyzed the levels of interleukin-4 (IL-4), IL-10, IL-2, and γ-interferon (IFN-γ) by ELISA kits. The results revealed that PNS and SR1 inhibited the production of IL-4; PNS, SR1 and SSD inhibited the secretion of IL-10; SSA, SSD and AB4 up-regulated IL-2 expression; SSA and SSD increased the level of IFN-γ. All these changes were significant. Taken together, the data suggested that these 5 saponins might effectively regulate immune responses via changes in the levels of these select cytokines. PMID:27144658

  8. Osteoarthritic changes in vervet monkey knees correlate with meniscus degradation and increased matrix metalloproteinase and cytokine secretion

    PubMed Central

    Stone, Austin V.; Vanderman, Kadie S.; Willey, Jeffrey S.; Long, David L.; Register, Thomas C.; Shively, Carol A.; Stehle, John R.; Loeser, Richard F.; Ferguson, Cristin M.

    2015-01-01

    Objective Meniscus injury increases osteoarthritis risk but its pathobiology in osteoarthritis is unclear. We hypothesized that older adult vervet monkeys would exhibit knee osteoarthritic changes and the degenerative menisci from these animals would secrete matrix metalloproteinases (MMPs) and pro-inflammatory cytokines that contribute to the development of osteoarthritis. Design In a cross sectional analysis of healthy young adult (9-12 years) and old (19-26 years) adult female vervet monkeys, knees were evaluated in vivo with computed tomography (CT) imaging, and joint tissues were morphologically graded at necropsy. Meniscus explants were subsequently cultured to evaluate meniscal MMP and cytokine secretion. Results CT images revealed significant bony osteoarthritic changes in 80% of older monkeys which included increases in osteophyte number and meniscal calcification. Meniscus and cartilage degradation scores were greater in the older monkeys and were positively correlated (r>0.7). Menisci from older animals exhibiting osteoarthritic changes secreted significantly more MMP-1, MMP-3, and MMP-8 than healthy menisci from younger monkeys. Older menisci without significant osteoarthritic changes secreted more IL-7 than healthy young menisci while older osteoarthritic menisci secreted more IL-7 and granulocyte-macrophage colony-stimulating factor than healthy older menisci. Conclusions Aged vervets develop naturally occurring knee osteoarthritis that includes involvement of the meniscus. Degenerative menisci secreted markedly increased amounts of matrix-degrading enzymes and inflammatory cytokines. These factors would be expected to act on the meniscus tissue and local joint tissues and may ultimately promote osteoarthritis development. These finding also suggest vervet monkeys are a useful animal model for studying the progression of osteoarthritis. PMID:26033163

  9. Notch and presenilin regulate cellular expansion and cytokine secretion but cannot instruct Th1/Th2 fate acquisition.

    PubMed

    Ong, Chin-Tong; Sedy, John R; Murphy, Kenneth M; Kopan, Raphael

    2008-01-01

    Recent reports suggested that Delta1, 4 and Jagged1, 2 possessed the ability to instruct CD4(+) T cell into selection of Th1 or Th2 fates, respectively, although the underlying mechanism endowing the cleaved Notch receptor with memory of ligand involved in its activation remains elusive. To examine this, we prepared artificial antigen-presenting cells expressing either DLL1 or Jag1. Although both ligands were efficient in inducing Notch2 cleavage and activation in CD4(+) T or reporter cells, the presence of Lunatic Fringe in CD4(+) T cells inhibited Jag1 activation of Notch1 receptor. Neither ligand could induce Th1 or Th2 fate choice independently of cytokines or redirect cytokine-driven Th1 or Th2 development. Instead, we find that Notch ligands only augment cytokine production during T cell differentiation in the presence of polarizing IL-12 and IL-4. Moreover, the differentiation choices of naïve CD4(+) T cells lacking gamma-secretase, RBP-J, or both in response to polarizing cytokines revealed that neither presenilin proteins nor RBP-J were required for cytokine-induced Th1/Th2 fate selection. However, presenilins facilitate cellular proliferation and cytokine secretion in an RBP-J (and thus, Notch) independent manner. The controversies surrounding the role of Notch and presenilins in Th1/Th2 polarization may reflect their role as genetic modifiers of T-helper cells differentiation. PMID:18665263

  10. Eosinophils Reduce Chronic Inflammation in Adipose Tissue by Secreting Th2 Cytokines and Promoting M2 Macrophages Polarization

    PubMed Central

    Zhang, Yi; Yang, Peng; Cui, Ran; Zhang, Manna; Li, Hong; Qian, Chunhua; Sheng, Chunjun; Qu, Shen; Bu, Le

    2015-01-01

    Obesity is now recognized as a low-grade, chronic inflammatory disease that is linked to a myriad of disorders including cardiovascular diseases, type 2 diabetes, and liver diseases. Recently it is found that eosinophils accelerate alternative activation macrophage (AAM) polarization by secreting Th2 type cytokines such as interleukin-4 and interleukin-13, thereby reducing metainflammation in adipose tissue. In this review, we focused on the role of eosinophils in regulating metabolic homeostasis and obesity. PMID:26688684

  11. Role of p38 mitogen-activated protein kinase in Kupffer cell secretion of the proinflammatory cytokines after burn trauma.

    PubMed

    Chen, Xu-Lin; Xia, Zhao-Fan; Wei, Duo; Han, Sheng; Ben, Dao-Feng; Wang, Guang-Qing

    2003-09-01

    This study was designed to investigate the role of p38 mitogen-activated protein (MAP) kinase on Kupffer cells (KCs) secretion of proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta and hepatic injury following burn trauma. Sprague-Dawley rats were randomized into four groups: (1) sham burn rats given vehicle, (2) sham burn rats given the p38 MAP kinase inhibitor SB203580 (10mg/kg i.v., 15min and 12h after sham burn), (3) rats given a 30% total body surface area (TBSA) full-thickness burn and fluid resuscitation plus vehicle, and (4) burn rats given injury and fluid resuscitation plus SB203580. Rats from each group were killed at 24h post-burn to examine plasma aspartate transaminase (AST) and alanine transaminase (ALT) and KCs were isolated. The KCs secretion of TNF-alpha and IL-1beta and p38 MAP kinase activity (by Western blot analysis) were also examined. These studies showed by more significant activation of p38 MAP kinase in KCs harvested from burn rats than from shams. Burn trauma resulted in hepatic dysfunction and promoted KCs secretion of TNF-alpha and IL-1beta. SB203580 inhibited p38 MAP kinase activity, reduced KCs secretion of proinflammatory cytokines, and alleviated burn-mediated hepatic dysfunction. These data suggest p38 MAP kinase activation is one important aspect of the signaling event that may mediate the KCs secretion of proinflammatory cytokines TNF-alpha and IL-1beta following burn trauma.

  12. The plasma levels of the cytokines in opium-addicts and the effects of opium on the cytokines secretion by their lymphocytes.

    PubMed

    Nabati, Saeedeh; Asadikaram, Gholamreza; Arababadi, Mohammad Kazemi; Shahabinejad, Gholamabbas; Rezaeian, Mohsen; Mahmoodi, Mehdi; Kennedy, Derek

    2013-04-01

    The aim of this study was to evaluate the effects of opium addiction on the secretion of IL-4, IFN-γ, IL-6 and TGF-β under in vivo and in vitro conditions. The blood samples were collected and PBMCs were cultured in RPMI1640 with and without opium for 48 h. The levels of the cytokines were measured using ELISA technique. The results showed that plasma levels of IL-4 and IFN-γ were significantly lower and IL-6 and TGF-β were higher in plasma taken from opium-addicted subjects. The concentrations of all the cytokines in opium-addicted subjects in in vitro condition were significantly lower than the control group. Addicted subjects cultured lymphocytes significantly decrease secreted IL-4, IL-6 and TGF-β but not IFN-γ in response to being cultured with opium, where as IFN-γ was increased in controls. These results may explain the frequent microbial infections and an increased tumor incidence seen in addicted patients.

  13. Changes in cytokine and nitric oxide secretion by rat alveolar macrophages after oral administration of bacterial extracts.

    PubMed Central

    Broug-Holub, E; Persoons, J H; Schornagel, K; Kraal, G

    1995-01-01

    Oral administration of the bacterial immunomodulator Broncho-Vaxom (OM-85), a lysate of eight bacteria strains commonly causing respiratory disease, has been shown to enhance the host defence of the respiratory tract. In this study we examined the effect of orally administered (in vivo) OM-85 on stimulus-induced cytokine and nitric oxide secretion by rat alveolar macrophages in vitro. The results show that alveolar macrophages isolated from OM-85-treated rats secreted significantly more nitric oxide, tumour necrosis factor-alpha (TNF-alpha) and IL-1 beta upon in vitro stimulation with lipopolysaccharide (LPS), whereas, in contrast, LPS-induced IL-6 secretion was significantly lower. The observed effects of in vivo OM-85 treatment on stimulus-induced cytokine secretion in vitro are not due to a direct effect of OM-85 on the cells, because in vitro incubation of alveolar macrophages with OM-85 did not result in altered activity, nor did direct intratracheal instillation of OM-85 in the lungs of rats result in altered alveolar macrophage activity in vitro. It is hypothesized that oral administration of OM-85 leads to priming of alveolar macrophages in such a way that immune responses are non-specifically enhanced upon stimulation. The therapeutic action of OM-85 may therefore result from an enhanced clearance of infectious bacteria from the respiratory tract due to increased alveolar macrophage activity. PMID:7648713

  14. Inflammatory cytokines regulate secretion of VEGF and chemokines by human conjunctival fibroblasts: Role in dysfunctional tear syndrome.

    PubMed

    Nagineni, Chandrasekharam N; William, Abitha; Cherukuri, Aswini; Samuel, William; Hooks, John J; Detrick, Barbara

    2016-02-01

    Ocular surface inflammation is one of the primary mechanisms associated with dysfunctional tear syndrome (DTS), also known as dry eye disease. DTS, more prevalent in older populations, causes ocular discomfort and visual disturbance due to dryness on the surface layer in the eye. We used human conjunctival fibroblast cultures (HCJVF) to investigate the effects of inflammatory cytokines IFN-γ, TNF-α and IL-1β (ITI) on the secretions of VEGF and chemokines. Our results demonstrate the elevated secretion of angiogenic VEGF molecules by ITI without affecting anti-angiogenic molecules, PEDF, endostatin, thrombospondin and sVEGF-R1. The secretion of interferon-γ inducible chemokines, CXCL9, -10, -11 by HCJVF were significantly enhanced by ITI. Our in vitro study supports previously reported observations of elevated VEGF and chemokines in tear fluids of DTS patients, reiterating the role of inflammatory reactions in DTS. PMID:26615568

  15. Areca nut exposure increases secretion of tumor‐promoting cytokines in gingival fibroblasts that trigger DNA damage in oral keratinocytes

    PubMed Central

    Illeperuma, Rasika P.; Kim, Do Kyeong; Park, Young Jin; Son, Hwa Kyung; Kim, Jue Young; Kim, Jinmi; Lee, Doo Young; Kim, Ki‐Yeol; Jung, Da‐Woon; Tilakaratne, Wanninayake M.

    2015-01-01

    Molecular crosstalk between cancer cells and fibroblasts has been an emerging hot issue in understanding carcinogenesis. As oral submucous fibrosis (OSF) is an inflammatory fibrotic disease that can potentially transform into squamous cell carcinoma, OSF has been considered to be an appropriate model for studying the role of fibroblasts during early stage carcinogenesis. In this sense, this study aims at investigating whether areca nut (AN)‐exposed fibroblasts cause DNA damage of epithelial cells. For this study, immortalized hNOF (hTERT‐hNOF) was used. We found that the levels of GRO‐α, IL‐6 and IL‐8 increased in AN‐exposed fibroblasts. Cytokine secretion was reduced by antioxidants in AN‐exposed fibroblasts. Increase in DNA double strand breaks (DSB) and 8‐oxoG FITC‐conjugate was observed in immortalized human oral keratinocytes (IHOK) after the treatment of cytokines or a conditioned medium derived from AN‐exposed fibroblasts. Cytokine expression and DNA damage were also detected in OSF tissues. The DNA damage was reduced by neutralizing cytokines or antioxidant treatment. Generation of reactive oxygen species (ROS) and DNA damage response, triggered by cytokines, were abolished when NADPH oxidase (NOX) 1 and 4 were silenced in IHOK, indicating that cytokine‐triggered DNA damage was caused by ROS generation through NOX1 and NOX4. Taken together, this study provided strong evidence that blocking ROS generation might be a rewarding approach for cancer prevention and intervention in OSF. PMID:26076896

  16. Brucella outer membrane protein Omp25 induces microglial cells in vitro to secrete inflammatory cytokines and inhibit apoptosis

    PubMed Central

    Ma, Qiao-Li; Liu, Ai-Cui; Ma, Xiao-Juan; Wang, Yan-Bai; Hou, Yu-Ting; Wang, Zhen-Hai

    2015-01-01

    Omp25 protein, an outer membrane protein of Brucella, can cause damage to the central nervous system. As one type of macrophage, microglial cells play a role in immune surveillance and immune protection in the central nervous system; therefore, they are major targets of bacterial attack. The present study examined BV2 mouse microglial cells that were stimulated with different concentrations of Omp25 recombinant protein, and the secretion of inflammatory cytokines by the BV2 cells as well as their level of apoptosis were observed. The objective of the study was to preliminarily illustrate the possible mechanism that Omp25 uses to damage the central nervous system. Mouse BV2 microglial cells were incubated with different concentrations of Omp25 for 24 h, and an enzyme-linked immunosorbent assay (ELISA) was used to detect the secretion of the inflammatory cytokines interleukin (IL)-6, tumour necrosis factor (TNF)-α and HMGB1 (high mobility group box-1 protein); reverse transcription polymerase chain reaction (RT-PCR) was used to detect the expression of TLR4 (Toll-like receptor 4) mRNA; Annexin V-fluorescein isothiocyanate (FITC) double staining was used to detect apoptosis in the BV2 cells. After the BV2 cells were stimulated with different concentrations of Omp25, the levels of IL-6, TNF-α and HMGB1 was increased, and the difference was statistically significant compared with the control group (P<0.05). The secretion of TNF-α and HMGB1 showed a trend toward an initial increase followed by a decrease. The expression level of TLR4 mRNA was increased. Omp25 protein can inhibit apoptosis in BV2 cells. The outer membrane protein Omp25 of Brucella promotes microglial cells to secrete inflammatory cytokines and inhibit apoptosis. TLR4 may be involved in the immune response of the central nervous system to Brucella infection. PMID:26770344

  17. The Use of Glass Substrates with Bi-Functional Silanes for Designing Micropatterned Cell-Secreted Cytokine Immunoassays

    PubMed Central

    Seo, Jeong Hyun; Chen, Li-Jung; Verkhoturov, Stanislav V.; Schweikert, Emile A.; Revzin, Alexander

    2011-01-01

    It is often desirable to sequester cells in specific locations on the surface and to integrate sensing elements next to the cells. In the present study, surfaces were fabricated so as to position cytokine sensing domains inside non-fouling poly(ethylene glycol) (PEG) hydrogel microwells. Our aim was to increase sensitivity of micropatterned cytokine immunoassays through covalent attachment of biorecognition molecules. To achieve this, glass substrates were functionalized with a binary mixture of acrylate- and thiol-terminated methoxysilanes. During subsequent hydrogel photopatterning step acrylate moieties served to anchor hydrogel microwells to glass substrates. Importantly, glass attachment sites within the microwells contained thiol groups that could be activated with a hetero-bifunctional cross-linker for covalent immobilization of proteins. After incubation with fluorescently-labeled avidin, microwells fabricated on a mixed acryl/thiol silane layer emitted ~6 times more fluorescence compared to microwells fabricated on an acryl silane alone. This result highlighted the advantages of covalent attachment of avidin inside the microwells. To create cytokine immunoassays, micropatterned surfaces were incubated with biotinylated IFN-γ or TNF-α antibodies (Abs). Micropatterned immunoassays prepared in this manner were sensitive down to 1 ng/ml or 60 pM IFN-γ. To further prove utility of this bionterface design, macrophages were seeded into 30 µm diameter microwells fabricated on either bi-functional (acryl/thiol) or monofunctional silane layers. Both types of microwells were coated with avidin and biotin-anti-TNF-α prior to cell seeding. Short mitogenic activation followed by immunostaining for TNF-α revealed that microwells created on bi-functional silane layer had 3 times higher signal due to macrophage-secreted TNF-α compared to microwells fabricated on mono-functional silane. The rational design of cytokine-sensing surfaces described here will be leveraged

  18. A single peptide-major histocompatibility complex ligand triggers digital cytokine secretion in CD4(+) T cells.

    PubMed

    Huang, Jun; Brameshuber, Mario; Zeng, Xun; Xie, Jianming; Li, Qi-jing; Chien, Yueh-hsiu; Valitutti, Salvatore; Davis, Mark M

    2013-11-14

    We have developed a single-molecule imaging technique that uses quantum-dot-labeled peptide-major histocompatibility complex (pMHC) ligands to study CD4(+) T cell functional sensitivity. We found that naive T cells, T cell blasts, and memory T cells could all be triggered by a single pMHC to secrete tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2) cytokines with a rate of ∼1,000, ∼10,000, and ∼10,000 molecules/min, respectively, and that additional pMHCs did not augment secretion, indicating a digital response pattern. We also found that a single pMHC localized to the immunological synapse induced the slow formation of a long-lasting T cell receptor (TCR) cluster, consistent with a serial engagement mechanism. These data show that scaling up CD4(+) T cell cytokine responses involves increasingly efficient T cell recruitment rather than greater cytokine production per cell. PMID:24120362

  19. Ichthyosis in Sjögren-Larsson syndrome reflects defective barrier function due to abnormal lamellar body structure and secretion.

    PubMed

    Rizzo, William B; S'Aulis, Dana; Jennings, M Anitia; Crumrine, Debra A; Williams, Mary L; Elias, Peter M

    2010-08-01

    Sjögren-Larsson syndrome is a genetic disease characterized by ichthyosis, mental retardation, spasticity and mutations in the ALDH3A2 gene coding for fatty aldehyde dehydrogenase, an enzyme necessary for oxidation of fatty aldehydes and fatty alcohols. We investigated the cutaneous abnormalities in 9 patients with Sjögren-Larsson syndrome to better understand how the enzymatic deficiency results in epidermal dysfunction. Histochemical staining for aldehyde oxidizing activity was profoundly reduced in the epidermis. Colloidal lanthanum perfusion studies showed abnormal movement of tracer into the extracellular spaces of the stratum corneum consistent with a leaky water barrier. The barrier defect could be attributed to the presence of abnormal lamellar bodies, many with disrupted limiting membranes or lacking lamellar contents. Entombed lamellar bodies were present in the cytoplasm of corneocytes suggesting blockade of lamellar body secretion. At the stratum granulosum-stratum corneum interface, non-lamellar material displaced or replaced secreted lamellar membranes, and in the stratum corneum, the number of lamellar bilayers declined and lamellar membrane organization was disrupted by foci of lamellar/non-lamellar phase separation. These studies demonstrate the presence of a permeability barrier abnormality in Sjögren-Larsson syndrome, which localizes to the stratum corneum interstices and can be attributed to abnormalities in lamellar body formation and secretion.

  20. Droplet-based microfluidic platforms for single T cell secretion analysis of IL-10 cytokine.

    PubMed

    Konry, Tania; Dominguez-Villar, Margarita; Baecher-Allan, Clare; Hafler, David A; Yarmush, Martin L

    2011-01-15

    Here we present a microfluidic method for the analysis of single cell secretions. The method co-encapsulates cells with microspheres conjugated with capture antibodies and detection fluorescence-labeled antibodies. The secreted substance captured on the microsphere surface and detected via detection antibodies generating a localized fluorescent signal on a microsphere surface. Using this method, CD4+CD25+ regulatory T cells were encapsulated and assayed to detect IL-10 secreting cell in population.

  1. Gallic Acid Decreases Inflammatory Cytokine Secretion Through Histone Acetyltransferase/Histone Deacetylase Regulation in High Glucose-Induced Human Monocytes.

    PubMed

    Lee, Wooje; Lee, Sang Yeol; Son, Young-Jin; Yun, Jung-Mi

    2015-07-01

    Hyperglycemia contributes to diabetes and several diabetes-related complications. Gallic acid is a polyhydroxy phenolic compound found in various natural products. In this study, we investigated the effects and mechanism of gallic acid on proinflammatory cytokine secretion in high glucose-induced human monocytes (THP-1 cells). THP-1 cells were cultured under normoglycemic or hyperglycemic conditions, in the absence or presence of gallic acid. Hyperglycemic conditions significantly induced histone acetylation, nuclear factor-κB (NF-κB) activation, and proinflammatory cytokine release from THP-1 cells, whereas gallic acid suppressed NF-κB activity and cytokine release. It also significantly reduced CREB-binding protein/p300 (CBP/p300, a NF-κB coactivator) gene expression, acetylation levels, and CBP/p300 histone acetyltransferase (HAT) activity. In addition, histone deacetylase 2 (HDAC2) expression was significantly induced. These results suggest that gallic acid inhibits hyperglycemic-induced cytokine production in monocytes through epigenetic changes involving NF-κB. Therefore, gallic acid may have potential for the treatment and prevention of diabetes and its complications.

  2. [Secreted cytokines in the uterine lumina are predictive of subsequent implantation. Presence of IL18 in the uterine flushing].

    PubMed

    Ledée-Bataille, N

    2004-02-01

    The materno-foetal relationship is not simply maternal tolerance of a foreign tissue, but a series of intricate mutual cytokine interactions governing selective immune regulation and also control of the adhesion and vascularisation processes during this dialogue. There is strong evidence that locally secreted cytokines, such as interleukine 18 (IL18) control the implantation process and can cause implantation failure in case of absence or overactivation. Uterine flushing fluids may be analysed to determine the level of several cytokines. At the time of egg retrieval, the flushing procedure does not adversely affect pregnancy rates. We report a strong positive correlation between the presence of IL18 in the uterine flushing and bad implantation rates. The presence of IL18 in the lumina is the traduction of an overactivation of endometrial IL18 that should be diagnosed and treated. Moreover, endometrial biopsy could define which type of cytokinic dysregulation is implicated in repeated implantation failure and define which type of treatment need to be introduced.

  3. Comparison of the proliferation, cytotoxic activity and cytokine secretion function of cascade primed immune cells and cytokine-induced killer cells in vitro.

    PubMed

    Li, Gui-Xin; Zhao, Shu-Shu; Zhang, Xu-Guang; Wang, Wen-Hao; Liu, Jin; Xue, Ke-Wei; Li, Xiao-Yan; Guo, Ying-Xue; Wang, Li-Hua

    2015-08-01

    The present study aimed to compare the antitumor effects of cascade primed immune (CAPRI) cells and cytokine-induced killer (CIK) cells in vitro, through investigating cell morphology, proliferation, cytotoxic activity to tumor cells and the ability of these cells to secrete cytokines. Peripheral blood samples (50 ml) were obtained from three healthy volunteers and peripheral blood mononuclear cells (PBMCs) were obtained from each via Ficoll-Conray density gradient centrifugation. Each suspension of PBMCs (1 x 10(6)/ml) was divided into two parts; CAPRI cells were obtained from one part through a series of induction, amplification and cytokine cultures, while CIK cells were obtained from the other part through induction with different cytokines. During the culture process, the proliferation and morphological changes were observed for the two cell types using Trypan blue staining. At day 14, the cytotoxic activity of the two cell types was examined through determining lactate dehydrogenase release in the presence of K562 leukemia cells and MCF-7 breast cancer cells. In addition, secretory levels of interferon (IFN)-γ and interleukin (IL)-2 were detected using enzyme-linked immunospot (ELISPOT) technology. The results revealed that at day 5 and 14 of culture, there were significantly fewer CAPRI cells compared with CIK cells (P<0.001), although the survival rate of each cell type was >95%. The cytotoxic activity of CAPRI cells towards the K562 cell line was effector-target ratio-dependent (40:1 and 20:1) with values of 55.1 ± 3.25 and 35.0 ± 2.65%, respectively, which were significantly reduced compared with the corresponding data in CIK cells, 60.0 ± 3.03 and 39.7 ± 3.42% (P=0.004 and 0.005, respectively). Furthermore, the cytotoxic activity of CAPRI cells towards MCF-7 cells were 71.5 ± 3.06, 56.0 ± 3.76 and 40.2 ± 2.90% at effector-target ratios 40:1, 20:1 and 10:1, respectively. These data were significantly higher than the corresponding values in CIK

  4. Yeast glucan particles activate murine resident macrophages to secrete proinflammatory cytokines via MyD88- and Syk kinase-dependent pathways.

    PubMed

    Li, Bing; Cramer, Daniel; Wagner, Stephanie; Hansen, Richard; King, Chelsea; Kakar, Shelly; Ding, Chuanlin; Yan, Jun

    2007-08-01

    The therapeutic benefits of fungal beta-glucans have been demonstrated as immuno-stimulating agents. In this study, we aimed to explore the mechanisms used by yeast beta-glucan-rich particles to activate murine resident macrophages for cytokine secretion. We demonstrated that resident macrophages were effectively activated by whole yeast beta-glucan particles (WGPs), such as with the upregulation of co-stimulatory molecules and the secretion of cytokines. The binding ability of WGPs and the levels of cytokine secretion in resident macrophages were significantly inhibited by soluble yeast beta-glucan but not by blockade of zymosan glucan receptor dectin-1. In addition, WGP-stimulated cytokine secretion was partially dependent on the MyD-88 pathway but was not significantly affected in CR3-deficient (CR3(-/-)) mice. Furthermore, we showed that Syk kinase was recruited upon WGP stimulation and was required for the production of cytokines. Taken together, these observations suggest that beta-glucan recognition is necessary but not sufficient to induce inflammatory response on resident macrophages. In addition, beta-glucan particles may use differential mechanisms for cytokine secretion in resident macrophages that may modulate both innate and adaptive immunity.

  5. Yeast Glucan Particles Activate Murine Resident Macrophages to Secrete Proinflammatory Cytokines Via MyD88- and Syk Kinase-dependent Pathways1

    PubMed Central

    Li, Bing; Cramer, Daniel; Wagner, Stephanie; Hansen, Richard; King, Chelsea; Kakar, Shelly; Ding, Chuanlin; Yan, Jun

    2007-01-01

    The therapeutic benefits of fungal β-glucans have been demonstrated as immuno-stimulating agents. In this study, we aimed to explore the mechanisms used by yeast β-glucan-rich particles to activate murine resident macrophages for cytokine secretion. We demonstrated that resident macrophages were effectively activated by whole yeast β-glucan particles (WGPs), such as with the up-regulation of co-stimulatory molecules and the secretion of cytokines. The binding ability of WGPs and the levels of cytokine secretion in resident macrophages were significantly inhibited by soluble yeast β-glucan but not by blockade of zymosan glucan receptor dectin-1. In addition, WGP-stimulated cytokine secretion was partially dependent on the MyD-88 pathway but was not significantly affected in CR3-deficient (CR3−/−) mice. Furthermore, we showed that Syk kinase was recruited upon WGP stimulation and was required for the production of cytokines. Taken together, these observations suggest that β-glucan recognition is necessary but not sufficient to induce inflammatory response on resident macrophages. In addition, β-glucan particles may use differential mechanisms for cytokine secretion in resident macrophages that may modulate both innate and adaptive immunity. PMID:17572156

  6. Ephedrine hydrochloride protects mice from LPS challenge by promoting IL-10 secretion and inhibiting proinflammatory cytokines.

    PubMed

    Zheng, Yuejuan; Guo, Ziyi; He, Weigang; Yang, Yang; Li, Yuhu; Zheng, Aoxiang; Li, Ping; Zhang, Yan; Ma, Jinzhu; Wen, Mingyue; Yang, Muyi; An, Huazhang; Ji, Guang; Yu, Yizhi

    2012-05-01

    Sepsis and its derivative endotoxic shock are still serious conditions with high mortality in the intensive care unit. The mechanisms that ensure the balance of proinflammatory cytokines and anti-inflammatory cytokine production are of particular importance. As an active α- and β-adrenergic agonist, ephedrine hydrochloride (EH) is a widely used agent for cardiovascular diseases, especially boosting blood pressure. Here we demonstrate that EH increased Toll-like receptor 4 (TLR4)-mediated production of interleukin 10 (IL-10) through p38 MAPK activation. Simultaneously, EH negatively regulated the production of proinflammatory cytokines. Consistently, EH increased lipopolysaccharide (LPS)-induced serum IL-10 and inhibited tumor necrotic factor-α (TNFα) production in vivo. As a result, EH treatment protected mice from endotoxic shock by lethal LPS challenge. In brief, our data demonstrated that EH could contribute to immune homeostasis by balancing the production of proinflammatory cytokines and anti-inflammatory cytokine in TLR4 signaling. This study provides a potential usage of EH in autoimmunologic diseases or other severe inflammations.

  7. Cytokine secretion effected by synergism of the immunomodulator AS101 and the protein kinase C inducer bryostatin.

    PubMed Central

    Sredni, B; Kalechman, Y; Albeck, M; Gross, O; Aurbach, D; Sharon, P; Sehgal, S N; Gurwith, M J; Michlin, H

    1990-01-01

    AS101, a synthetic organotellurium compound, was found to have immunomodulating properties by initiation of cytokine production in vitro and in vivo. Phase I/II clinical trials currently in progress on AIDS and cancer patients treated with AS101 show significant increases in various immunological parameters, with minimal toxicity. Recently, AS101 and the protein kinase C (PKC) inducer, phorbol myristate acetate (PMA), were shown to synergize in the secretion of interleukin-2 (IL-2) and colony-stimulating factor (CSF) in vitro, by human and mouse lymphoid cells. The bryostatins, a group of natural macrocyclic lactones isolated from marine invertebrates (Bugula neritina) have been reported to be potent PKC activators with no tumour promoting activity. In this study, we investigated the synergistic effect of AS101 and a partially purified preparation of bryostatin on the production of several cytokines. Our data confirm the presence of synergism, which greatly enhances cell proliferation, IL-2, tumour necrosis factor (TNF) and interferon-gamma (IFN-gamma) secretion by human mononuclear cells (MNC) and the production of IL-2 and TNF by mouse cells. The absence of tumour-promoting activity of the bryostatins makes them particularly good candidates, in combination with AS101, for immunomodulation in vivo in clinically immunosuppressed conditions. PMID:2118479

  8. Simian immunodeficiency virus-induced CD4+ T cell deficits in cytokine secretion profile are dependent on monkey origin.

    PubMed

    Marcondes, Maria Cecilia G; Penedo, Maria Cecilia T; Lanigan, Caroline; Hall, Deshon; Watry, Debbie D; Zandonatti, Michelle; Fox, Howard S

    2006-01-01

    Facets of the immune response early after human immunodeficiency virus (HIV) infection influence the course of disease. In the simian immunodeficiency virus (SIV)-rhesus monkey system, a global dysfunction of CD4(+) T cell cytokine secretion was reported to develop early after infection [McKay PF, Barouch DH, Schmitz JE, Veazey RS, Gorgone DA, Lifton MA, Williams KC, and Letvin NL: J Virol 2003;77:4695-4702]. Because differences have been found in SIV pathogenesis depending on the origin of the monkeys, we investigated the correlation between animal background, defined by country of origin (India or China), and circulating T cell cytokine secretion as well as cycling ability within the first 3 mo of SIV infection. An early loss of CD4(+) T cells that produce interferon (IFN)-gamma and interleukin (IL)-2, those that produce IFN-gamma but not tumor necrosis factor (TNF)-alpha, as well as those that do not express IFN-gamma but can express IL-2 or TNF-alpha, was observed in animals of Indian, but not of Chinese, origin after SIV infection. After infection CD4(+) T cells in Chinese macaques developed an increased proliferating pool of T cells compared with Indian animals. These data reveal host diversity in the global effects of SIV infection on functional subsets of immune cells, which can add to a better understanding of differences observed in populations from diverse ethnic origins.

  9. Human esophageal myofibroblasts secrete proinflammatory cytokines in response to acid and Toll-like receptor 4 ligands.

    PubMed

    Gargus, Matthew; Niu, Chao; Vallone, John G; Binkley, Jana; Rubin, Deborah C; Shaker, Anisa

    2015-06-01

    The pathophysiology of esophageal injury, repair, and inflammation in gastroesophageal reflux-disease (GERD) is complex. Whereas most studies have focused on the epithelial response to GERD injury, we are interested in the stromal response. We hypothesized that subepithelial esophageal myofibroblasts in GERD secrete proinflammatory cytokines in response to injurious agents encountered via epithelial barrier breaches or through dilated epithelial intercellular spaces. We determined the percentage of myofibroblasts [-smooth muscle actin (-SMA)+vimentin+CD31-] in the subepithelial GERD and normal esophageal stroma by immunomorphologic analysis. We performed -SMA coimmunostaining with IL-6 and p65. We established and characterized primary cultures of -SMA+vimentin+CD31-CD45- human esophageal myofibroblasts (HuEso MFs). We modeled GERD by treatment with pH 4.5-acidified media and Toll-like receptor 4 (TLR4) ligands, LPS and high-mobility group box 1 protein (HMGB1), and determined myofibroblast cytokine secretion in response to GERD injury. We demonstrate that spindle-shaped cell myofibroblasts are located near the basement membrane of stratified squamous epithelium in normal esophagus. We identify an increase in subepithelial myofibroblasts and activation of proinflammatory pathways in patients with GERD. Primary cultures of stromal cells obtained from normal esophagus retain myofibroblast morphology and express the acid receptor transient receptor potential channel vanilloid subfamily 1 (TRPV1) and TLR4. HuEso MFs stimulated with acid and TLR4 agonists LPS and HMGB1 increase IL-6 and IL-8 secretion via TRPV1 and NF-B activation. Our work implicates a role for human subepithelial stromal cells in the pathogenesis of GERD-related esophageal injury. Findings of this study can be extended to the investigation of epithelial-stromal interactions in inflammatory esophageal mucosal disorders. PMID:25882613

  10. Human esophageal myofibroblasts secrete proinflammatory cytokines in response to acid and Toll-like receptor 4 ligands

    PubMed Central

    Gargus, Matthew; Niu, Chao; Vallone, John G.; Binkley, Jana; Rubin, Deborah C.

    2015-01-01

    The pathophysiology of esophageal injury, repair, and inflammation in gastroesophageal reflux-disease (GERD) is complex. Whereas most studies have focused on the epithelial response to GERD injury, we are interested in the stromal response. We hypothesized that subepithelial esophageal myofibroblasts in GERD secrete proinflammatory cytokines in response to injurious agents encountered via epithelial barrier breaches or through dilated epithelial intercellular spaces. We determined the percentage of myofibroblasts [α-smooth muscle actin (α-SMA)+vimentin+CD31−] in the subepithelial GERD and normal esophageal stroma by immunomorphologic analysis. We performed α-SMA coimmunostaining with IL-6 and p65. We established and characterized primary cultures of α-SMA+vimentin+CD31−CD45− human esophageal myofibroblasts (HuEso MFs). We modeled GERD by treatment with pH 4.5-acidified media and Toll-like receptor 4 (TLR4) ligands, LPS and high-mobility group box 1 protein (HMGB1), and determined myofibroblast cytokine secretion in response to GERD injury. We demonstrate that spindle-shaped cell myofibroblasts are located near the basement membrane of stratified squamous epithelium in normal esophagus. We identify an increase in subepithelial myofibroblasts and activation of proinflammatory pathways in patients with GERD. Primary cultures of stromal cells obtained from normal esophagus retain myofibroblast morphology and express the acid receptor transient receptor potential channel vanilloid subfamily 1 (TRPV1) and TLR4. HuEso MFs stimulated with acid and TLR4 agonists LPS and HMGB1 increase IL-6 and IL-8 secretion via TRPV1 and NF-κB activation. Our work implicates a role for human subepithelial stromal cells in the pathogenesis of GERD-related esophageal injury. Findings of this study can be extended to the investigation of epithelial-stromal interactions in inflammatory esophageal mucosal disorders. PMID:25882613

  11. Pancreatic-derived factor (FAM3B), a novel islet cytokine, induces apoptosis of insulin-secreting beta-cells.

    PubMed

    Cao, Xiaopei; Gao, Zhiyong; Robert, Claudia E; Greene, Scott; Xu, Gang; Xu, Weizhen; Bell, Ewan; Campbell, Don; Zhu, Yuan; Young, Robert; Trucco, Matteo; Markmann, James F; Naji, Ali; Wolf, Bryan A

    2003-09-01

    PANDER (PANcreatic DERived factor, FAM3B), a newly discovered secreted cytokine, is specifically expressed at high levels in the islets of Langerhans of the endocrine pancreas. To evaluate the role of PANDER in beta-cell function, we investigated the effects of PANDER on rat, mouse, and human pancreatic islets; the beta-TC3 cell line; and the alpha-TC cell line. PANDER protein was present in alpha- and beta-cells of pancreatic islets, insulin-secreting beta-TC3 cells, and glucagon-secreting alpha-TC cells. PANDER induced islet cell death in rat and human islets. Culture of beta-TC3 cells with recombinant PANDER had a dose-dependent inhibitory effect on cell viability. This effect was also time-dependent. PANDER caused apoptosis of beta-cells as assessed by electron microscopy, annexin V fluorescent staining, and flow-cytometric terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. PANDER did not affect cytosolic Ca(2+) levels or nitric oxide levels. However, PANDER activated caspase-3. Hence, PANDER may have a role in the process of pancreatic beta-cell apoptosis.

  12. Assessment of lymphocyte subpopulations and cytokine secretion in children exposed to arsenic.

    PubMed

    Soto-Peña, Gerson A; Luna, Ana L; Acosta-Saavedra, Leonor; Conde, Patricia; López-Carrillo, Lizbeth; Cebrián, Mariano E; Bastida, Mariana; Calderón-Aranda, Emma S; Vega, Libia

    2006-04-01

    Exposure of several human populations to arsenic has been associated with a high incidence of detrimental dermatological and carcinogenic effects. To date, studies examining the immunotoxic effects of arsenic in humans, and specifically in children, are lacking. Therefore, we evaluated several parameters of immunological status in a group of children exposed to arsenic through their drinking water. Peripheral blood mononuclear cells (PBMCs) of 90 children (6 to 10 years old) were collected. Proportions of lymphocyte subpopulations, PBMC mitogenic proliferative response, and urinary arsenic levels were evaluated. Increased urine arsenic levels were associated with a reduced proliferative response to phytohemaglutinin (PHA) stimulation (P=0.005), CD4 subpopulation proportion (P=0.092), CD4/CD8 ratio (P=0.056), and IL-2 secretion levels (P=0.003). Increased arsenic exposure was also associated with an increase in GM-CSF secretion by mononucleated cells (P=0.000). We did not observe changes in CD8, B, or NK cell proportions, nor did we observe changes in the secretion of IL-4, IL-10, or IFN-gamma by PHA-activated PBMCs. These data indicate that arsenic exposure could alter the activation processes of T cells, such that an immunosuppression status that favors opportunistic infections and carcinogenesis is produced together with increased GM-CSF secretion that may be associated with chronic inflammation.

  13. Transcription of innate immunity genes and cytokine secretion by canine macrophages resistant or susceptible to intracellular survival of Leishmania infantum.

    PubMed

    Turchetti, Andréia Pereira; da Costa, Luciana Fachini; Romão, Everton de Lima; Fujiwara, Ricardo Toshio; da Paixão, Tatiane Alves; Santos, Renato Lima

    2015-01-15

    In this study we assessed the basal transcription of genes associated with innate immunity (i.e. Nramp1, NOD1, NOD2, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, and TLR9) in canine monocyte-derived macrophages from Leishmania-free dogs. Additionally, secretion of cytokines (IL-10, IL-12, TNF-α and IFN-γ) and nitric oxide in culture supernatants of macrophages with higher or lower resistance to intracellular survival of Leishmania infantum was also measured. Constitutive transcription of TLR9 and NOD2 were negligible; NOD1, TLR1, and TLR7 had low levels of transcription, whereas Nramp1 and TLR2, 3, 4, 5, and 6 had higher levels of constitutive transcription in canine monocyte-derived macrophages. There were no significant differences in transcription between macrophages with higher or lower resistance to intracellular survival of L. infantum. Secretion of TNF-α was higher in more resistant macrophages (designated as resistant) at 24h after infection when compared to less resistant macrophages (designated as susceptible), as well as the secretion of IFN-γ at 72 h post infection. Secretion of IL-10 was lower in resistant macrophages at 24h after infection. No detectable production of nitric oxide was observed. Interestingly, there was a negative correlation between NOD2 transcript levels and intracellular survival of L. infantum in resistant macrophages. This study demonstrated that decreased intracellular survival of L. infantum in canine macrophages was associated with increased production of TNF-α and IFN-γ and decreased production of IL-10; and that constitutive transcription of Nramp1, TLR and NLR does not interfere in intracellular survival of L. infantum.

  14. Inflammatory cytokines, interleukin-1 beta and tumor necrosis factor-alpha, upregulated in glioblastoma multiforme, raise the levels of CRYAB in exosomes secreted by U373 glioma cells

    PubMed Central

    Kore, Rajshekhar A.; Abraham, Edathara C.

    2014-01-01

    In the brain, levels of inflammatory cytokines, interleukin-1 beta (IL-1β) and tumor Necrosis factor-alpha (TNF-α), are elevated under traumatic brain injury, neuroinflammatory conditions and glioblastoma multiforme (GBM). In GBM, the levels of small heat shock protein, CRYAB (HspB5) are also reported to be elevated, where it has been shown to exert anti-apoptotic activity. Interestingly, CRYAB is secreted via exosomes by various cells. In order to understand the relation between inflammatory cytokines and CRYAB, U373 glioma cells, were stimulated with proinflammatory cytokines, IL-1β and TNF-α, and their effect on CRYAB levels in cells and secreted exosomes was studied. Our results show that U373 cells produce and secrete CRYAB via exosomes and that stimulation with IL-1β and TNF-α significantly increase the levels of CRYAB in not only the cells but also in the secreted exosomes. In addition, cytokine stimulation of U373 cells brings about changes in the secreted exosomal proteome, many of which are involved in cancer progression. PMID:25261722

  15. Inflammatory cytokines, interleukin-1 beta and tumor necrosis factor-alpha, upregulated in glioblastoma multiforme, raise the levels of CRYAB in exosomes secreted by U373 glioma cells.

    PubMed

    Kore, Rajshekhar A; Abraham, Edathara C

    2014-10-24

    In the brain, levels of inflammatory cytokines, interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α), are elevated under traumatic brain injury, neuroinflammatory conditions and glioblastoma multiforme (GBM). In GBM, the levels of small heat shock protein, CRYAB (HspB5) are also reported to be elevated, where it has been shown to exert anti-apoptotic activity. Interestingly, CRYAB is secreted via exosomes by various cells. In order to understand the relation between inflammatory cytokines and CRYAB, U373 glioma cells, were stimulated with proinflammatory cytokines, IL-1β and TNF-α, and their effect on CRYAB levels in cells and secreted exosomes was studied. Our results show that U373 cells produce and secrete CRYAB via exosomes and that stimulation with IL-1β and TNF-α significantly increase the levels of CRYAB in not only the cells but also in the secreted exosomes. In addition, cytokine stimulation of U373 cells brings about changes in the secreted exosomal proteome, many of which are involved in cancer progression.

  16. Cytokine IL-6 secretion by trophoblasts regulated via sphingosine-1-phosphate receptor 2 involving Rho/Rho-kinase and Rac1 signaling pathways.

    PubMed

    Goyal, Pankaj; Brünnert, Daniela; Ehrhardt, Jens; Bredow, Marike; Piccenini, Svea; Zygmunt, Marek

    2013-08-01

    Various cytokines derived from placental cells are essential for normal placenta development and successful pregnancy. Interleukin-6 (IL-6) is a multifunctional cytokine produced by extravillous and cytotrophoblasts regulating the functions of these cells, e.g. migration, invasion, trophoblast differentiation and proliferation. In macrophages, newly synthesized IL-6 accumulates in the Golgi complex and exits in tubulovesicular carriers fused with recycling endosomes and secreted as a soluble protein. Sphingosine-1-phosphate (S1P) induces various cytokine secretions including IL-6 in different cell types. The signaling mechanisms regulating the IL-6 secretion are unknown. In this study, we found that S1PR2 was the major S1P receptor being expressed in BeWo cells. S1P regulated IL-6 protein secretion in early phase (6 h) and gene expression in later phase (24 h). IL-6 secretion was completely inhibited via inhibitor of transcription (Actinomycin D) or protein synthesis (Cycloheximide) confirming that IL-6 releases constitutively from BeWo cells. By using specific S1PR2 inhibitor JTE-013 and S1PR2 gene silencing, we found that S1PR2 was the main receptor that regulates IL-6 secretion. Furthermore, S1P induced RhoGTPases-dependent pathways that are required for IL-6 secretion. Pretreatment of cells with specific Rho-kinase inhibitor (Y27632) and Rac1 inhibitor (NSC23766) drastically inhibited S1P-induced IL-6 secretion. By using a specific Phosphoinositide 3-kinase (PI3K) inhibitor (LY294002), we found that basal activity of PI3K was required for secretion but was independent of S1P/S1PR2 axis activation. In summary, we report first time that binding of S1P to S1PR2 activates multiple RhoGTPases-dependent pathways that coordinate with PI3K pathway for secretion of IL-6 in BeWo cells.

  17. Borrelia burgdorferi Stimulates Macrophages to Secrete Higher Levels of Cytokines and Chemokines than Borrelia afzelii or Borrelia garinii

    PubMed Central

    Strle, Klemen; Drouin, Elise E.; Shen, Shiqian; El Khoury, Joseph; McHugh, Gail; Ruzic-Sabljic, Eva; Strle, Franc; Steere, Allen C.

    2009-01-01

    To delineate the inflammatory potential of the 3 pathogenic species of Borrelia burgdorferi sensu lato, we stimulated monocyte-derived macrophages from healthy human donors with 10 isolates each of B. burgdorferi, B. afzelii, or B. garinii recovered from erythema migrans (EM) skin lesions of Lyme borreliosis patients from the United States or Slovenia. U.S. B. burgdorferi isolates induced macrophages to secrete significantly higher levels of IL-8, CCL3, CCL4, IL-6, IL-10 and TNF than B. garinii or B. afzelii isolates. Consistent with this response in cultured macrophages, the cytokine levels in sera of patients from whom the isolates were obtained were significantly greater in B. burgdorferi-infected patients than in B. afzelii- or B. garinii-infected patients. These results demonstrate in vitro and in vivo that B. burgdorferi has greater inflammatory potential than B. afzelii and B. garinii, which may account in part for variations in the clinical manifestations of Lyme borreliosis. PMID:19909078

  18. The high mobility group box 1 protein of Sciaenops ocellatus is a secreted cytokine that stimulates macrophage activation.

    PubMed

    Zhao, Lu; Hu, Yong-Hua; Sun, Jin-Sheng; Sun, Li

    2011-10-01

    High mobility group box 1 protein (HMGB1) is a chromatin-associated nonhistone protein that is involved in nucleosome formation and transcriptional regulation. In addition, HMGB1 is also known as an extracellular cytokine that triggers inflammation and immune responses. HMGB1-like sequences have been identified in a number of fish species, however, the function of piscine HMGB1 remains uninvestigated. In this study, we reported the identification and analysis of SoHMGB1, an HMGB1 homologue from red drum (Sciaenops ocellatus). SoHMGB1 is 206 residues in length and contains two basic HMG boxes and a highly acidic C-terminal domain. SoHMGB1 shares 71-87% overall sequence identities with the HMGB1 counterparts from human, rat, and several fish species. Quantitative real time RT-PCR analysis showed that constitutive SoHMGB1 expression was detected in various tissues, with the lowest and highest levels found in kidney and muscle respectively. Bacterial challenge upregulated SoHMGB1 expression in head kidney (HK) and HK macrophages and induced extracellular secretion of SoHMGB1 by the activated macrophages. Recombinant SoHMGB1 (rSoHMGB1) purified from yeast exhibited no direct antimicrobial effect but was significantly stimulatory on the proliferation, activation, and bactericidal activity of HK macrophages. Taken together, these results indicate for the first time that a fish HMGB1, SoHMGB1, can function as a secreted cytokine in the event of bacterial infection and promote innate defense through the activation of macrophages. PMID:21527276

  19. Airway Epithelium Interactions with Aeroallergens: Role of Secreted Cytokines and Chemokines in Innate Immunity

    PubMed Central

    Gandhi, Vivek D.; Vliagoftis, Harissios

    2015-01-01

    Airway epithelial cells are the first line of defense against the constituents of the inhaled air, which include allergens, pathogens, pollutants, and toxic compounds. The epithelium not only prevents the penetration of these foreign substances into the interstitium, but also senses their presence and informs the organism’s immune system of the impending assault. The epithelium accomplishes the latter through the release of inflammatory cytokines and chemokines that recruit and activate innate immune cells at the site of assault. These epithelial responses aim to eliminate the inhaled foreign substances and minimize their detrimental effects to the organism. Quite frequently, however, the innate immune responses of the epithelium to inhaled substances lead to chronic and high level release of pro-inflammatory mediators that may mediate the lung pathology seen in asthma. The interactions of airway epithelial cells with allergens will be discussed with particular focus on interactions-mediated epithelial release of cytokines and chemokines and their role in the immune response. As pollutants are other major constituents of inhaled air, we will also discuss how pollutants may alter the responses of airway epithelial cells to allergens. PMID:25883597

  20. Sea cucumber (Codonopsis pilosula) oligopeptides: immunomodulatory effects based on stimulating Th cells, cytokine secretion and antibody production.

    PubMed

    He, Li-Xia; Zhang, Zhao-Feng; Sun, Bin; Chen, Qi-He; Liu, Rui; Ren, Jin-Wei; Wang, Jun-Bo; Li, Yong

    2016-02-01

    This study aimed to investigate the immunomodulating activity of small molecule oligopeptides from sea cucumber (Codonopsis pilosula) (SOP) in mice. Seven assays were performed to determine the immunomodulatory effects, including splenic lymphocyte proliferation and delayed-type hypersensitivity assays (cell-mediated immunity), IgM antibody response of spleen to sheep red blood cells (SRBC) and serum hemolysin level assays (humoral immunity), the carbon clearance assay and the phagocytic capacity of peritoneal cavity phagocytes assay (macrophage phagocytosis), and the NK cell activity assay. Spleen T lymphocyte subpopulations, multiplex sandwich immunoassays of serum cytokine and immunoglobulin levels and enzyme-linked immunosorbent assays for small intestinal secretory immunoglobulin were performed to study the mechanism by which SOP affects the immune system. We found that SOP could improve immune functions in mice, which may be due to the enhancement of the functions of cell-mediated immunity, humoral immunity, macrophage phagocytosis and NK cell activity. From the cellular and molecular assays, we postulated that the immunomodulatory effects are most likely attributed to the stimulation of Th cells, cytokine secretion and antibody production. PMID:26838796

  1. Mice Survival and Plasmatic Cytokine Secretion in a "Two Hit" Model of Sepsis Depend on Intratracheal Pseudomonas Aeruginosa Bacterial Load.

    PubMed

    Restagno, Damien; Venet, Fabienne; Paquet, Christian; Freyburger, Ludovic; Allaouchiche, Bernard; Monneret, Guillaume; Bonnet, Jeanne-Marie; Louzier, Vanessa

    2016-01-01

    Sepsis is characterized by pro- and anti-inflammatory responses following infection. While inflammation is responsible for widespread organ damage, anti-inflammatory mediators lead to immunoparalysis increasing susceptibility to secondary infections (nosocomial pneumonia). We aimed to investigate the impact of bacterial load on survival and cytokine release in a two-hit murine (C57BL/6J) model of CLP followed by P. aeruginosa pneumonia. Plasmatic TNFα, IL-6, IL-10, sTNFr I and II were quantified until 13 days. At D5, splenocytes were processed for immunological assays or mice were intratracheally instilled with Pseudomonas aeruginosa (5.106, 2.107 and 108 CFU) to evaluate survival and cytokines production. TNFα, sTNFrs, IL-6 and IL-10 increased 2h post CLP. TNFα and sTNFrs declined respectively one and two days later. In CLP mice, IL-6 and IL-10 remained high for the whole experiment, as compared to Sham. At D5, for CLP mice, whereas total T cells population (CD3+) decreased, Treg fraction (CD4+/CD25+) increased. In parallel, T cells proliferation and LPS-stimulated splenocytes ability to release TNFα decreased. At D13, survival was 100% after 5.106 CFU, 50% for CLP mice after 2.107 CFU and 0% for CLP and Sham after 108 CFU. After instillation, IL-10 and IL-6 increased and appeared to be dose and time dependent. Pseudomonas was detected in all CLP and Sham's lungs; in spleen and liver only in CLP at 2.107 CFU, and in CLP and Sham at 108 CFU. We demonstrated that post-CLP immunosuppression followed by Pseudomonas aeruginosa lung instillation increases mortality reactivates cytokines secretion and is associated with systemic dissemination in septic mice depending on bacterial load. PMID:27574993

  2. Dimethylarsinic acid (DMA(V) ) changed the expressions of proliferative related factors and secretion of inflammatory cytokines in rat bladder.

    PubMed

    Lin, Zhang; Shengnan, Liu; Fei, Wang; Yingli, Song; Qingshan, Sun; Wei, Sheng; Shuhua, Xi; Guifan, Sun

    2015-02-01

    Dimethylarsinic acid (DMA(V) ), the major urinary metabolite of inorganic arsenic, is a urinary bladder carcinogen and bladder tumor promoter in adult rats. Increased urothelial cellular proliferation has been considered as an earlier phenotype in DMA(V) -induced bladder carcinogenesis. The present study examined the ultrastructural changes of bladder epithelial cells and expressions of proliferation factors, as well as the secretion of inflammatory cytokines in rats exposed to DMA(V) for 10 weeks by transmission electron microscopy (TEM), qRT-PCR, immunohistochemical staining and ELISA methods. The results showed that DMA(V) administered in the drinking water produced urothelial cytotoxicity and ultrastructural changes in rats. PCNA, cyclin D1 and COX-2 mRNA expressions and immunoreactivities were elevated in bladder urothelium. In addition, 200 ppm DMA(V) treatment increased the transforming growth factor-beta 1 (TGF-β1) secretion and decreased tumor necrosis factor-alpha (TNF)-α level in the urine of rats. These data suggest that chronic inflammation, bladder epithelium lesions and proliferation might be the basic process of the chronic toxicity effects in DMA(V) -treated rats.

  3. Dimethylarsinic acid (DMA(V) ) changed the expressions of proliferative related factors and secretion of inflammatory cytokines in rat bladder.

    PubMed

    Lin, Zhang; Shengnan, Liu; Fei, Wang; Yingli, Song; Qingshan, Sun; Wei, Sheng; Shuhua, Xi; Guifan, Sun

    2015-02-01

    Dimethylarsinic acid (DMA(V) ), the major urinary metabolite of inorganic arsenic, is a urinary bladder carcinogen and bladder tumor promoter in adult rats. Increased urothelial cellular proliferation has been considered as an earlier phenotype in DMA(V) -induced bladder carcinogenesis. The present study examined the ultrastructural changes of bladder epithelial cells and expressions of proliferation factors, as well as the secretion of inflammatory cytokines in rats exposed to DMA(V) for 10 weeks by transmission electron microscopy (TEM), qRT-PCR, immunohistochemical staining and ELISA methods. The results showed that DMA(V) administered in the drinking water produced urothelial cytotoxicity and ultrastructural changes in rats. PCNA, cyclin D1 and COX-2 mRNA expressions and immunoreactivities were elevated in bladder urothelium. In addition, 200 ppm DMA(V) treatment increased the transforming growth factor-beta 1 (TGF-β1) secretion and decreased tumor necrosis factor-alpha (TNF)-α level in the urine of rats. These data suggest that chronic inflammation, bladder epithelium lesions and proliferation might be the basic process of the chronic toxicity effects in DMA(V) -treated rats. PMID:24832369

  4. Expansion of cytokine-producing CD4-CD8- T cells associated with abnormal Fas expression and hypereosinophilia

    PubMed Central

    1996-01-01

    The mechanisms of sustained overproduction of eosinophils in the idiopathic hypereosinophilic syndrome and in some human immunodeficiency virus (HIV)-1-infected individuals are largely unknown. We hypothesized that T cells may release soluble products that regulate eosinophilia in these patients, as has been previously shown in bronchial asthma. We identified one patient with idiopathic hypereosinophilic syndrome and one HIV-1-infected individual with associated hypereosinophilia who demonstrated high numbers of CD4-CD8- T cells in peripheral blood. CD4-CD8- T cells from both patients, although highly activated, did not express functional Fas receptors. In one case, the lack of functional Fas receptors was associated with failure of Fas mRNA and protein expression, and in another, expression of a soluble form of the Fas molecule that may have antagonized normal signaling of Fas ligand. In contrast to the recently described lymphoproliferative/autoimmune syndrome, which is characterized by accumulation of CD4-CD8- T cells and mutations within the Fas gene, this study suggests somatic variations in Fas expression and function quite late in life. Both genetic and somatic abnormalities in regulation of the Fas gene are therefore associated with failures to undergo T cell apoptosis. Furthermore, the expanded population of CD4- CD8- T cells from both patients elaborated cytokines with antiapoptotic properties for eosinophils, indicating a major role of these T cells in the development of eosinophilia. Thus, this study demonstrates a sequential dysregulation of apoptosis in different cell types. PMID:8642249

  5. IM-133N modulates cytokine secretion by RAW264.7 and THP-1 cells.

    PubMed

    Varma, R Sandeep; Guruprasad, Kanive P; Satyamoorthy, Kapaettu; Kumar, L M Sharath; Babu, U Venkanna; Patki, S Pralhad

    2016-01-01

    An indigenous herbal extract IM-133N containing extracts of Prosopis glandulosa Torr and Symplocos racemosa Roxb were evaluated for potential immunomodulatory effects using RAW264.7 and THP-1 cells. The incubation of the cells for 24 h with IM-133N over a dose range 0-125 µg/ml did not cause cytotoxicity that exceeded 10%. The results indicated that non-cytotoxic doses of IM-133N effectively up-regulated iNOS, TNFα, IL-6, IL-10, IL-8 and IFNγ gene expression in both the RAW264.7 and THP-1 cells. The results also indicated IM-133N elicited dose-related increases in nitric oxide (NO) and tumor necrosis factor (TNF)-α production by RAW264.7 or THP-1 cells. These results demonstrated that IM-133N could stimulate NO and induced pro-inflammatory cytokine expression by monocytes/macrophages. As clinical studies have shown IM-133N to be an effective immunomodulator without any adverse effects, the results of the present study provide further support for the potential use of this agent as an immunostimulant or as an immunotherapy adjuvant.

  6. Secretion of Unconjugated Androgens and Estrogens by the Normal and Abnormal Human Testis before and after Human Chorionic Gonadotropin

    PubMed Central

    Weinstein, R. L.; Kelch, R. P.; Jenner, M. R.; Kaplan, S. L.; Grumbach, M. M.

    1974-01-01

    The secretion of androgens and estrogens by normal and abnormal testes was compared by determining the concentrations of dehydroepiandrosterone (DHEA), androstenedione (Δ4A), testosterone (T), estrone (E1), and 17β-estradiol (E2) in peripheral and spermatic venous plasma samples from 14 normal men and 5 men with unilateral testicular atrophy. Four normal men and one patient with unilateral atrophy of the testis were given human chorionic gonadotropin (HCG) before surgery. Plasma estrogens were determined by radioimmunoassay; plasma androgens were measured by the double-isotope dilution derivative technique. Peripheral concentrations of these steroids before and after HCG were similar in both the normal men and the patients with unilateral testicular atrophy. In normal men, the mean ±SE spermatic venous concentrations were DHEA, 73.1±11.7 ng/ml; Δ4A, 30.7±7.9 ng/ml; T, 751±114 ng/ml; E1, 306±55 pg/ml; and E2, 1298±216 pg/ml. Three of four subjects with unilateral testicular atrophy had greatly diminished spermatic venous levels of androgens and estrogens. HCG treatment increased the testicular secretion of DHEA and T fivefold, Δ4A threefold, E1 sixfold, and E2 eightfold in normal men. In the single subject with an atrophic testis who received HCG, the spermatic venous concentrations of androgens and estrogens were much less than in normal men similarly treated. We conclude that: (a) E1 is secreted by the human testis, but testicular secretion of E1 accounts for less than 5% of E1 production in normal men; (b) HCG stimulation produces increases in spermatic venous estrogens equal to or greater than the changes in androgens, including testosterone; and (c) strikingly decreased secretion of androgen and estrogen by unilateral atrophic human tests cannot be appreciated by analyses of peripheral steroid concentrations. PMID:4271572

  7. Rhaphidophora korthalsii modulates peripheral blood natural killer cell proliferation, cytokine secretion and cytotoxicity

    PubMed Central

    2013-01-01

    Background Rhaphidophora korthalsii (Araceae) is a root-climber plant which has been widely used in Chinese traditional medicine for cancer and skin disease treatment. Previous reports have recorded its immunomodulatory effects on mice splenocyte and human peripheral blood. This study investigated the potential immunostimulatory effect of Rhaphidophora korthalsii on human PBMC enriched NK cell. Methods PBMC was exposed to various concentrations of R. korthalsii extract and the T and NK cell population in the control and extract treated PBMC were identified by immunophenotyping. Intracellular perforin and granzyme B expressions were detected by flow cytometry and extra-cellular Granzyme B, IFN-γ and TNF-α production in the isolated NK cells were determined by ELISA. The cytotoxicity of effector NK cell towards target K562 cell was assessed by CytoTox 96 assay. Results Rhaphidophora korthalsii methanol extract significantly increased PBMC NK cell population and intracellular perforin and granzyme B expressions. Moreover, the extract also enhanced the secretion of IFN-γ and TNF-α which subsequently enhanced the cytotoxicity of NK cell against the NK sensitive target K562 cell line. NK cell enriched with extract treated PBMC showed better activation than NK cell directly treated with the extract. Conclusion Our findings indicated a potential IL-2 free immunotherapy through direct and indirect R. korthalsii stimulation on NK cell activation. PMID:23800124

  8. High Systemic Levels of the Cytokine-Inducing HMGB1 Isoform Secreted in Severe Macrophage Activation Syndrome

    PubMed Central

    Palmblad, Karin; Schierbeck, Hanna; Sundberg, Erik; Horne, Anna-Carin; Harris, Helena Erlandsson; Henter, Jan-Inge; Antoine, Daniel J; Andersson, Ulf

    2014-01-01

    Macrophage activation syndrome (MAS) is a potentially fatal complication of systemic inflammation. High mobility group box 1 (HMGB1) is a nuclear protein extensively leaked extracellularly during necrotic cell death or actively secreted by natural killer (NK) cells, macrophages and additional cells during infection or sterile injury. Extracellular HMGB1 orchestrates key events in inflammation as a prototypic alarmin. The redox states of its three cysteines render the molecule mutually exclusive functions: fully reduced “all-thiol HMGB1” exerts chemotactic activity; “disulfide HMGB1” has cytokine-inducing, toll-like receptor 4 (TLR4)-mediated effects—while terminally oxidized “sulfonyl HMGB1” lacks inflammatory activity. This study examines the kinetic pattern of systemic HMGB1 isoform expression during therapy in four children with severe MAS. Three of the four patients with underlying systemic rheumatic diseases were treated with biologics and two suffered from triggering herpes virus infections at the onset of MAS. All patients required intensive care unit therapy due to life-threatening illness. Tandem mass-spectrometric analysis revealed dramatically increased systemic levels of the cytokine-inducing HMGB1 isoform during early MAS. Disease control coincided with supplementary etoposide therapy initiated to boost apoptotic cell death, when systemic HMGB1 levels drastically declined and the molecule emerged mainly in its oxidized, noninflammatory isoform. Systemic interferon (IFN)-γ and ferritin peaked concomitantly with HMGB1, whereas interleukin (IL)-18 and monocyte chemotactic protein (MCP)-1 levels developed differently. In conclusion, this work provides new insights in HMGB1 biology, suggesting that the molecule is not merely a biomarker of inflammation, but most likely also contributes to the pathogenesis of MAS. These observations encourage further studies of disulfide HMGB1 antagonists to improve outcome of MAS. PMID:25247290

  9. [Lipopolysaccharide promotes the proliferation of CD4(+) T cells by modulating the survive and cytokine secretion of dendritic cells].

    PubMed

    Chen, Song; Lu, Lisha; Wang, Weiqiang; Xue, Ting; Yu, Juan; Sun, Zhina; Zhao, Chunxiao; Liao, Fang

    2016-09-01

    Objective To explore the mechanism modulating the function of dendritic cells (DCs) and promoting the T cell response by lipopolysaccharide (LPS). Methods Splenic DCs were purified with anti-CD11c immunomagnetic beads. After DCs were stimulated with LPS, the expressions of co-stimulatory molecules CD80 and CD86 on the DCs were detected by flow cytometry. The protein levels of pro-inflammatory cytokines interleukin 4 (IL-4), IL-5, IL-6, IL-12p40, IL-12p70 and tumor necrosis factor alpha (TNF-α) in the culture supernatant were measured by ELISA. The apoptotic levels of DCs which were labeled with annexinV-FITC/PI were determined by flow cytometry. The phosphorylation level of nuclear factor κB P65 (NF-κB P65) was assessed by phos-flow. The mRNA levels of variable genes in microarray were determined by real-time PCR. The proliferation of CD4(+) T cells which were co-cultured with OVA323-329-treated DCs was analyzed by flow cytometry. Results The purity of DCs reached over 93% after isolation. LPS up-regulated the expressions of CD80 and CD86 and enhanced DCs-mediated proliferation of CD4(+) T cells. In addition, LPS increased the protein levels of IL-12p40, TNF-α and IL-6, and inhibited the apoptosis of DCs through the NF-κB signaling pathway. Conclusion LPS could enhance DC-mediated proliferation of CD4(+) T cells by modulating the DCs survival and cytokine secretion. PMID:27609566

  10. Melatonin secretion is impaired in women with preeclampsia and an abnormal circadian blood pressure rhythm.

    PubMed

    Bouchlariotou, Sofia; Liakopoulos, Vassilios; Giannopoulou, Myrto; Arampatzis, Spyridon; Eleftheriadis, Theodoros; Mertens, Peter R; Zintzaras, Elias; Messinis, Ioannis E; Stefanidis, Ioannis

    2014-08-01

    Non-dipping circadian blood pressure (BP) is a common finding in preeclampsia, accompanied by adverse outcomes. Melatonin plays pivotal role in biological circadian rhythms. This study investigated the relationship between melatonin secretion and circadian BP rhythm in preeclampsia. Cases were women with preeclampsia treated between January 2006 and June 2007 in the University Hospital of Larissa. Volunteers with normal pregnancy, matched for chronological and gestational age, served as controls. Twenty-four hour ambulatory BP monitoring was applied. Serum melatonin and urine 6-sulfatoxymelatonin levels were determined in day and night time samples by enzyme-linked immunoassays. Measurements were repeated 2 months after delivery. Thirty-one women with preeclampsia and 20 controls were included. Twenty-one of the 31 women with preeclampsia were non-dippers. Compared to normal pregnancy, in preeclampsia there were significantly lower night time melatonin (48.4 ± 24.7 vs. 85.4 ± 26.9 pg/mL, p<0.001) levels. Adjustment for circadian BP rhythm status ascribed this finding exclusively to non-dippers (p<0.01). Two months after delivery, in 11 of the 21 non-dippers both circadian BP and melatonin secretion rhythm reappeared. In contrast, in cases with retained non-dipping status (n=10) melatonin secretion rhythm remained impaired: daytime versus night time melatonin (33.5 ± 13.0 vs. 28.0 ± 13.8 pg/mL, p=0.386). Urinary 6-sulfatoxymelatonin levels were, overall, similar to serum melatonin. Circadian BP and melatonin secretion rhythm follow parallel course in preeclampsia, both during pregnancy and, at least 2 months after delivery. Our findings may be not sufficient to implicate a putative therapeutic effect of melatonin, however, they clearly emphasize that its involvement in the pathogenesis of a non-dipping BP in preeclampsia needs intensive further investigation.

  11. Discrimination of HLA null and low expression alleles by cytokine-induced secretion of recombinant soluble HLA.

    PubMed

    Hinrichs, Jan; Figueiredo, Constança; Hirv, Kaimo; Mytilineos, Joannis; Blasczyk, Rainer; Horn, Peter A; Eiz-Vesper, Britta

    2009-04-01

    The disruption of disulfide bridges can decrease or abolish the cell surface expression of HLA class I molecules. Such disulfide bridges are formed by cysteine residues between amino acid (aa) positions 101/164 (alpha(2) domain) and 203/259 (alpha(3) domain). Sequence alterations in codons 101, 164, 203 and 259 have been observed in eleven HLA-A molecules. All of these variants except of A*3014L and A*3211Q have been reported to result in null expression alleles. In the case of HLA-A*3014L, a transversion at nucleotide position 563 replaces cysteine by serine at position 164 of the mature polypeptide. HLA-A*3014L is not detectable by standard microlymphocytotoxicity assay. To verify low or non-expression of this allele, we cloned soluble HLA-A*3014L and the reference allele HLA-A*3001 into a eukaryotic expression vector and transfected K562, C1R and HEK293 cells. Expression of soluble HLA-A*3014L and HLA-A*3001 was measured in the supernatants of transfected and untransfected cells incubated with or without IFN-gamma and/or TNF-alpha using a W6/32 and anti-beta(2)-microglobulin-based sandwich ELISA. Expression of mRNA transcripts of both alleles was determined by real-time RT-PCR. HLA-A*3014L was not detected in the supernatant of unstimulated transfectants. Stimulation with IFN-gamma and/or TNF-alpha led to an increase of HLA-A*3014L secretion to a detectable level and increased HLA-A*3001 expression up to 8-fold, but did not show any difference in the increase of mRNA levels between HLA-A*3014L and A*3001. Because of this lack of any difference in the mRNA transcription, the protein expression defect is most likely caused by the missing disulfide bond formation in the alpha2 domain. Thus, exposing the cells to cytokine stress allows to distinguish between low- and non-expressed alleles and to classify alleles with a questionable expression pattern (Q alleles). Classifying HLA alleles in expressed and non-expressed variants is essential for matching assessments

  12. Structure-function studies of PANDER, an islet specific cytokine inducing cell death of insulin-secreting beta cells.

    PubMed

    Yang, Jichun; Gao, Zhiyong; Robert, Claudia E; Burkhardt, Brant R; Gaweska, Helena; Wagner, Amary; Wu, Jianmei; Greene, Scott R; Young, Robert A; Wolf, Bryan A

    2005-08-30

    PANDER (pancreatic derived factor, FAM3B) is a novel cytokine, present in insulin secretory granules, that induces apoptosis of alpha and beta cells of mouse, rat, and human islets in a dose- and time-dependent manner, and may be implicated in diabetes. PANDER has the predicted secondary structure of 4 alpha-helical bundles with an up-up-down-down topology, and two disulfide bonds. Eleven mutated PANDERs were constructed and expressed in beta-TC3 cells to identify the essential region of PANDER involved in beta-cell death. Beta-cell function was assessed by assays of cell viability and insulin secretion. Based on quantitative real-time RT-PCR all mutant PANDERs had similar mRNA expression levels in beta-TC3 cells. Immunoblotting showed that ten of eleven mutant PANDER proteins were synthesized and detected in beta-TC3 cells. A mutant PANDER with no signal peptide, however, was not expressed. Truncation of helix D alone caused a 40-50% decrease in PANDER's activity, while truncation of both helices C and D resulted in a 75% loss of activity. In contrast, truncation of the N-terminus of PANDER (helix A, the loop between helices A and B, and the first two cysteines) had no effect on PANDER-induced beta-cell death. The third and fourth cysteines of PANDER, C91 and C229, were shown to form one disulfide bond and be functionally important. Finally, the region between Cys91 and Phe152 constitutes the active part of PANDER, based on the demonstration that mutants with truncation of helix B or C caused decreased beta-cell death and did not inhibit insulin secretion, as compared to wild-type PANDER. Hence, helices B and C and the second disulfide bond of PANDER are essential for PANDER-induced beta-cell death.

  13. RETRACTED: Blockade of TNF-α signaling suppresses the AREG-mediated IL-6 and IL-8 cytokines secretion induced by anti-Ro/SSA autoantibodies.

    PubMed

    Sisto, Margherita; Lisi, Sabrina; Lofrumento, Dario Domenico; Cucci, Liana; Mitolo, Vincenzo; D'Amore, Massimo

    2010-09-20

    The aim of this study was to analyze the Furin-TNF-α-converting enzyme (TACE)-amphiregulin (AREG)-IL-6/IL-8 secretion pathway in non-neoplastic human salivary gland epithelial cells (SGECs) stimulated with anti-Ro/SSA autoantibodies (Abs). We examined whether anti-Ro/SSA Abs-mediated TACE activation is responsible for AREG activation. As recent studies have demonstrated that AREG could induce proinflammatory cytokines secretion in epithelial cells, we discuss how TACE-mediated AREG shedding, caused by anti-Ro/SSA Abs treatment, could have a critical role in TNF-α-induced IL-6 and IL-8 secretion by SGEC. Furthermore, the effects of TNF-α blockade on AREG expression and TNF-α-AREG-mediated IL-6 and IL-8 secretion were evaluated. We have discovered that the upregulation of AREG occurs through TNF-α produced after anti-Ro/SSA Abs uptake via Fcγ receptors. Biological drug adalimumab and the gene silencing technique were used to study the AREG-IL-6/IL-8 secretion pathway, demonstrating that (i) adalimumab-mediated TNF-α blocking and TNF-α gene silencing provoke a significant decrease of proinflammatory cytokines production and AREG expression in anti-Ro/SSA Abs-treated SGEC; (ii) AREG gene silencing has a potent inhibitory effect on TNF-α-induced IL-6 and IL-8 secretion in SGEC treated with anti-Ro/SSA Abs; (iii) an inspection of the kinetics of cytokine production after exogeni TNF-α and AREG addition, and the use of cycloheximide in the presence of exogenous TNF-α as stimulant, clarified that TNF-α induces IL-6 and IL-8 secretion through AREG.Laboratory Investigation advance online publication, 20 September 2010; doi:10.1038/labinvest.2010.168.

  14. IL-35 Decelerates the Inflammatory Process by Regulating Inflammatory Cytokine Secretion and M1/M2 Macrophage Ratio in Psoriasis.

    PubMed

    Zhang, Junfeng; Lin, Yi; Li, Chunlei; Zhang, Xiaomei; Cheng, Lin; Dai, Lei; Wang, Youcui; Wang, Fangfang; Shi, Gang; Li, Yiming; Yang, Qianmei; Cui, Xueliang; Liu, Yi; Wang, Huiling; Zhang, Shuang; Yang, Yang; Xiang, Rong; Li, Jiong; Yu, Dechao; Wei, Yuquan; Deng, Hongxin

    2016-09-15

    IL-35 downregulates Th17 cell development and suppresses certain types of autoimmune inflammation such as collagen-induced arthritis and experimental autoimmune uveitis. Psoriasis is thought to be initiated by abnormal interactions between cutaneous keratinocytes and systemic immune cells. However, the role of IL-35 in psoriasis remains unclear. In this study, we assessed IL-35 in three well-known psoriasis models: a human keratinocyte cell line (HaCaT), a keratin 14 (K14)-vascular endothelial growth factor A (VEGF-A)-transgenic (Tg) mouse model, and an imiquimod-induced psoriasis mouse model. First, we found that IL-35 suppressed the expression of IL-6, CXCL8, and S100A7, which are highly upregulated by a mixture of five proinflammatory cytokines in HaCaT. Second, a plasmid coding for the human IL-35 sequence coated with cationic liposomes showed potent immunosuppressive effects on K14-VEGF-A-Tg and imiquimod-induced psoriasis mouse models. In the K14-VEGF-A-Tg model, our results showed that several types of proinflammatory cytokines were significantly reduced, whereas IL-10 was remarkably induced by IL-35. Compared with pcDNA3.1, there was a small number of CD4(+)IL-17(+) T cells and a large number of CD4(+)IL-10(+) and CD4(+)CD25(+)Foxp3(+) T cells in the IL-35 group. Most importantly, we found that IL-35 decreased the total number of macrophages and ratio of M1/M2 macrophages, which has not been reported previously. In addition, compared with dexamethasone, IL-35 showed long-term therapeutic efficacy. In summary, our results strongly indicate that IL-35 plays a potent immunosuppressive role in psoriasis. Thus, IL-35 has potential for development as a new therapeutic strategy for patients with chronic psoriasis and other cutaneous inflammatory diseases.

  15. IL-35 Decelerates the Inflammatory Process by Regulating Inflammatory Cytokine Secretion and M1/M2 Macrophage Ratio in Psoriasis.

    PubMed

    Zhang, Junfeng; Lin, Yi; Li, Chunlei; Zhang, Xiaomei; Cheng, Lin; Dai, Lei; Wang, Youcui; Wang, Fangfang; Shi, Gang; Li, Yiming; Yang, Qianmei; Cui, Xueliang; Liu, Yi; Wang, Huiling; Zhang, Shuang; Yang, Yang; Xiang, Rong; Li, Jiong; Yu, Dechao; Wei, Yuquan; Deng, Hongxin

    2016-09-15

    IL-35 downregulates Th17 cell development and suppresses certain types of autoimmune inflammation such as collagen-induced arthritis and experimental autoimmune uveitis. Psoriasis is thought to be initiated by abnormal interactions between cutaneous keratinocytes and systemic immune cells. However, the role of IL-35 in psoriasis remains unclear. In this study, we assessed IL-35 in three well-known psoriasis models: a human keratinocyte cell line (HaCaT), a keratin 14 (K14)-vascular endothelial growth factor A (VEGF-A)-transgenic (Tg) mouse model, and an imiquimod-induced psoriasis mouse model. First, we found that IL-35 suppressed the expression of IL-6, CXCL8, and S100A7, which are highly upregulated by a mixture of five proinflammatory cytokines in HaCaT. Second, a plasmid coding for the human IL-35 sequence coated with cationic liposomes showed potent immunosuppressive effects on K14-VEGF-A-Tg and imiquimod-induced psoriasis mouse models. In the K14-VEGF-A-Tg model, our results showed that several types of proinflammatory cytokines were significantly reduced, whereas IL-10 was remarkably induced by IL-35. Compared with pcDNA3.1, there was a small number of CD4(+)IL-17(+) T cells and a large number of CD4(+)IL-10(+) and CD4(+)CD25(+)Foxp3(+) T cells in the IL-35 group. Most importantly, we found that IL-35 decreased the total number of macrophages and ratio of M1/M2 macrophages, which has not been reported previously. In addition, compared with dexamethasone, IL-35 showed long-term therapeutic efficacy. In summary, our results strongly indicate that IL-35 plays a potent immunosuppressive role in psoriasis. Thus, IL-35 has potential for development as a new therapeutic strategy for patients with chronic psoriasis and other cutaneous inflammatory diseases. PMID:27527600

  16. Vitamin D Supplementation Suppresses Hypoxia-Stimulated Placental Cytokine Secretion, Hypertension and CD4+ T Cell Stimulation in Response to Placental Ischemia

    PubMed Central

    Darby, Marie M; Wallace, Kedra; Cornelius, Denise; Chatman, Krystal T; Mosely, Janae N; Martin, James N; Purser, Christine A; Baker, Rodney C; Owens, Michelle T; Lamarca, B Babbette

    2014-01-01

    Objective To investigate a role of Vitamin D in the pathogenesis of preeclampsia (PE), and to discern any potential benefits of Vitamin D supplementation on hypertension in the RUPP rat model of PE. Study design Blood and placentas from normal pregnancies (NP) and PE were collected following elective cesarean delivery without evidence of infection. Circulating Vitamin D was extracted by HPLC and measured via mass spectrometry. Media for placenta explants was supplemented with Vitamin D and exposed to hypoxic (1% O2) or normoxic (6% O2) conditions for 24 hours. ELISAs were performed on media and normalized to total protein to determine cytokine secretion. RUPP rats were supplemented with vitamin D by oral gavage, and blood pressure (MAP) and pup weights were measured in NP and RUPP rats with or without Vitamin D supplementation. Flow cytometry was used to evaluate CD4+ Tcells in control RUPP rats and RUPP rats treated with Vitamin D. Results Inflammatory cytokine secretion was higher (p<0.05) while the anti-inflammatory cytokine, IL-10, was significantly lower in the media of PE placentas compared to NP (p=0.005). Vitamin D supplementation decreased hypoxia stimulated pro-inflammatory cytokine secretion (p=0.003) in the media of PE placentas. Vitamin D decreased MAP and circulating CD4+ T cells in the RUPP rat model of PE (p<0.05). Conclusion Vitamin D supplementation may be useful in the treatment or prevention of hypertensive disorders in pregnancy. PMID:25414911

  17. High IFN-γ Release and Impaired Capacity of Multi-Cytokine Secretion in IGRA Supernatants Are Associated with Active Tuberculosis

    PubMed Central

    Pisoni, Amandine; Bendriss, Sophie; Marin, Grégory; Peries, Marianne; Bolloré, Karine; Terru, Dominique; Godreuil, Sylvain; Bourdin, Arnaud; Van de Perre, Philippe; Tuaillon, Edouard

    2016-01-01

    Interferon gamma (IFN-γ) release assays (IGRAs) detect Mycobacterium tuberculosis (Mtb) infection regardless of the active (ATB) or latent (LTBI) forms of tuberculosis (TB). In this study, Mtb-specific T cell response against region of deletion 1 (RD1) antigens were explored by a microbead multiplex assay performed in T-SPOT TB assay (T-SPOT) supernatants from 35 patients with ATB and 115 patients with LTBI. T-SPOT is positive when over 7 IFN-γ secreting cells (SC)/250 000 peripheral blood mononuclear cells (PBMC) are enumerated. However, over 100 IFN-γ SC /250 000 PBMC were more frequently observed in the ATB group compared to the LTBI group. By contrast, lower cytokine concentrations and lower cytokine productions relative to IFN-γ secretion were observed for IL 4, IL-12, TNF-α, GM-CSF, Eotaxin and IFN-α when compared to LTBI. Thus, high IFN-γ release and low cytokine secretions in relation with IFN-γ production appeared as signatures of ATB, corroborating that multicytokine Mtb-specific response against RD1 antigens reflects host capacity to contain TB reactivation. In this way, testing cytokine profile in IGRA supernatants would be helpful to improve ATB screening strategy including immunologic tests. PMID:27603919

  18. High IFN-γ Release and Impaired Capacity of Multi-Cytokine Secretion in IGRA Supernatants Are Associated with Active Tuberculosis.

    PubMed

    Carrère-Kremer, Séverine; Rubbo, Pierre-Alain; Pisoni, Amandine; Bendriss, Sophie; Marin, Grégory; Peries, Marianne; Bolloré, Karine; Terru, Dominique; Godreuil, Sylvain; Bourdin, Arnaud; Van de Perre, Philippe; Tuaillon, Edouard

    2016-01-01

    Interferon gamma (IFN-γ) release assays (IGRAs) detect Mycobacterium tuberculosis (Mtb) infection regardless of the active (ATB) or latent (LTBI) forms of tuberculosis (TB). In this study, Mtb-specific T cell response against region of deletion 1 (RD1) antigens were explored by a microbead multiplex assay performed in T-SPOT TB assay (T-SPOT) supernatants from 35 patients with ATB and 115 patients with LTBI. T-SPOT is positive when over 7 IFN-γ secreting cells (SC)/250 000 peripheral blood mononuclear cells (PBMC) are enumerated. However, over 100 IFN-γ SC /250 000 PBMC were more frequently observed in the ATB group compared to the LTBI group. By contrast, lower cytokine concentrations and lower cytokine productions relative to IFN-γ secretion were observed for IL 4, IL-12, TNF-α, GM-CSF, Eotaxin and IFN-α when compared to LTBI. Thus, high IFN-γ release and low cytokine secretions in relation with IFN-γ production appeared as signatures of ATB, corroborating that multicytokine Mtb-specific response against RD1 antigens reflects host capacity to contain TB reactivation. In this way, testing cytokine profile in IGRA supernatants would be helpful to improve ATB screening strategy including immunologic tests. PMID:27603919

  19. Cytokine/Chemokine Secretion and Proteomic Identification of Upregulated Annexin A1 from Peripheral Blood Mononuclear Cells Cocultured with the Liver Fluke Opisthorchis viverrini

    PubMed Central

    Hongsrichan, Nuttanan; Intuyod, Kitti; Pinlaor, Porntip; Khoontawad, Jarinya; Yongvanit, Puangrat; Wongkham, Chaisiri; Roytrakul, Sittiruk

    2014-01-01

    We investigated the cytokine/chemokine secretions and alteration of protein expression from peripheral blood mononuclear cells (PBMCs) cocultured with adult liver flukes (Opisthorchis viverrini) for 6 to 24 h. PBMC-derived proteins were identified by two-dimensional electrophoresis and mass spectrometry, and the cytokines/chemokines in the supernatant were assessed using a cytokine array. Exposure to O. viverrini induced increases in secretion of proinflammatory cytokines, costimulating protein, adhesion molecules, and chemotactic chemokines relative to untreated controls. In contrast, secretion of the CD40 ligand, interleukin 16, and macrophage inflammatory protein 1β decreased. Proteomic analysis revealed that expression of 48 proteins was significantly altered in PBMCs stimulated with O. viverrini. Annexin A1 (ANXA1) was selected for further study, and immunoblotting showed upregulation of ANXA1 expression in PBMCs after 12 and 24 h coculture with liver flukes. In an in vivo study, transcription and translation of ANXA1 significantly increased in livers of hamsters infected with O. viverrini at 21 days and from 3 months onwards compared to normal controls. Interestingly, immunohistochemistry revealed that ANXA1 was present not only in the cytoplasm of inflammatory cells but also in the cytoplasm of cholangiocytes, which are in close contact with the parasite and its excretory/secretory products in the biliary system. Expression of ANXA1 increased with time concomitant with bile duct enlargement, bile duct formation, and epithelial cell proliferation. In conclusion, several cytokines/chemokines secreted by PBMCs and upregulation of ANXA1 in PBMCs and biliary epithelial cells might have a role in host defense against O. viverrini infection and tissue resolution of inflammation. PMID:24614660

  20. Effect of Endometrial Injury on Secretion of Endometrial Cytokines and IVF Outcomes in Women with Unexplained Subfertility

    PubMed Central

    Liang, Yu; Han, Junyan; Jia, Chanwei; Ma, Yanmin; Lan, Yonglian; Li, Ying; Wang, Shuyu

    2015-01-01

    In order to determine the effect of endometrial injury (EI) on in vitro fertilization (IVF) outcomes in women with unexplained subfertility and explore the relationship between EI and endometrial inflammatory cytokines, 66 women with unexplained subfertility undergoing IVF treatment were recruited. 38 patients in the EI group underwent EI in the mid-luteal phase of the cycle and 28 patients in the non-EI (NEI) group. According to the pregnancy outcome, the NEI and EI groups were divided into NEI-nonpregnant (NEI-NP), NEI-pregnant (NEI-P), EI-NP, and EI-P. All patients underwent aspiration of endometrial secretions immediately before embryo transfer. The concentrations of ten mediators were measured using Milliplex Magnetic Bead assay. The clinical pregnancy was significantly higher in the EI than in the NEI group. The concentrations of interleukin- (IL-) 6, IL-8, IL-12 (p70), IL-13, interferon- (IFN-) γ, monocyte chemotactic protein- (MCP-) 1, and vascular endothelial growth factor (VEGF) were significantly higher in the EI than the NEI group. The expression of IFN-γ and VEGF in the EI-P was significantly increased compared to the EI-NP group. These findings suggest that, in women with unexplained subfertility, endometrial injury might be a potential method to improve clinical pregnancy rates by promoting the expression of IFN-γ and VEGF. PMID:26586929

  1. Borrelia burgdorferi stimulates macrophages to secrete higher levels of cytokines and chemokines than Borrelia afzelii or Borrelia garinii.

    PubMed

    Strle, Klemen; Drouin, Elise E; Shen, Shiqian; El Khoury, Joseph; McHugh, Gail; Ruzic-Sabljic, Eva; Strle, Franc; Steere, Allen C

    2009-12-15

    To delineate the inflammatory potential of the 3 pathogenic species of Borrelia burgdorferi sensu lato, we stimulated monocyte-derived macrophages from healthy human donors with 10 isolates each of B. burgdorferi, Borrelia afzelii, or Borrelia garinii recovered from erythema migrans skin lesions of patients with Lyme borreliosis from the United States or Slovenia. B. burgdorferi isolates from the United States induced macrophages to secrete significantly higher levels of interleukin (IL)-8, CCL3, CCL4, IL-6, IL-10, and tumor necrosis factor than B. garinii or B. afzelii isolates. Consistent with this response in cultured macrophages, chemokine and cytokine levels in serum samples of patients from whom the isolates were obtained were significantly greater in B. burgdorferi-infected patients than in B. afzelii- or B. garinii-infected patients. These results demonstrate in vitro and in vivo that B. burgdorferi has greater inflammatory potential than B. afzelii and B. garinii, which may account in part for variations in the clinical manifestations of Lyme borreliosis.

  2. Effect of Endometrial Injury on Secretion of Endometrial Cytokines and IVF Outcomes in Women with Unexplained Subfertility.

    PubMed

    Liang, Yu; Han, Junyan; Jia, Chanwei; Ma, Yanmin; Lan, Yonglian; Li, Ying; Wang, Shuyu

    2015-01-01

    In order to determine the effect of endometrial injury (EI) on in vitro fertilization (IVF) outcomes in women with unexplained subfertility and explore the relationship between EI and endometrial inflammatory cytokines, 66 women with unexplained subfertility undergoing IVF treatment were recruited. 38 patients in the EI group underwent EI in the mid-luteal phase of the cycle and 28 patients in the non-EI (NEI) group. According to the pregnancy outcome, the NEI and EI groups were divided into NEI-nonpregnant (NEI-NP), NEI-pregnant (NEI-P), EI-NP, and EI-P. All patients underwent aspiration of endometrial secretions immediately before embryo transfer. The concentrations of ten mediators were measured using Milliplex Magnetic Bead assay. The clinical pregnancy was significantly higher in the EI than in the NEI group. The concentrations of interleukin- (IL-) 6, IL-8, IL-12 (p70), IL-13, interferon- (IFN-) γ, monocyte chemotactic protein- (MCP-) 1, and vascular endothelial growth factor (VEGF) were significantly higher in the EI than the NEI group. The expression of IFN-γ and VEGF in the EI-P was significantly increased compared to the EI-NP group. These findings suggest that, in women with unexplained subfertility, endometrial injury might be a potential method to improve clinical pregnancy rates by promoting the expression of IFN-γ and VEGF.

  3. Effect of Endometrial Injury on Secretion of Endometrial Cytokines and IVF Outcomes in Women with Unexplained Subfertility.

    PubMed

    Liang, Yu; Han, Junyan; Jia, Chanwei; Ma, Yanmin; Lan, Yonglian; Li, Ying; Wang, Shuyu

    2015-01-01

    In order to determine the effect of endometrial injury (EI) on in vitro fertilization (IVF) outcomes in women with unexplained subfertility and explore the relationship between EI and endometrial inflammatory cytokines, 66 women with unexplained subfertility undergoing IVF treatment were recruited. 38 patients in the EI group underwent EI in the mid-luteal phase of the cycle and 28 patients in the non-EI (NEI) group. According to the pregnancy outcome, the NEI and EI groups were divided into NEI-nonpregnant (NEI-NP), NEI-pregnant (NEI-P), EI-NP, and EI-P. All patients underwent aspiration of endometrial secretions immediately before embryo transfer. The concentrations of ten mediators were measured using Milliplex Magnetic Bead assay. The clinical pregnancy was significantly higher in the EI than in the NEI group. The concentrations of interleukin- (IL-) 6, IL-8, IL-12 (p70), IL-13, interferon- (IFN-) γ, monocyte chemotactic protein- (MCP-) 1, and vascular endothelial growth factor (VEGF) were significantly higher in the EI than the NEI group. The expression of IFN-γ and VEGF in the EI-P was significantly increased compared to the EI-NP group. These findings suggest that, in women with unexplained subfertility, endometrial injury might be a potential method to improve clinical pregnancy rates by promoting the expression of IFN-γ and VEGF. PMID:26586929

  4. Pericentrin Is Related to Abnormal β-Cell Insulin Secretion through F-Actin Regulation in Mice

    PubMed Central

    Wan, Lijuan; Lv, Yang; Cui, Shaoyuan; Jin, Xinye; Li, Chunlin; Chen, Xiangmei

    2015-01-01

    The aim of this study was to investigate the regulating effect of pericentrin (PCNT) on insulin secretion in the development of insulin resistance and to determine the underlying mechanism. PCNT expression was studied in different tissues of C57/B6 mice by reverse transcriptase-PCR and immunofluorescence. PCNT was highly expressed in organs involved in the regulation of metabolism, while cytoplasmic expression was only enriched in islet cells. PCNT expression was significantly lower in the central regions of insulin resistance (IR) mouse islets than in those of control mouse islets. PCNT expression was further studied in mouse MIN6 cells exposed to glucose stimulation, small interfering RNA (siRNA) against PCNT, and an ERK inhibitor (PD98095). The results revealed that PCNT expression in glucose-stimulated MIN6 cells reduced linearly with cytoplasmic insulin levels. MIN6 cells transfected with PCNT siRNA showed significantly decreased intracellular insulin and F-actin expression. The change in F-actin expression in MIN6 cells during PCNT siRNA interference showed a linear relationship with PCNT expression at different time points. The ERK inhibitor affected PCNT expression and F-actin expression linearly. The abnormal insulin secretion observed both in vivo and in vitro was associated with decreased PCNT expression, and F-actin was found to be the target of PCNT regulation. PMID:26083368

  5. Th1 Cytokine-Secreting Recombinant Mycobacterium bovis Bacillus Calmette-Guérin and Prospective Use in Immunotherapy of Bladder Cancer

    PubMed Central

    Luo, Yi; Henning, Jonathan; O'Donnell, Michael A.

    2011-01-01

    Intravesical instillation of Mycobacterium bovis bacillus Calmette-Guérin (BCG) has been used for treating bladder cancer for 3 decades. However, BCG therapy is ineffective in approximately 30–40% of cases. Since evidence supports the T helper type 1 (Th1) response to be essential in BCG-induced tumor destruction, studies have focused on enhancing BCG induction of Th1 immune responses. Although BCG in combination with Th1 cytokines (e.g., interferon-α) has demonstrated improved efficacy, combination therapy requires multiple applications and a large quantity of cytokines. On the other hand, genetic manipulation of BCG to secrete Th1 cytokines continues to be pursued with considerable interest. To date, a number of recombinant BCG (rBCG) strains capable of secreting functional Th1 cytokines have been developed and demonstrated to be superior to BCG. This paper discusses current rBCG research, concerns, and future directions with an intention to inspire the development of this very promising immunotherapeutic modality for bladder cancer. PMID:21941579

  6. Specific inhibition of T-cell adhesion to extracellular matrix and proinflammatory cytokine secretion by human recombinant galectin-1.

    PubMed

    Rabinovich, G A; Ariel, A; Hershkoviz, R; Hirabayashi, J; Kasai, K I; Lider, O

    1999-05-01

    The migration of immune cells through the extracellular matrix (ECM) towards inflammatory sites is co-ordinated by receptors recognizing ECM glycoproteins, chemokines and proinflammatory cytokines. In this context, galectins are secreted to the extracellular milieu, where they recognize poly-N-acetyllactosamine chains on major ECM glycoproteins, such as fibronectin and laminin. We investigated the possibility that galectin-1 could modulate the adhesion of human T cells to ECM and ECM components. T cells were purified from human blood, activated with interleukin-2 (IL-2), labelled, and incubated further with intact immobilized ECM and ECM glycoproteins in the presence of increasing concentrations of human recombinant galectin-1, or its more stable, related, C2-S molecule obtained by site-directed mutagenesis. The presence of galectin-1 was shown to inhibit T-cell adhesion to intact ECM, laminin and fibronectin, and to a lesser extent to collagen type IV, in a dose-dependent manner. This effect was specifically blocked by anti-galectin-1 antibody and was dependent on the lectin's carbohydrate-binding properties. The inhibition of T-cell adhesion by galectin-1 correlates with the ability of this molecule to block the re-organization of the activated cell's actin cytoskeleton. Furthermore, tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) production was markedly reduced when IL-2-activated T cells were incubated with galectin-1 or its mutant. This effect was prevented by beta-galactoside-related sugars. The present study reveals an alternative inhibitory mechanism for explaining the suppressive properties of the galectin-1 subfamily on inflammatory and autoimmune processes. PMID:10447720

  7. Abnormal secretion of interleukin-1 and tumor necrosis factor alpha by alveolar macrophages in coal worker's pneumoconiosis: Comparison between simple pneumoconiosis and progressive massive fibrosis

    SciTech Connect

    Lassalle, P.; Gosset, P.; Aerts, C.; Fournier, E.; Lafitte, J.J.; Degreef, J.M.; Wallaert, B.; Tonnel, A.B.; Voisin, C. )

    1990-01-01

    The aim of this study was to compare the secretion of tumor necrosis factor alpha (TNF alpha) and interleukin-1 (IL-1) by alveolar macrophages (AMs) harvested from patients with coal worker's pneumoconiosis (CWP) and control subjects. We observed higher levels of spontaneous TNF alpha and IL-1 secretion by AMs from patients with CWP than in those from healthy controls. We did not find any significant difference between the two groups in the incidence of simple pneumoconiosis and progressive massive fibrosis. In the group of coal miners without radiologic signs of pneumoconiosis, we found high levels of both cytokines in a subgroup of subjects still exposed to the mineral dust but not in the subgroup of subjects removed from exposure. These results indicate that AMs are involved in chronic lung inflammatory reactions to mineral dusts, partly by way of cytokine secretion. Moreover, cytokine secretion by AMs appears to be an early event that is detectable at the moment of mineral dust exposure. The results open new perspectives in the study of the mechanisms leading to CWP.

  8. Nitric oxide inhibits the secretion of T-helper 1- and T-helper 2-associated cytokines in activated human T cells.

    PubMed Central

    Bauer, H; Jung, T; Tsikas, D; Stichtenoth, D O; Frölich, J C; Neumann, C

    1997-01-01

    Mechanisms regulating the balance of T-helper 1 (Th1) and T-helper 2 (Th2) immune responses are of great interest as they may determine the outcome of allergic and infectious diseases. Recently, in mice, nitric oxide (NO), a powerful modulator of inflammation, has been reported to preferentially down-regulate Th1-mediated immune responses. In the present study, we investigated the effect of NO on the production of Th1- and Th2-associated cytokines by activated human T cells and human T-cell clones. Cytokine secretion was measured in the presence of the NO-donating agents 3-morpholinosydnonimine (SIN-1) and S-nitroso-N-acetylpenicillamine (SNAP). Both NO-donors markedly inhibited the release of interferon-gamma (IFN-gamma), interleukin-2 (IL-2), IL-5, IL-10 and IL-4 by anti-CD3 activated T cells. A preferential inhibition of Th1-associated cytokines was not observed. Neither was nitrite found in the supernatants of activated T cells, nor was specific mRNA for inducible and constitutive NO synthase detectable, indicating that T cells themselves did not contribute to the observed effect of the NO donors. Costimulation with anti-CD28 monoclonal antibodies (mAb) prevented SIN-1/SNAP-mediated down-regulation of cytokine production only in part. In contrast, when T cells were stimulated by phorbol-ester and ionomycin, they were refractory to SIN-1-induced inhibition of cytokine production. When SIN-1 was added after the onset of anti-CD3 stimulation, the inhibitory effect was found to be less pronounced, indicating that SIN-1 may interfere with early signal transduction events. The addition of superoxide dismutase (SOD) and catalase did not restore the effects of SIN-1, demonstrating that the inhibition of cytokines was due to NO and not to oxygen intermediates. Furthermore, 8-Br-cGMP-mediated increase of intracellular cGMP caused the same pattern of cytokine inhibition as observed with SIN-1 and SNAP. Using a single cell assay, these agents were shown to reduce the

  9. Chlamydia trachomatis infection results in a modest pro-inflammatory cytokine response and a decrease in T cell chemokine secretion in human polarized endocervical epithelial cells

    PubMed Central

    Buckner, Lyndsey R.; Lewis, Maria E.; Greene, Sheila J.; Foster, Timothy P.; Quayle, Alison J.

    2013-01-01

    The endocervical epithelium is a major reservoir for Chlamydia trachomatis in women, and genital infections are extended in their duration. Epithelial cells act as mucosal sentinels by secreting cytokines and chemokines in response to pathogen challenge and infection. We therefore determined the signature cytokine and chemokine response of primary-like endocervix-derived epithelial cells in response to a common genital serovar (D) of C. trachomatis. For these studies, we used a recently-established polarized, immortalized, endocervical epithelial cell model (polA2EN) that maintains, in vitro, the architectural and functional characteristics of endocervical epithelial cells in vivo including the production of pro-inflammatory cytokines. PolA2EN cells were susceptible to C. trachomatis infection, and chlamydiae in these cells underwent a normal developmental cycle as determined by a one-step growth curve. IL1α protein levels were increased in both apical and basolateral secretions of C. trachomatis infected polA2EN cells, but this response did not occur until 72 hours after infection. Furthermore, protein levels of the pro-inflammatory cytokines and chemokines IL6, TNFα and CXCL8 were not significantly different between C. trachomatis infected polA2EN cells and mock infected cells at any time during the chlamydial developmental cycle up to 120 hours post-infection. Intriguingly, C. trachomatis infection resulted in a significant decrease in the constitutive secretion of T cell chemokines IP10 and RANTES, and this required a productive C. trachomatis infection. Examination of anti-inflammatory cytokines revealed a high constitutive apical secretion of IL1ra from polA2EN cells that was not significantly modulated by C. trachomatis infection. IL-11 was induced by C. trachomatis, although only from the basolateral membrane. These results suggest that C. trachomatis can use evasion strategies to circumvent a robust pro-inflammatory cytokine and chemokine response. These

  10. Effects of free amino acids on cytokine secretion and proliferative activity of feline T cells in an in vitro study using the cell line MYA-1.

    PubMed

    Paßlack, Nadine; Doherr, Marcus G; Zentek, Jürgen

    2016-10-01

    In vitro studies might be an interesting screening method for targeted in vivo studies in the field of immunonutrition and help to reduce and refine animal studies. As the role of amino acids for immune function of cats has not been evaluated in detail so far, the present study aimed at investigating the effects of eight different amino acids (arginine, leucine, isoleucine, valine, glutamine, lysine, threonine and tryptophan) in six concentrations each (0, 0.25, 0.5, 1, 2 and 8x the cat blood level) on cytokine secretion and proliferative activity of feline T cells (MYA-1) in vitro. The results demonstrated that high doses of arginine increased IL-4, IL-10 and TNF-α secretion of T cells, while increasing concentrations of lysine increased IL-10 secretion and proliferative activity of the T cells. High doses of leucine enhanced GM-CSF and IL-10 secretion, while concentrations of threonine in the cell culture media greater than blood concentration also increased GM-CSF and additionally TNF-α secretion of the cells. The effects of glutamine and isoleucine on T cell function were only small. In conclusion, the present in vitro study could evaluate the immunomodulating potential of specific amino acids for feline T cell function. High doses of arginine, lysine, leucine and threonine had a significant impact on cytokine secretion and proliferative activity of the T cells. Targeted in vivo studies should investigate the clinical relevance of dietary supplementation of those amino acids in healthy and diseased cats as a next step. PMID:27510653

  11. Effects of free amino acids on cytokine secretion and proliferative activity of feline T cells in an in vitro study using the cell line MYA-1.

    PubMed

    Paßlack, Nadine; Doherr, Marcus G; Zentek, Jürgen

    2016-10-01

    In vitro studies might be an interesting screening method for targeted in vivo studies in the field of immunonutrition and help to reduce and refine animal studies. As the role of amino acids for immune function of cats has not been evaluated in detail so far, the present study aimed at investigating the effects of eight different amino acids (arginine, leucine, isoleucine, valine, glutamine, lysine, threonine and tryptophan) in six concentrations each (0, 0.25, 0.5, 1, 2 and 8x the cat blood level) on cytokine secretion and proliferative activity of feline T cells (MYA-1) in vitro. The results demonstrated that high doses of arginine increased IL-4, IL-10 and TNF-α secretion of T cells, while increasing concentrations of lysine increased IL-10 secretion and proliferative activity of the T cells. High doses of leucine enhanced GM-CSF and IL-10 secretion, while concentrations of threonine in the cell culture media greater than blood concentration also increased GM-CSF and additionally TNF-α secretion of the cells. The effects of glutamine and isoleucine on T cell function were only small. In conclusion, the present in vitro study could evaluate the immunomodulating potential of specific amino acids for feline T cell function. High doses of arginine, lysine, leucine and threonine had a significant impact on cytokine secretion and proliferative activity of the T cells. Targeted in vivo studies should investigate the clinical relevance of dietary supplementation of those amino acids in healthy and diseased cats as a next step.

  12. Anti-inflammatory effects of 27 selected terpenoid compounds tested through modulating Th1/Th2 cytokine secretion profiles using murine primary splenocytes.

    PubMed

    Ku, Chi-Mei; Lin, Jin-Yuarn

    2013-11-15

    This study investigated 27 selected terpenoid compounds, including 8 monoterpenoids, 7 sesqui-terpenoids, 3 di-terpenoids, 8 tri-terpenoids, and 1 tetra-terpenoid, for their Th1/Th2 immunomodulatory potential using mouse primary splenocytes. Changes in Th1 cytokines, including interleukin (IL)-2 and interferon (IFN)-γ, and Th2 cytokines, including IL-4, IL-5 and IL-10, secreted by terpenoid-treated splenocytes were measured using the ELISA method. The results showed that triptolide, a diterpenoid, was most cytotoxic, reflecting an IC50 value of 46nM. Eucalyptol, limonene, linalool, thymol, parthenolide, andrographolide, 18β-glycyrrhetinic acid, lupeol, ursolic acid and β-sitosterol showed a strong Th2-inclination and anti-inflammation potential in vitro. In addition, (-)-trans-caryophyllene, oridonin, triptolide, diosgenin, betulinic acid, escin, and β-sitosterol treatments significantly inhibited both IL-2 (Th1) and IL-10 (Th2) cytokine production at the same time, suggesting that these terpenoid compounds have an anti-inflammation potential through the inhibition of T-cell immune responses. Diosgenin treatments significantly increased IFN-γ secretion levels using mouse splenocytes, suggesting that diosgenin may be useful in treating a viral infection through the stimulation of IFN-γ production. Menthone, farnesol and oridonin treatments did not markedly increase IL-10/IL-2 (Th2/Th1) cytokine secretion ratios, suggesting that menthone, farnesol and oridonin may have a relative Th1-inclination property, compared to the other selected terpenoid compounds. The relative Th1-inclination property of menthone, farnesol and oridonin may be applied to improve Th2-skewed allergic diseases.

  13. Bacterial siderophores that evade or overwhelm lipocalin 2 induce hypoxia inducible factor 1α and proinflammatory cytokine secretion in cultured respiratory epithelial cells.

    PubMed

    Holden, Victoria I; Lenio, Steven; Kuick, Rork; Ramakrishnan, Sadeesh K; Shah, Yatrik M; Bachman, Michael A

    2014-09-01

    Iron is essential for many cellular processes and is required by bacteria for replication. To acquire iron from the host, pathogenic Gram-negative bacteria secrete siderophores, including enterobactin (Ent). However, Ent is bound by the host protein lipocalin 2 (Lcn2), preventing bacterial reuptake of aferric or ferric Ent. Furthermore, the combination of Ent and Lcn2 (Ent+Lcn2) leads to enhanced secretion of interleukin-8 (IL-8) compared to that induced by either stimulus alone. Modified or structurally distinct siderophores, including yersiniabactin (Ybt) and glycosylated Ent (GlyEnt, or salmochelin), deliver iron to bacteria despite the presence of Lcn2. We hypothesized that the robust immune response to Ent and Lcn2 requires iron chelation rather than the Ent+Lcn2 complex itself and also can be stimulated by Lcn2-evasive siderophores. To test this hypothesis, cultured respiratory epithelial cells were stimulated with combinations of purified siderophores and Lcn2 and analyzed by gene expression microarrays, quantitative PCR, and cytokine immunoassays. Ent caused HIF-1α protein stabilization, induced the expression of genes regulated by hypoxia-inducible factor 1α (HIF-1α), and repressed genes involved in cell cycle and DNA replication, whereas Lcn2 induced expression of proinflammatory cytokines. Iron chelation by excess Ent or Ybt significantly increased Lcn2-induced secretion of IL-8, IL-6, and CCL20. Stabilization of HIF-1α was sufficient to enhance Lcn2-induced IL-6 secretion. These data indicate that respiratory epithelial cells can respond to bacterial siderophores that evade or overwhelm Lcn2 binding by increasing proinflammatory cytokine production.

  14. The Endogenous Cell-Fate Factor Dachshund restrains Prostate Epithelial Cell Migration via Repression of Cytokine Secretion via a CXCL Signaling Module

    PubMed Central

    Chen, Ke; Wu, Kongming; Jiao, Xuanmao; Wang, Liping; Ju, Xiaoming; Wang, Min; Di Sante, Gabriele; Xu, Shaohua; Wang, Qiong; Li, Kevin; Sun, Xin; Xu, Congwen; Li, Zhiping; Casimiro, Mathew C.; Ertel, Adam; Addya, Sankar; McCue, Peter; Lisanti, Michael P.; Wang, Chenguang; Davis, Richard J.; Mardon, Graeme; Pestell, Richard G.

    2015-01-01

    Prostate cancer (PCa) is the second leading form of cancer death in men. In a subset of PCa patients increased chemokine signaling IL-8 and IL-6 correlates with androgen therapy-resistant prostate cancer (CRPC). IL-8 and IL-6 are produced by prostate epithelial cells and promote PCa cell invasion, however the mechanisms restraining prostate epithelial cell cytokine secretion are poorly understood. Herein the cell-fate determinant factor DACH1 inhibited androgen therapy-resistant prostate cancer (CRPC) tumor growth in mice. Using Dach1fl/fl/Probasin-Cre bi-transgenic mice, we show IL-8 and IL-6 secretion was altered ~1000 fold by endogenous Dach1. Endogenous Dach1 is shown to serve as a key endogenous restraint to prostate epithelial cell growth and restrains migration via CXCL signaling. DACH1 inhibited expression, transcription and secretion of the CXCL genes (IL-8, IL-6) by binding to their promoter regulatory regions in chromatin. DACH1 is thus a newly defined determinant of benign and malignant prostate epithelium cellular growth, migration and cytokine abundance in vivo. PMID:25769723

  15. Closing the gap: discrimination of the expression profile of HLA questionable alleles by a cytokine-induced secretion approach using HLA-A*32:11Q.

    PubMed

    Föll, D; Hinrichs, J; Tischer, S; Battermann, A; Schambach, A; Figueiredo, C; Immenschuh, S; Blasczyk, R; Eiz-Vesper, B

    2012-05-01

    Matching of human leukocyte antigen (HLA) alleles between donors and recipients plays a major role in hematopoietic stem cell transplantation (HSCT). Null or questionably expressed HLA allelic variants are a major issue in HLA matching, because the aberrant expression of such alleles can have a major impact on the outcome of HSCT and/or its complications such as graft-versus-host disease. The goal of this study was to investigate the potential of a recently developed cytokine-induced secretion assay to differentiate the expression levels of HLA-A*32:11Q (questionable) into a null (N) or low (L) expression variant. An amino acid mutation at position 164 of HLA-A*32:11Q disrupts the disulfide bridge in the α2 domain. HLA-A*32:11Q is not detectable by standard microlymphocytotoxicity assay. To this end, we cloned soluble HLA-A*32:11Q and a reference allele (HLA-A*32:01) into expression vectors and transfected/transduced HEK293 and K562 cells. Allele-expressing K562 cells were simultaneously transfected/transduced with a β2-microglobulin (B2M)-encoding vector to ensure the intact HLA structure with B2M. After treatment with proinflammatory cytokines, secreted soluble HLA molecules were determined by enzyme-linked immunosorbent assay in the supernatant and intracellular accumulation of the recombinant proteins by flow cytometry. HLA-A*32:11Q was nearly undetectable in untreated transfectants. Cytokine treatment increased the secretion of HLA-A*32:11Q to detectable levels and resulted in intracellular accumulation of the allele. There was no difference in mRNA transcription between the A*32 alleles. On the basis of these results, we recommend reclassification of HLA-A*32:11Q as a low expression (L) variant.

  16. The Effect of Solar Irradiated Vibrio cholerae on the Secretion of Pro-Inflammatory Cytokines and Chemokines by the JAWS II Dendritic Cell Line In Vitro.

    PubMed

    Ssemakalu, Cornelius Cano; Ubomba-Jaswa, Eunice; Motaung, Keolebogile Shirley; Pillay, Michael

    2015-01-01

    The use of solar irradiation to sterilize water prior to its consumption has resulted in the reduction of water related illnesses in waterborne disease endemic communities worldwide. Currently, research on solar water disinfection (SODIS) has been directed towards understanding the underlying mechanisms through which solar irradiation inactivates the culturability of microorganisms in water, enhancement of the disinfection process, and the health impact of SODIS water consumption. However, the immunological consequences of SODIS water consumption have not been explored. In this study, we investigated the effect that solar irradiated V. cholerae may have had on the secretion of cytokines and chemokines by the JAWS II dendritic cell line in vitro. The JAWS II dendritic cell line was stimulated with the different strains of V. cholerae that had been: (i) prepared in PBS, (ii) inactivated through a combination of heat and chemical, (iii) solar irradiated, and (iv) non-solar irradiated, in bottled water. As controls, LPS (1 μg/ml) and CTB (1 μg/ml) were used as stimulants. After 48 hours of stimulation the tissue culture media from each treatment was qualitatively and quantitatively analysed for the presence of IL-1α, IL-1β, IL-6, IL-7, IL-10, IL-12p40, IL-12p70, IL-15, MIP-1α, MIP-1β, MIP-2, RANTES, TNF-α, IL-23 and IL-27. Results showed that solar irradiated cultures of V. cholerae induced dendritic cells to secrete significant (p<0.05) levels of pro-inflammatory cytokines in comparison to the unstimulated dendritic cells. Furthermore, the amount of pro-inflammatory cytokines secreted by the dendritic cells in response to solar irradiated cultures of V. cholerae was not as high as observed in treatments involving non-solar irradiated cultures of V. cholerae or LPS. Our results suggest that solar irradiated microorganisms are capable of inducing the secretion of pro-inflammatory cytokines and chemokines. This novel finding is key towards understanding the

  17. The Effect of Solar Irradiated Vibrio cholerae on the Secretion of Pro-Inflammatory Cytokines and Chemokines by the JAWS II Dendritic Cell Line In Vitro.

    PubMed

    Ssemakalu, Cornelius Cano; Ubomba-Jaswa, Eunice; Motaung, Keolebogile Shirley; Pillay, Michael

    2015-01-01

    The use of solar irradiation to sterilize water prior to its consumption has resulted in the reduction of water related illnesses in waterborne disease endemic communities worldwide. Currently, research on solar water disinfection (SODIS) has been directed towards understanding the underlying mechanisms through which solar irradiation inactivates the culturability of microorganisms in water, enhancement of the disinfection process, and the health impact of SODIS water consumption. However, the immunological consequences of SODIS water consumption have not been explored. In this study, we investigated the effect that solar irradiated V. cholerae may have had on the secretion of cytokines and chemokines by the JAWS II dendritic cell line in vitro. The JAWS II dendritic cell line was stimulated with the different strains of V. cholerae that had been: (i) prepared in PBS, (ii) inactivated through a combination of heat and chemical, (iii) solar irradiated, and (iv) non-solar irradiated, in bottled water. As controls, LPS (1 μg/ml) and CTB (1 μg/ml) were used as stimulants. After 48 hours of stimulation the tissue culture media from each treatment was qualitatively and quantitatively analysed for the presence of IL-1α, IL-1β, IL-6, IL-7, IL-10, IL-12p40, IL-12p70, IL-15, MIP-1α, MIP-1β, MIP-2, RANTES, TNF-α, IL-23 and IL-27. Results showed that solar irradiated cultures of V. cholerae induced dendritic cells to secrete significant (p<0.05) levels of pro-inflammatory cytokines in comparison to the unstimulated dendritic cells. Furthermore, the amount of pro-inflammatory cytokines secreted by the dendritic cells in response to solar irradiated cultures of V. cholerae was not as high as observed in treatments involving non-solar irradiated cultures of V. cholerae or LPS. Our results suggest that solar irradiated microorganisms are capable of inducing the secretion of pro-inflammatory cytokines and chemokines. This novel finding is key towards understanding the

  18. The Effect of Solar Irradiated Vibrio cholerae on the Secretion of Pro-Inflammatory Cytokines and Chemokines by the JAWS II Dendritic Cell Line In Vitro

    PubMed Central

    Ssemakalu, Cornelius Cano; Ubomba-Jaswa, Eunice; Motaung, Keolebogile Shirley; Pillay, Michael

    2015-01-01

    The use of solar irradiation to sterilize water prior to its consumption has resulted in the reduction of water related illnesses in waterborne disease endemic communities worldwide. Currently, research on solar water disinfection (SODIS) has been directed towards understanding the underlying mechanisms through which solar irradiation inactivates the culturability of microorganisms in water, enhancement of the disinfection process, and the health impact of SODIS water consumption. However, the immunological consequences of SODIS water consumption have not been explored. In this study, we investigated the effect that solar irradiated V. cholerae may have had on the secretion of cytokines and chemokines by the JAWS II dendritic cell line in vitro. The JAWS II dendritic cell line was stimulated with the different strains of V. cholerae that had been: (i) prepared in PBS, (ii) inactivated through a combination of heat and chemical, (iii) solar irradiated, and (iv) non-solar irradiated, in bottled water. As controls, LPS (1 μg/ml) and CTB (1 μg/ml) were used as stimulants. After 48 hours of stimulation the tissue culture media from each treatment was qualitatively and quantitatively analysed for the presence of IL-1α, IL-1β, IL-6, IL-7, IL-10, IL-12p40, IL-12p70, IL-15, MIP-1α, MIP-1β, MIP-2, RANTES, TNF-α, IL-23 and IL-27. Results showed that solar irradiated cultures of V. cholerae induced dendritic cells to secrete significant (p<0.05) levels of pro-inflammatory cytokines in comparison to the unstimulated dendritic cells. Furthermore, the amount of pro-inflammatory cytokines secreted by the dendritic cells in response to solar irradiated cultures of V. cholerae was not as high as observed in treatments involving non-solar irradiated cultures of V. cholerae or LPS. Our results suggest that solar irradiated microorganisms are capable of inducing the secretion of pro-inflammatory cytokines and chemokines. This novel finding is key towards understanding the

  19. Mushroom acidic glycosphingolipid induction of cytokine secretion from murine T cells and proliferation of NK1.1 {alpha}/{beta} TCR-double positive cells in vitro

    SciTech Connect

    Nozaki, Hirofumi; Itonori, Saki; Sugita, Mutsumi; Nakamura, Kimihide; Ohba, Kiyoshi; Suzuki, Akemi; Kushi, Yasunori

    2008-08-29

    Interferon (IFN)-{gamma} and interleukin (IL)-4 regulate many types of immune responses. Here we report that acidic glycosphingolipids (AGLs) of Hypsizigus marmoreus and Pleurotus eryngii induced secretion of IFN- {gamma} and IL-4 from T cells in a CD11c-positive cell-dependent manner similar to that of {alpha}-galactosylceramide ({alpha}-GalCer) and isoglobotriaosylceramide (iGb3), although activated T cells by AGLs showed less secretion of cytokine than those activated by {alpha}-GalCer. In addition, stimulation of these mushroom AGLs induced proliferation of NK1.1 {alpha}/{beta} TCR-double positive cells in splenocytes. Administration of a mixture of {alpha}-GalCer and AGLs affected the stimulation of {alpha}-GalCer and generally induced a subtle Th1 bias for splenocytes but induced an extreme Th2 bias for thymocytes. These results suggested that edible mushroom AGLs contribute to immunomodulation.

  20. Resveratrol inhibits enterovirus 71 replication and pro-inflammatory cytokine secretion in rhabdosarcoma cells through blocking IKKs/NF-κB signaling pathway.

    PubMed

    Zhang, Li; Li, Yuanyuan; Gu, Zhiwen; Wang, Yuyue; Shi, Mei; Ji, Yun; Sun, Jing; Xu, Xiaopeng; Zhang, Lirong; Jiang, Jingtin; Shi, Weifeng

    2015-01-01

    Polydatin and resveratrol, as major active components in Polygonum cuspidatum, have anti-inflammatory, antioxidant and antitumor functions. However, the effect and mechanism of polydatin and resveratrol on enterovirus 71 (EV71) have not been reported. In this study, resveratrol revealed strong antiviral activity on EV71, while polydatin had weak effect. Neither polydatin nor resveratrol exhibited influence on viral attachment. Resveratrol could effectively inhibit the synthesis of EV71/VP1 and the phosphorylation of IKKα, IKKβ, IKKγ, IKBα, NF-κB p50 and NF-κB p65, respectively. Meanwhile, the remarkably increased secretion of IL-6 and TNF-α in EV71-infected rhabdosarcoma (RD) cells could be blocked by resveratrol. These results demonstrated that resveratrol inhibited EV71 replication and cytokine secretion in EV71-infected RD cells through blocking IKKs/NF-κB signaling pathway. Thus, resveratrol may have potent antiviral effect on EV71 infection. PMID:25692777

  1. Resveratrol Inhibits Enterovirus 71 Replication and Pro-Inflammatory Cytokine Secretion in Rhabdosarcoma Cells through Blocking IKKs/NF-κB Signaling Pathway

    PubMed Central

    Zhang, Li; Li, Yuanyuan; Gu, Zhiwen; Wang, Yuyue; Shi, Mei; Ji, Yun; Sun, Jing; Xu, Xiaopeng; Zhang, Lirong; Jiang, Jingtin; Shi, Weifeng

    2015-01-01

    Polydatin and resveratrol, as major active components in Polygonum cuspidatum, have anti-inflammatory, antioxidant and antitumor functions. However, the effect and mechanism of polydatin and resveratrol on enterovirus 71 (EV71) have not been reported. In this study, resveratrol revealed strong antiviral activity on EV71, while polydatin had weak effect. Neither polydatin nor resveratrol exhibited influence on viral attachment. Resveratrol could effectively inhibit the synthesis of EV71/VP1 and the phosphorylation of IKKα, IKKβ, IKKγ, IKBα, NF-κB p50 and NF-κB p65, respectively. Meanwhile, the remarkably increased secretion of IL-6 and TNF-α in EV71-infected rhabdosarcoma (RD) cells could be blocked by resveratrol. These results demonstrated that resveratrol inhibited EV71 replication and cytokine secretion in EV71-infected RD cells through blocking IKKs/NF-κB signaling pathway. Thus, resveratrol may have potent antiviral effect on EV71 infection. PMID:25692777

  2. Resveratrol inhibits enterovirus 71 replication and pro-inflammatory cytokine secretion in rhabdosarcoma cells through blocking IKKs/NF-κB signaling pathway.

    PubMed

    Zhang, Li; Li, Yuanyuan; Gu, Zhiwen; Wang, Yuyue; Shi, Mei; Ji, Yun; Sun, Jing; Xu, Xiaopeng; Zhang, Lirong; Jiang, Jingtin; Shi, Weifeng

    2015-01-01

    Polydatin and resveratrol, as major active components in Polygonum cuspidatum, have anti-inflammatory, antioxidant and antitumor functions. However, the effect and mechanism of polydatin and resveratrol on enterovirus 71 (EV71) have not been reported. In this study, resveratrol revealed strong antiviral activity on EV71, while polydatin had weak effect. Neither polydatin nor resveratrol exhibited influence on viral attachment. Resveratrol could effectively inhibit the synthesis of EV71/VP1 and the phosphorylation of IKKα, IKKβ, IKKγ, IKBα, NF-κB p50 and NF-κB p65, respectively. Meanwhile, the remarkably increased secretion of IL-6 and TNF-α in EV71-infected rhabdosarcoma (RD) cells could be blocked by resveratrol. These results demonstrated that resveratrol inhibited EV71 replication and cytokine secretion in EV71-infected RD cells through blocking IKKs/NF-κB signaling pathway. Thus, resveratrol may have potent antiviral effect on EV71 infection.

  3. A heteroglycan from the cyanobacterium Nostoc commune modulates LPS-induced inflammatory cytokine secretion by THP-1 monocytes through phosphorylation of ERK1/2 and Akt.

    PubMed

    Olafsdottir, Astridur; Thorlacius, Gudny Ella; Omarsdottir, Sesselja; Olafsdottir, Elin Soffia; Vikingsson, Arnor; Freysdottir, Jona; Hardardottir, Ingibjorg

    2014-09-25

    Cyanobacteria (blue-green algae) have been consumed as food and used in folk medicine since ancient times to alleviate a variety of diseases. Cyanobacteria of the genus Nostoc have been shown to produce complex exopolysaccharides with antioxidant and antiviral activity. Furthermore, Nostoc sp. are common in cyanolichen symbiosis and lichen polysaccharides are known to have immunomodulating effects. Nc-5-s is a heteroglycan isolated from free-living colonies of Nostoc commune and its structure has been characterized in detail. The aim of this study was to determine the effects of Nc-5-s on the inflammatory response of lipopolysaccharide (LPS)-stimulated human THP-1 monocytes and how the effects are mediated. THP-1 monocytes primed with interferon-γ and stimulated with LPS in the presence of Nc-5-s secreted less of the pro-inflammatory cytokine interleukin (IL)-6 and more of the anti-inflammatory cytokine IL-10 than THP-1 monocytes stimulated without Nc-5-s. In contrast, Nc-5-s increased LPS-induced secretion of the pro-inflammatory cytokines tumor necrosis factor (TNF)-α and IL-8. Nc-5-s decreased LPS-induced phosphorylation of the extracellular regulated kinase (ERK)1/2 and Akt kinase, but did not affect phosphorylation of the p38 kinase, activation of the nuclear factor kappa B pathway, nor DNA binding of c-fos. These results show that Nc-5-s has anti-inflammatory effects on IL-6 and IL-10 secretion by THP-1 monocytes, but its effects are pro-inflammatory when it comes to TNF-α and IL-8. Furthermore, they show that the effects of Nc-5-s may be mediated through the ERK1/2 pathway and/or the Akt/phosphoinositide 3-kinase pathway and their downstream effectors. The ability of Nc-5-s to decrease IL-6 secretion, increase IL-10 secretion and moderate ERK1/2 activation indicates a potential for its development as an anti-inflammatory agent. PMID:24877713

  4. Tea polyphenols inhibit the activation of NF-κB and the secretion of cytokines and matrix metalloproteinases by macrophages stimulated with Fusobacterium nucleatum

    PubMed Central

    Lagha, Amel Ben; Grenier, Daniel

    2016-01-01

    Fusobacterium nucleatum has been associated with both periodontal disease and inflammatory bowel disease. This Gram-negative bacterium possesses a high inflammatory potential that may contribute to the disease process. We hypothesized that green and black tea polyphenols attenuate the inflammatory response of monocytes/macrophages mediated by F. nucleatum. We first showed that the tea extracts, EGCG and theaflavins reduce the NF-κB activation induced by F. nucleatum in monocytes. Since NF-κB is a key regulator of genes coding for inflammatory mediators, we tested the effects of tea polyphenols on secretion of IL-1β, IL-6, TNF-α, and CXCL8 by macrophages. A pre-treatment of macrophages with the tea extracts, EGCG, or theaflavins prior to a stimulation with F. nucleatum significantly inhibited the secretion of all four cytokines and reduced the secretion of MMP-3 and MMP-9, two tissue destructive enzymes. TREM-1 expressed by macrophages is a cell-surface receptor involved in the propagation of the inflammatory response to bacterial challenges. Interestingly, tea polyphenols inhibited the secretion/shedding of soluble TREM-1 induced by a stimulation of macrophages with F. nucleatum. The anti-inflammatory properties of tea polyphenols identified in the present study suggested that they may be promising agents for the prevention and/or treatment of periodontal disease and inflammatory bowel disease. PMID:27694921

  5. SPI-1-encoded type III secretion system of Salmonella enterica is required for the suppression of porcine alveolar macrophage cytokine expression.

    PubMed

    Pavlova, Barbora; Volf, Jiri; Ondrackova, Petra; Matiasovic, Jan; Stepanova, Hana; Crhanova, Magdalena; Karasova, Daniela; Faldyna, Martin; Rychlik, Ivan

    2011-01-24

    Genes localized at Salmonella pathogenicity island-1 (SPI-1) are involved in Salmonella enterica invasion of host non-professional phagocytes. Interestingly, in macrophages, SPI-1-encoded proteins, in addition to invasion, induce cell death via activation of caspase-1 which also cleaves proIL-1β and proIL-18, precursors of 2 proinflammatory cytokines. In this study we were therefore interested in whether SPI-1-encoded type III secretion system (T3SS) may influence proinflammatory response of macrophages. To test this hypothesis, we infected primary porcine alveolar macrophages with wild-type S. Typhimurium and S. Enteritidis and their isogenic SPI-1 deletion mutants. ΔSPI1 mutants of both serovars invaded approx. 5 times less efficiently than the wild-type strains and despite this, macrophages responded to the infection with ΔSPI1 mutants by increased expression of proinflammatory cytokines IL-1β, IL-8, TNFα, IL-23α and GM-CSF. Identical macrophage responses to that induced by the ΔSPI1 mutants were also observed to the infection with sipB but not the sipA mutant. The hilA mutant exhibited an intermediate phenotype between the ΔSPI1 mutant and the wild-type S. Enteritidis. Our results showed that the SPI-1-encoded T3SS is required not only for cell invasion but in macrophages also for the suppression of early proinflammatory cytokine expression.

  6. Lack of correlation between membrane CD30 expression and cytokine secretion pattern in allergen-primed naive cord blood T-cell lines and clones.

    PubMed

    Spinozzi, F; Agea, E; Piattoni, S; Falini, B; Grignani, F; Bertotto, A

    1997-04-01

    Various surface molecules are expressed by activated T cells. Among them, the CD30 antigen has been proposed as a reproducible marker that identifies a subset of differentiated and/or activated T lymphocytes that produce T helper (Th)-2-type cytokines, i.e. interleukin (IL)-4 and IL-5. However, because CD30 has mainly been detected on established T-cell clones, it is still unclear whether a priming allergen and/or cytokine can induce its membrane expression on naive T cells, perhaps in parallel with the up-regulation of other relevant activation markers, such as CD25, HLA-DR and L-selectin. It is also unknown whether proper allergen stimulation affects the cytokine secretion pattern by CD30+ T-cell clones derived from antigen-unprimed (naive) T lymphocytes. More information on these questions was sought by adopting a model that used cord blood as a source of virgin T cells and exposing them to native cypress allergen or cytokine (IL-2 or IL-4) stimulation, as well as to conventional polyclonal activators such as PHA or anti-CD3. Peripheral blood MC from four adult cypress-sensitive patients was also assayed and used as controls for all culture experiments. Freshly isolated cord and adult T cells did not express the CD30 antigen on their membrane. Many of the stimulating agents tested were able to up-regulate the expression of CD30. However, despite high expression of this molecule, cloned allergen-specific cord CD4+ T lymphocytes were unable to produce IFN-gamma and/or IL-4. In contrast, they retained the capability to produce IL-2. Thus, expression of the CD30 antigen on virgin T cells does not correlate with a polarized model of T helper (Th)-1 or Th-2 cytokine-producing cells, suggesting that these types of lymphokine-secreting lymphocytes are not a paradigmatic example of T-cell subpopulations that display stable phenotypical features. PMID:9105430

  7. Histoplasma capsulatum-Induced Cytokine Secretion in Lung Epithelial Cells Is Dependent on Host Integrins, Src-Family Kinase Activation, and Membrane Raft Recruitment

    PubMed Central

    Maza, Paloma K.; Suzuki, Erika

    2016-01-01

    Histoplasma capsulatum var. capsulatum is a dimorphic fungus that causes histoplasmosis, a human systemic mycosis with worldwide distribution. In the present work, we demonstrate that H. capsulatum yeasts are able to induce cytokine secretion by the human lung epithelial cell line A549 in integrin- and Src-family kinase (SFK)-dependent manners. This conclusion is supported by small interfering RNA (siRNA) directed to α3 and α5 integrins, and PP2, an inhibitor of SFK activation. siRNA and PP2 reduced IL-6 and IL-8 secretion in H. capsulatum-infected A549 cell cultures. In addition, α3 and α5 integrins from A549 cells were capable of associating with H. capsulatum yeasts, and this fungus promotes recruitment of these integrins and SFKs to A549 cell membrane rafts. Corroborating this finding, membrane raft disruption with the cholesterol-chelator methyl-β-cyclodextrin reduced the levels of integrins and SFKs in these cell membrane domains. Finally, pretreatment of A549 cells with the cholesterol-binding compound, and also a membrane raft disruptor, filipin, significantly reduced IL-6 and IL-8 levels in A549-H.capsulatum cultures. Taken together, these results indicate that H. capsulatum yeasts induce secretion of IL-6 and IL-8 in human lung epithelial cells by interacting with α3 and α5 integrins, recruiting these integrins to membrane rafts, and promoting SFK activation. PMID:27148251

  8. An experimental mixed bacterial infection induced differential secretion of proinflammatory cytokines (IL-1β, TNFα) and proMMP-9 in human fetal membranes.

    PubMed

    Flores-Herrera, H; García-López, G; Díaz, N F; Molina-Hernández, A; Osorio-Caballero, M; Soriano-Becerril, D; Zaga-Clavellina, V

    2012-04-01

    Overall, 1-4% of all births in the US are complicated by choriamnionitis. Choriamnionitis is a polymicrobial infection most often due to ascending genital microbes which, in over 65% of positive amniotic fluid cultures, involves two or more organisms. In this study, we determine the cytokines expression (IL-1β, TNFα) and prometalloproteinase activation (proMMP-2 and proMMP-9) after double o single infection an in vitro model of human fetal membranes. Fetal membranes at term were mounted in the Transwell culture system and after 24 h of infection, choriodecidual, and amnion media was collected. IL-1β and TNFα were evaluated by ELISA, whereas proMMP-9 and proMMP-2 were determined by substrate gel zymography. The choriodecidual and amnion compartments actively respond to the infectious process, which induced the secretion of IL-1β, TNFα, and proMMP-9 after either mixed or single infection. The proMMP-2 secretion profile was the same after all experimental conditions. There was no synergy between Streptococcus agalactiae and Escherichia coli for inducing the secretion of inflammatory factors or degradative metalloproteinase. In conclusion, these two bacteria could initiate different pathways to induce chorioamnioitis.

  9. Leishmania mexicana: promastigotes and amastigotes secrete protein phosphatases and this correlates with the production of inflammatory cytokines in macrophages.

    PubMed

    Escalona-Montaño, A R; Ortiz-Lozano, D M; Rojas-Bernabé, A; Wilkins-Rodriguez, A A; Torres-Guerrero, H; Mondragón-Flores, R; Mondragón-Gonzalez, R; Becker, I; Gutiérrez-Kobeh, L; Aguirre-Garcia, M M

    2016-09-01

    Phosphatase activity of Leishmania spp. has been shown to deregulate the signalling pathways of the host cell. We here show that Leishmania mexicana promastigotes and amastigotes secrete proteins with phosphatase activity to the culture medium, which was higher in the Promastigote Secretion Medium (PSM) as compared with the Amastigote Secretion Medium (ASM) and was not due to cell lysis, since parasite viability was not affected by the secretion process. The biochemical characterization showed that the phosphatase activity present in PSM was higher in dephosphorylating the peptide END (pY) INASL as compared with the peptide RRA (pT)VA. In contrast, the phosphatase activity in ASM showed little dephosphorylating capacity for both peptides. Inhibition assays demonstrated that the phosphatase activity of both PSM and ASM was sensible only to protein tyrosine phosphatases inhibitors. An antibody against a protein phosphatase 2C (PP2C) of Leishmania major cross-reacted with a 44·9 kDa molecule in different cellular fractions of L. mexicana promastigotes and amastigotes, however, in PSM and ASM, the antibody recognized a protein about 70 kDa. By electron microscopy, the PP2C was localized in the flagellar pocket of amastigotes. PSM and ASM induced the production of tumor necrosis factor alpha, IL-1β, IL-12p70 and IL-10 in human macrophages. PMID:27220404

  10. Acute exposure to air pollution particulate matter aggravates experimental myocardial infarction in mice by potentiating cytokine secretion from lung macrophages.

    PubMed

    Marchini, Timoteo; Wolf, Dennis; Michel, Nathaly Anto; Mauler, Maximilian; Dufner, Bianca; Hoppe, Natalie; Beckert, Jessica; Jäckel, Markus; Magnani, Natalia; Duerschmied, Daniel; Tasat, Deborah; Alvarez, Silvia; Reinöhl, Jochen; von Zur Muhlen, Constantin; Idzko, Marco; Bode, Christoph; Hilgendorf, Ingo; Evelson, Pablo; Zirlik, Andreas

    2016-07-01

    Clinical, but not experimental evidence has suggested that air pollution particulate matter (PM) aggravates myocardial infarction (MI). Here, we aimed to describe mechanisms and consequences of PM exposure in an experimental model of MI. C57BL/6J mice were challenged with a PM surrogate (Residual Oil Fly Ash, ROFA) by intranasal installation before MI was induced by permanent ligation of the left anterior descending coronary artery. Histological analysis of the myocardium 7 days after MI demonstrated an increase in infarct area and enhanced inflammatory cell recruitment in ROFA-exposed mice. Mechanistically, ROFA exposure increased the levels of the circulating pro-inflammatory cytokines TNF-α, IL-6, and MCP-1, activated myeloid and endothelial cells, and enhanced leukocyte recruitment to the peritoneal cavity and the vascular endothelium. Notably, these effects on endothelial cells and circulating leukocytes could be reversed by neutralizing anti-TNF-α treatment. We identified alveolar macrophages as the primary source of elevated cytokine production after PM exposure. Accordingly, in vivo depletion of alveolar macrophages by intranasal clodronate attenuated inflammation and cell recruitment to infarcted tissue of ROFA-exposed mice. Taken together, our data demonstrate that exposure to environmental PM induces the release of inflammatory cytokines from alveolar macrophages which directly worsens the course of MI in mice. These findings uncover a novel link between air pollution PM exposure and inflammatory pathways, highlighting the importance of environmental factors in cardiovascular disease. PMID:27240856

  11. Acute exposure to air pollution particulate matter aggravates experimental myocardial infarction in mice by potentiating cytokine secretion from lung macrophages.

    PubMed

    Marchini, Timoteo; Wolf, Dennis; Michel, Nathaly Anto; Mauler, Maximilian; Dufner, Bianca; Hoppe, Natalie; Beckert, Jessica; Jäckel, Markus; Magnani, Natalia; Duerschmied, Daniel; Tasat, Deborah; Alvarez, Silvia; Reinöhl, Jochen; von Zur Muhlen, Constantin; Idzko, Marco; Bode, Christoph; Hilgendorf, Ingo; Evelson, Pablo; Zirlik, Andreas

    2016-07-01

    Clinical, but not experimental evidence has suggested that air pollution particulate matter (PM) aggravates myocardial infarction (MI). Here, we aimed to describe mechanisms and consequences of PM exposure in an experimental model of MI. C57BL/6J mice were challenged with a PM surrogate (Residual Oil Fly Ash, ROFA) by intranasal installation before MI was induced by permanent ligation of the left anterior descending coronary artery. Histological analysis of the myocardium 7 days after MI demonstrated an increase in infarct area and enhanced inflammatory cell recruitment in ROFA-exposed mice. Mechanistically, ROFA exposure increased the levels of the circulating pro-inflammatory cytokines TNF-α, IL-6, and MCP-1, activated myeloid and endothelial cells, and enhanced leukocyte recruitment to the peritoneal cavity and the vascular endothelium. Notably, these effects on endothelial cells and circulating leukocytes could be reversed by neutralizing anti-TNF-α treatment. We identified alveolar macrophages as the primary source of elevated cytokine production after PM exposure. Accordingly, in vivo depletion of alveolar macrophages by intranasal clodronate attenuated inflammation and cell recruitment to infarcted tissue of ROFA-exposed mice. Taken together, our data demonstrate that exposure to environmental PM induces the release of inflammatory cytokines from alveolar macrophages which directly worsens the course of MI in mice. These findings uncover a novel link between air pollution PM exposure and inflammatory pathways, highlighting the importance of environmental factors in cardiovascular disease.

  12. Cytokines associated with amyloid plaques in Alzheimer's disease brain stimulate human glial and neuronal cell cultures to secrete early complement proteins, but not C1-inhibitor.

    PubMed

    Veerhuis, R; Janssen, I; De Groot, C J; Van Muiswinkel, F L; Hack, C E; Eikelenboom, P

    1999-11-01

    Complement activation products C1q, C4c/d, and C3c/d in amyloid plaques in Alzheimer's disease probably result from direct binding and activation of C1 by amyloid beta peptides. RT-PCR and in situ hybridization studies have shown that several complement factors are produced in the brain parenchyma. In the present study, cytokines that can be detected in amyloid plaques (i.e., interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-alpha) were found to differentially stimulate the expression of C1 subcomponents, C1-Inhibitor (C1-Inh), C4, and C3, by astrocyte and microglial cell cultures derived from postmortem adult, human brain specimens and by neuroblastoma cell lines in culture. C1r and C1s were secreted at low levels by astrocytes and neuroblastoma cell lines. Exposure of cells to IL-1 alpha, IL-1 beta, TNF-alpha and to a far lesser extent IL-6, markedly upregulated C1r, C1s, and C3 production. C4 synthesis increased in response to interferon (IFN)-gamma and IL-6, whereas that of C1-Inh could be stimulated only by IFN-gamma. Thus, C1-Inh production is refractory to stimulation by plaque-associated cytokines, whereas these cytokines do stimulate C1r, C1s, and also C4 and C3 secretion by astrocytes and neuronal cells in culture. In contrast to the amyloid plaque associated cytokines IL-1 beta, IL-1 alpha, and TNF-alpha, the amyloid peptide A beta 1-42 itself did not stimulate C1r and C1s synthesis by astrocytes, microglial cells, or neuroblastoma cell lines. Microglial cells were the only cell type that constitutively expressed C1q. The ability of C1q to reassociate with newly formed C1r and C1s upon activation of C1 and subsequent inactivation by C1-Inh, may enable ongoing complement activation at sites of amyloid deposition, especially when C1-Inh is consumed and not replaced.

  13. Sasa borealis leaves extract improves insulin resistance by modulating inflammatory cytokine secretion in high fat diet-induced obese C57/BL6J mice.

    PubMed

    Yang, Jung-Hwa; Lim, Hyeon-Sook; Heo, Young-Ran

    2010-04-01

    Obesity is considered a mild inflammatory state, and the secretion of inflammation-related cytokines rises as adipose tissue expands. Inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), interlukin 6 (IL-6) and monocyte-chemoattractant protein 1 (MCP-1), are modulated by adipose tissue and known to play an important role in insulin resistance which is the common characteristics of obesity related disorders. In this study we analyzed the effects of Sasa borealis leaves extract on inflammatory cytokines and insulin resistance in diet induced obese C57/BL6J mice. The obese state was induced by a high fat diet for 20 weeks and then the mice were divided into two groups; obese control group (OBC, n = 7) and experimental group (OB-SBE, n = 7). The OBC group was fed a high fat diet and the OB-SBE group was fed a high fat diet containing 5% Sasa borealis leaves extract (SBE) for 12 weeks. We also used mice fed a standard diet as a normal control (NC, n = 7). The body weight and adipose tissue weight in the OB group were significantly higher than those in the NC group. The effects of the high fat diet were reduced by SBE treatments, and the body weight and adipose tissue deposition in the OB-SBE group were significantly decreased compared to the OBC group. The OBC group showed higher serum glucose and insulin levels which resulted in a significant increase of incremental area under the curve (IAUC) and HOMA-IR than the NC group. Also, serum leptin, TNF-alpha, and IL-6 levels were significantly higher in the OBC group than in the NC group. In contrast, the OB-SBE group showed a reversal in the metabolic defects, including a decrease in glucose, insulin, IAUC, HOMA-IR, TNF-alpha, IL-6 and leptin levels. These results suggest that BSE can suppress increased weight gain and/or fat deposition induced by a high fat diet and theses effects are accompanied by modulation of the inflammatory cytokines, TNF-alpha and IL-6 secretion resulting in improved insulin

  14. Sasa borealis leaves extract improves insulin resistance by modulating inflammatory cytokine secretion in high fat diet-induced obese C57/BL6J mice

    PubMed Central

    Yang, Jung-Hwa; Lim, Hyeon-Sook

    2010-01-01

    Obesity is considered a mild inflammatory state, and the secretion of inflammation-related cytokines rises as adipose tissue expands. Inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interlukin 6 (IL-6) and monocyte-chemoattractant protein 1 (MCP-1), are modulated by adipose tissue and known to play an important role in insulin resistance which is the common characteristics of obesity related disorders. In this study we analyzed the effects of Sasa borealis leaves extract on inflammatory cytokines and insulin resistance in diet induced obese C57/BL6J mice. The obese state was induced by a high fat diet for 20 weeks and then the mice were divided into two groups; obese control group (OBC, n = 7) and experimental group (OB-SBE, n = 7). The OBC group was fed a high fat diet and the OB-SBE group was fed a high fat diet containing 5% Sasa borealis leaves extract (SBE) for 12 weeks. We also used mice fed a standard diet as a normal control (NC, n = 7). The body weight and adipose tissue weight in the OB group were significantly higher than those in the NC group. The effects of the high fat diet were reduced by SBE treatments, and the body weight and adipose tissue deposition in the OB-SBE group were significantly decreased compared to the OBC group. The OBC group showed higher serum glucose and insulin levels which resulted in a significant increase of incremental area under the curve (IAUC) and HOMA-IR than the NC group. Also, serum leptin, TNF-α, and IL-6 levels were significantly higher in the OBC group than in the NC group. In contrast, the OB-SBE group showed a reversal in the metabolic defects, including a decrease in glucose, insulin, IAUC, HOMA-IR, TNF-α, IL-6 and leptin levels. These results suggest that BSE can suppress increased weight gain and/or fat deposition induced by a high fat diet and theses effects are accompanied by modulation of the inflammatory cytokines, TNF-α and IL-6 secretion resulting in improved insulin resistance. PMID

  15. Mycobacterium tuberculosis PE_PGRS17 Promotes the Death of Host Cell and Cytokines Secretion via Erk Kinase Accompanying with Enhanced Survival of Recombinant Mycobacterium smegmatis

    PubMed Central

    Chen, Tian; Zhao, Quanju; Li, Wu

    2013-01-01

    Tuberculosis (TB) remains a serious threat to global public health, largely due to the successful manipulation of the host immunity by its etiological agent Mycobacterium tuberculosis. The PE_PGRS protein family of M. tuberculosis might be a contributing factor. To investigate the roles of PE_PGRS17, the gene of PE_PGRS 17 was expressed in nonpathogenic fast growing Mycobacterium smegmatis. We found that the recombinant strain survives better than the control in macrophage cultures, accompanied by more host cell death and a marked higher secretion of tumor necrosis factor-alpha by a recombinant strain compared with control. Blocking the action of Erk kinase by an inhibitor can abolish the above effects. In brief, our data showed that PE_PGRS 17 might facilitate pathogen survival and disserve the host cell via remodeling the macrophages immune niche largely consisting of inflammatory cytokines. This furnishes a novel insight into the immune role of this mycobacterium unique gene family. PMID:23663047

  16. Novel innate immune functions for galectin-1: galectin-1 inhibits cell fusion by Nipah virus envelope glycoproteins and augments dendritic cell secretion of proinflammatory cytokines.

    PubMed

    Levroney, Ernest L; Aguilar, Hector C; Fulcher, Jennifer A; Kohatsu, Luciana; Pace, Karen E; Pang, Mabel; Gurney, Kevin B; Baum, Linda G; Lee, Benhur

    2005-07-01

    Galectin-1 (gal-1), an endogenous lectin secreted by a variety of cell types, has pleiotropic immunomodulatory functions, including regulation of lymphocyte survival and cytokine secretion in autoimmune, transplant disease, and parasitic infection models. However, the role of gal-1 in viral infections is unknown. Nipah virus (NiV) is an emerging pathogen that causes severe, often fatal, febrile encephalitis. The primary targets of NiV are endothelial cells. NiV infection of endothelial cells results in cell-cell fusion and syncytia formation triggered by the fusion (F) and attachment (G) envelope glycoproteins of NiV that bear glycan structures recognized by gal-1. In the present study, we report that NiV envelope-mediated cell-cell fusion is blocked by gal-1. This inhibition is specific to the Paramyxoviridae family because gal-1 did not inhibit fusion triggered by envelope glycoproteins of other viruses, including two retroviruses and a pox virus, but inhibited fusion triggered by envelope glycoproteins of the related Hendra virus and another paramyxovirus. The physiologic dimeric form of gal-1 is required for fusion inhibition because a monomeric gal-1 mutant had no inhibitory effect on cell fusion. gal-1 binds to specific N-glycans on NiV glycoproteins and aberrantly oligomerizes NiV-F and NiV-G, indicating a mechanism for fusion inhibition. gal-1 also increases dendritic cell production of proinflammatory cytokines such as IL-6, known to be protective in the setting of other viral diseases such as Ebola infections. Thus, gal-1 may have direct antiviral effects and may also augment the innate immune response against this emerging pathogen.

  17. Intranasal vaccination in mice with an attenuated Salmonella enterica Serovar 908htr A expressing Cp15 of Cryptosporidium: impact of malnutrition with preservation of cytokine secretion.

    PubMed

    Roche, James K; Rojo, Ana Lara; Costa, Lourrany B; Smeltz, Ronald; Manque, Patricio; Woehlbier, Ute; Bartelt, Luther; Galen, James; Buck, Gregory; Guerrant, Richard L

    2013-01-30

    Cryptosporidium is a protozoan parasite associated with acute and persistent diarrhea that, even in asymptomatic persons, can impair normal growth and potentially cognitive and physical development in young children. The recent availability of the complete gene sequence for Cryptosporidium hominis antigen Cp15 allows examination of innovative vaccine regimens involving intra-nasal antigen priming with live bacterial vectors applicable to human populations. We used a recently described weaned mouse model of cryptosporidiosis, where nourished and malnourished vaccinated mice receive the Cp15 antigen recombinant with cytolysinA on a Salmonella serovar Typhi CVD 908-htr A vector, followed by parenteral exposure to antigen with adjuvant. After challenge with Cryptosporidium oocysts via gavage, parameters of infection and disease (stool shedding of parasites, growth rates) were quantified, and serum/lymphoid tissue harvested to elucidate the Cp15-specific adaptive immune response. In vaccinated nourished mice, the regimen was highly immunogenic, with strong antigen-specific IL-6 and IFN-γ secretion and robust Cp15-specific immunoglobulin titers. In vaccinated malnourished mice, secretion of cytokines, particularly IFN-γ, and antigen-specific humoral immunity were generally undiminished despite protein deprivation and stunted growth. In contrast, after natural (oral) challenge with an identical inoculum of Cryptosporidium oocysts, cytokine and humoral responses to Cp15 were less than one-fourth those in vaccinated mice. Nevertheless, vaccination resulted in only transient reduction in stool shedding of parasites and was not otherwise protective against disease. Overall, immunogenicity for a C. hominis antigen was documented in mice, even in the setting of prolonged malnutrition, using an innovative vaccine regimen involving intra-nasal antigen priming with a live enteric bacterial vector, that has potential applicability to vulnerable human populations irrespective of

  18. Myrrh and artesunate modulate some Th1 and Th2 cytokines secretion in Schistosoma mansoni infected mice

    PubMed Central

    Abdelaziz, Mohamed M.

    2016-01-01

    The effects of artesunate and myrrh on S. mansoni infection and the levels of some Th1 and Th2 cytokines were evaluated in the present study. Six weeks after infection, a group of mice was treated with 4 mg/kg of artesunate and other group was treated with 10 mg/kg of myrrh for 3 successive days. Worm burden was reduced with a percentage of 53.7% and 58.78% after treatment with myrrh and artesunate respectively as well as the levels of IgG antibodies were significantly reduced compared with infected group. No obvious changes were observed in the level of interferon γ after treatment. After treatment with artesunate, interleukin 2 (IL-2) level was significantly decreased, while no significant difference was observed in myrrh-treated group compared with the infected group. On the other hand, the level of IL-10 was not significantly decreased after treatment with artesunate, but it was significantly increased after treatment with myrrh. However, IL-12 levels were significantly decreased after treatment with artesunate. The results demonstrated that, artesunate or myrrh treatment could give a level of protection against S. mansoni infection and modulate the levels of some Th1 and Th2 cytokines in mice infected with S. mansoni. PMID:27536198

  19. 1,25(OH)2D deficiency induces temporomandibular joint osteoarthritis via secretion of senescence-associated inflammatory cytokines.

    PubMed

    Shen, Ming; Luo, Yuqian; Niu, Yuming; Chen, Lulu; Yuan, Xiaoqin; Goltzman, David; Chen, Ning; Miao, Dengshun

    2013-08-01

    1,25-Dihydroxyvitamin D [1,25(OH)(2)D] insufficiency appears to be associated with several age-related diseases. Insufficient levels of serum 25-hydroxyvitamin D has been shown to lead to the progression of osteoarthritis (OA) while underlying biological mechanisms remain largely unknown. In this study, we sought to determine whether 1,25(OH)(2)D deficiency has a direct effect on the process of murine temporomandibular joint (TMJ) OA in 25-hydroxyvitamin D 1α-hydroxylase knockout [1α(OH)ase(-/-)] mice that had been fed a rescue diet (high calcium, phosphate, and lactose) from weaning until 6 or 18 months of age. Our results showed that the bone mineral density and subchondral bone volume were reduced in mandibular condyles, articular surfaces were collapsed, the thickness of articular cartilage and cartilage matrix protein abundance were progressively decreased and eventually led to an erosion of articular cartilage of mandibular condyles. We also found that DNA damage, cellular senescence and the production of senescence-associated inflammatory cytokines were increased significantly in 1α(OH)ase(-/-) mice. This study demonstrates that 1,25(OH)(2)D deficiency causes an erosive TMJ OA phenotype by inducing DNA damage, cellular senescence and the production of senescence-associated inflammatory cytokines. Our results indicate that 1,25(OH)(2)D plays an important role in preventing the development and progression of OA. PMID:23624390

  20. Mice Survival and Plasmatic Cytokine Secretion in a “Two Hit” Model of Sepsis Depend on Intratracheal Pseudomonas Aeruginosa Bacterial Load

    PubMed Central

    Restagno, Damien; Venet, Fabienne; Paquet, Christian; Freyburger, Ludovic; Allaouchiche, Bernard; Monneret, Guillaume; Bonnet, Jeanne-Marie; Louzier, Vanessa

    2016-01-01

    Sepsis is characterized by pro- and anti-inflammatory responses following infection. While inflammation is responsible for widespread organ damage, anti-inflammatory mediators lead to immunoparalysis increasing susceptibility to secondary infections (nosocomial pneumonia). We aimed to investigate the impact of bacterial load on survival and cytokine release in a two-hit murine (C57BL/6J) model of CLP followed by P. aeruginosa pneumonia. Plasmatic TNFα, IL-6, IL-10, sTNFr I and II were quantified until 13 days. At D5, splenocytes were processed for immunological assays or mice were intratracheally instilled with Pseudomonas aeruginosa (5.106, 2.107 and 108 CFU) to evaluate survival and cytokines production. TNFα, sTNFrs, IL-6 and IL-10 increased 2h post CLP. TNFα and sTNFrs declined respectively one and two days later. In CLP mice, IL-6 and IL-10 remained high for the whole experiment, as compared to Sham. At D5, for CLP mice, whereas total T cells population (CD3+) decreased, Treg fraction (CD4+/CD25+) increased. In parallel, T cells proliferation and LPS-stimulated splenocytes ability to release TNFα decreased. At D13, survival was 100% after 5.106 CFU, 50% for CLP mice after 2.107 CFU and 0% for CLP and Sham after 108 CFU. After instillation, IL-10 and IL-6 increased and appeared to be dose and time dependent. Pseudomonas was detected in all CLP and Sham’s lungs; in spleen and liver only in CLP at 2.107 CFU, and in CLP and Sham at 108 CFU. We demonstrated that post-CLP immunosuppression followed by Pseudomonas aeruginosa lung instillation increases mortality reactivates cytokines secretion and is associated with systemic dissemination in septic mice depending on bacterial load. PMID:27574993

  1. Identification of cytokine-induced modulation of microRNA expression and secretion as measured by a novel microRNA specific qPCR assay

    PubMed Central

    Benes, Vladimir; Collier, Paul; Kordes, Claus; Stolte, Jens; Rausch, Tobias; Muckentaler, Martina U.; Häussinger, Dieter; Castoldi, Mirco

    2015-01-01

    microRNAs are an abundant class of small non-coding RNAs that control gene expression post-transcriptionally. Importantly, microRNA activity participates in the regulation of cellular processes and is a potentially valuable source of biomarkers in the diagnosis and prognosis of human diseases. Here we introduce miQPCR, an innovative method to quantify microRNAs expression by using Real-Time PCR. miQPCR exploits T4 RNA ligase activities to extend uniformly microRNAs’ 3′-ends by addition of a linker-adapter. The adapter is then used as ‘anchor’ to prime cDNA synthesis and throughout qPCR to amplify specifically target amplicons. miQPCR is an open, adaptable and cost-effective procedure, which offers the following advantages; i) universal elongation and reverse transcription of all microRNAs; ii) Tm-adjustment of microRNA-specific primers; iii) high sensitivity and specificity in discriminating among closely related sequences and; iv) suitable for the analysis of cellular and cell-free circulating microRNAs. Analysis of cellular and cell-free circulating microRNAs secreted by rat primary hepatocytes stimulated with cytokines and growth factors identifies for the first time a widespread modulation of both microRNAs expression and secretion. Altogether, our findings suggest that the pleiotropic activity of humoral factors on microRNAs may extensively affect liver function in response to injury and regeneration. PMID:26108880

  2. IL-33-Induced Cytokine Secretion and Survival of Mouse Eosinophils Is Promoted by Autocrine GM-CSF

    PubMed Central

    Willebrand, Ralf; Voehringer, David

    2016-01-01

    Eosinophils are major effector cells during allergic responses and helminth infections. Recent studies further highlight eosinophils as important players in many other biological processes. Therefore it is important to understand how these cells can be modulated in terms of survival and effector function. In the present study we investigated how eosinophils respond to the alarmin IL-33. We show that IL-33 promotes eosinophil survival in a ST2- and MyD88-dependent manner. IL-33-mediated protection from apoptosis was dependent on autocrine GM-CSF release. In addition, GM-CSF increased the IL-33-induced secretion of IL-4 and IL-13 from eosinophils. Unexpectedly, this effect was further enhanced by cross-linking of Siglec-F, a proposed inhibitory and apopotosis-inducing receptor on eosinophils. Co-culture experiments with eosinophils and macrophages revealed that the IL-33-induced release of IL-4 and IL-13 from eosinophils was required for differentiation of alternatively activated macrophages (AAMs). The differentiation of AAMs could be further increased in the presence of GM-CSF. These results indicate that cross-talk between Siglec-F and the receptors for IL-33, LPS and GM-CSF plays an important role for efficient secretion of IL-4 and IL-13. Deciphering the molecular details of this cross-talk could lead to the development of new therapeutic option to treat eosinophil-associated diseases. PMID:27690378

  3. JAK inhibition induces silencing of T Helper cytokine secretion and a profound reduction in T regulatory cells.

    PubMed

    Keohane, Clodagh; Kordasti, Shahram; Seidl, Thomas; Perez Abellan, Pilar; Thomas, Nicholas S B; Harrison, Claire N; McLornan, Donal P; Mufti, Ghulam J

    2015-10-01

    CD4(+) T cells maintain cancer surveillance and immune tolerance. Chronic inflammation has been proposed as a driver of clonal evolution in myeloproliferative neoplasms (MPN), suggesting that T cells play an important role in their pathogenesis. Treatment with JAK inhibitors (JAKi) results in improvements in MPN-associated constitutional symptoms as well as reductions in splenomegaly. However, effects of JAKi on T cells in MPN are not well established and the baseline immune signature remains unclear. We investigated the frequency and function of CD4(+) T cell subsets in 50 MPN patients at baseline as well as during treatment with either ruxolitinib or fedratinib in a subset. We show that CD4(+)  CD127(low)  CD25(high)  FOXP3(+) T regulatory cells are reduced in MPN patients compared to healthy controls and that this decrease is even more pronounced following JAKi therapy. Moreover, we show that after 6 months of treatment the number of T helper (Th)-17 cells increased. We also describe a functional 'silencing' of T helper cells both in vivo and in vitro and a blockade of pro-inflammatory cytokines from these cells. This profound effect of JAKi on T cell function may underlay augmented rates of atypical infections that have been reported with use of these drugs.

  4. 1,25(OH)2D3 Deficiency Induces Colon Inflammation via Secretion of Senescence-Associated Inflammatory Cytokines

    PubMed Central

    Zhi, Chunchun; Shen, Ming; Sun, Weiwei; Miao, Dengshun; Yuan, Xiaoqin

    2016-01-01

    Epidemiological studies showed that 1,25-Dihydroxyvitamin D[1,25(OH)2D3] insufficiency appears to be associated with aging and colon cancer while underlying biological mechanisms remain largely unknown. Inflammatory bowel disease is one of the risk factors for colon cancer. In this study, we investigated whether 1,25(OH)2D3 deficiency has an impact on the colon of 25-hydroxyvitamin D 1α-hydroxylase knockout [Cyp27b1−/−] mice fed on a rescue diet (high calcium, phosphate, and lactose) from weaning to 10 months of age. We found that 1,25(OH)2D3 deficient mice displayed significant colon inflammation phenotypes including shortened colon length, thinned and disordered mucosal structure, and inflammatory cell infiltration. DNA damage, cellular senescence and the production of senescence-associated inflammatory cytokines were also increased significantly in the colon of Cyp27b1−/−mice. Furthermore, the levels of ROS in the colon were increased significantly, whereas the expression levels of antioxidative genes were down-regulated dramatically in the colon of Cyp27b1−/−mice. Taken together, our results demonstrated that 1,25(OH)2D3 deficiency could induce colon inflammation, which may result from increased oxidative stress and DNA damage, subsequently, induced cell senescence and overproduction of senescence-associated secretory factors. Therefore, our findings suggest that 1,25(OH)2D3 may play an important role in preventing the development and progression of colon inflammation and colon cancer. PMID:26790152

  5. Intraperitoneal injection of tetracyclines protects mice from lethal endotoxemia downregulating inducible nitric oxide synthase in various organs and cytokine and nitrate secretion in blood.

    PubMed Central

    Milano, S; Arcoleo, F; D'Agostino, P; Cillari, E

    1997-01-01

    We have tested whether tetracyclines (TETs) are able to protect mice from lipopolysaccharide (LPS)-induced shock, a cytokine-mediated inflammatory reaction. Mice, injected with a single dose of tetracycline base (TETb; 1.5, 10 and 20 mg/kg of body weight) or doxycycline (DOXY; 1.5 mg/kg), were significantly protected from a lethal intraperitoneal injection of LPS (500 micrograms per mouse). TETs acted in early events triggered in response to LSP; in fact, they were no longer significantly protective if injected more than 1 h after the injection of endotoxin. LPS-treated mice protected by TETs showed a significant inhibition of tumor necrosis factor alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha), and nitrate secretion in the blood, events that were directly related with the survival. In mice treated with TETs a significant decrease of inducible nitric oxide synthase (iNOS) activity was observed in spleen and peritoneal cells compared with that detected in mice treated with LPS alone. Furthermore, TETs were found to inhibit NO synthesis by peritoneal macrophages stimulated in vitro with LPS. On the contrary, TETs were unable to decrease the ability of the macrophages to synthesize IL-1 alpha and TNF-alpha in vitro. These results indicate that TETs are not able to act directly on the synthesis of these cytokines, but they may modulate other pathways that could in turn be responsible for the inhibition of IL-1 alpha and TNF-alpha synthesis. Altogether, these results indicate that TETs are advantageous candidates for the prophylaxis and treatment of septic shock in mice, having both antimicrobial activity and the ability to inhibit endogenous TNF-alpha, IL-1 alpha, and iNOS, hence, exerting, potent anti-inflammatory effects. PMID:8980766

  6. Giardia duodenalis stimulates partial maturation of bovine dendritic cells associated with altered cytokine secretion and induction of T-cell proliferation.

    PubMed

    Grit, G H; Devriendt, B; Van Coppernolle, S; Geurden, T; Hope, J; Vercruysse, J; Cox, E; Geldhof, P; Claerebout, E

    2014-04-01

    Giardia duodenalis is an important intestinal parasite in animals and humans. The role of dendritic cells (DC) in the initiation of the immune response against G. duodenalis is poorly documented. The aim of this study was to test the hypothesis that G. duodenalis interferes with bovine DC function. Therefore, the effect of trophozoites and excretion/secretion products on bovine monocyte-derived dendritic cells (MoDC) was investigated. We assessed MoDC maturation and cytokine production of G. duodenalis-stimulated MoDC and the ability of these MoDC to take up antigen and induce lymphocyte proliferation. Little or no upregulation of maturation markers CD40 and CD80 was measured, but MHCII expression was increased after stimulation with low parasite concentrations. A dose-dependent decrease in ovalbumin uptake was observed in G. duodenalis-stimulated MoDC. In addition, stimulated MoDC induced proliferation of CD3(-) , γδ-T-cells and TCRαβ(+) CD4(+) and CD8(+) T-cells. Increased transcription of TGF-β was shown in CD4(+) T cells, and increased TNF-α, TGF-β, IL-10 and IL-4 were seen in γδ-T-cells. We found no evidence that G. duodenalis has a regulatory or inhibitory effect on bovine MoDC. MoDC stimulated with G. duodenalis are functionally active and able to induce proliferation of T cells that produce both pro- and anti-inflammatory cytokines.

  7. Key role of regulated upon activation normal T-cell expressed and secreted, nonstructural protein1 and myeloperoxidase in cytokine storm induced by influenza virus PR-8 (A/H1N1) infection in A549 bronchial epithelial cells.

    PubMed

    Phung, Thuy Thi Bich; Sugamata, Ryuichi; Uno, Kazuko; Aratani, Yasuaki; Ozato, Keiko; Kawachi, Shoji; Thanh Nguyen, Liem; Nakayama, Toshinori; Suzuki, Kazuo

    2011-12-01

    Influenza virus infection causes severe respiratory disease such as that due to avian influenza (H5N1). Influenza A viruses proliferate in human epithelial cells, which produce inflammatory cytokines/chemokines as a "cytokine storm" attenuated with the viral nonstructural protein 1 (NS1). Cytokine/chemokine production in A549 epithelial cells infected with influenza A/H1N1 virus (PR-8) or nonstructural protein 1 (NS1) plasmid was examined in vitro. Because tumor necrosis factor-α (TNF-α) and regulated upon activation normal T-cell expressed and secreted (RANTES) are predominantly produced from cells infected with PR-8 virus, the effects of mRNA knockdown of these cytokines were investigated. Small interfering (si)TNF-α down-regulated RANTES expression and secretion of RANTES, interleukin (IL)-8, and monocyte chemotactic protein-1 (MCP-1). In addition, siRANTES suppressed interferon (IFN)-γ expression and secretion of RANTES, IL-8, and MCP-1, suggesting that TNF-α stimulates production of RANTES, IL-8, MCP-1, and IFN-γ, and RANTES also increased IL-8, MCP-1, and IFN-γ. Furthermore, administration of TNF-α promoted increased secretion of RANTES, IL-8, and MCP-1. Administration of RANTES enhanced IL-6, IL-8, and MCP-1 production without PR-8 infection. These results strongly suggest that, as an initial step, TNF-α regulates RANTES production, followed by increase of IL-6, IL-8, and MCP-1 and IFNs concentrations. At a later stage, cells transfected with viral NS1 plasmid showed production of a large amount of IL-8 and MCP-1 in the presence of the H(2)O(2)-myeloperoxidse (MPO) system, suggesting that NS1 of PR-8 may induce a "cytokine storm" from epithelial cells in the presence of an H(2)O(2)-MPO system.

  8. Synergistic Effect of Bolus Exposure to Zinc Oxide Nanoparticles on Bleomycin-Induced Secretion of Pro-Fibrotic Cytokines without Lasting Fibrotic Changes in Murine Lungs

    PubMed Central

    Wu, Wenting; Ichihara, Gaku; Hashimoto, Naozumi; Hasegawa, Yoshinori; Hayashi, Yasuhiko; Tada-Oikawa, Saeko; Suzuki, Yuka; Chang, Jie; Kato, Masashi; D’Alessandro-Gabazza, Corina N.; Gabazza, Esteban C.; Ichihara, Sahoko

    2014-01-01

    Zinc oxide (ZnO) nanoparticles are widely used in various products, and the safety evaluation of this manufactured material is important. The present study investigated the inflammatory and fibrotic effects of pulmonary exposure to ZnO nanoparticles in a mouse model of pulmonary fibrosis. Pulmonary fibrosis was induced by constant subcutaneous infusion of bleomycin (BLM). Female C57BL/6Jcl mice were divided into BLM-treated and non-treated groups. In each treatment group, 0, 10, 20 or 30 µg of ZnO nanoparticles were delivered into the lungs through pharyngeal aspiration. Bronchoalveolar lavage fluid (BALF) and the lungs were sampled at Day 10 or 14 after administration. Pulmonary exposure by a single bolus of ZnO nanoparticles resulted in severe, but transient inflammatory infiltration and thickening of the alveolar septa in the lungs, along with the increase of total and differential cell counts in BLAF. The BALF level of interleukin (IL)-1β and transforming growth factor (TGF)-β was increased at Day 10 and 14, respectively. At Day 10, the synergistic effect of BLM and ZnO exposure was detected on IL-1β and monocyte chemotactic protein (MCP)-1 in BALF. The present study demonstrated the synergistic effect of pulmonary exposure to ZnO nanoparticles and subcutaneous infusion of BLM on the secretion of pro-fibrotic cytokines in the lungs. PMID:25561223

  9. PCNA-interacting peptides reduce Akt phosphorylation and TLR-mediated cytokine secretion suggesting a role of PCNA in cellular signaling.

    PubMed

    Olaisen, Camilla; Müller, Rebekka; Nedal, Aina; Otterlei, Marit

    2015-07-01

    Proliferating cell nuclear antigen (PCNA), commonly known as a nuclear protein essential for regulation of DNA replication, DNA repair, and epigenetics, has recently been associated with multiple cytosolic functions. Many proteins containing one of the two known PCNA-interacting motifs, the AlkB homologue 2 PCNA interacting motif (APIM) and the PCNA-interacting peptide (PIP)-box, are considered to be mainly cytosolic. APIM is found in more than 20 kinases and/or associated proteins including several direct or indirect members of the mitogen-activated protein kinase (MAPK) and PI3K/Akt pathways. Mass spectrometry analysis of PCNA-pull downs verified that many cytosolic proteins involved in the MAPK and PI3K/Akt pathways are in complex with PCNA. Furthermore, treatment of cells with a PCNA-interacting APIM-containing peptide (APIM-peptide) reduced Akt phosphorylation in human peripheral blood monocytes and a human keratinocyte cell line (HaCaT). Additionally, the APIM-peptide strongly reduced the cytokine secretion from monocytes stimulated with toll like receptor (TLR) ligands and potentiated the effects of MAPK and PI3K/Akt inhibitors. Interestingly, the protein level of the APIM-containing PKR/RIG-1 activator protein (PACT) was initially strongly reduced in HaCaT cells stimulated with APIM-peptide in combination with the TLR ligand polyinosinic-polycytidylic acid (polyIC). Our results suggest that PCNA has a platform role in cytosol affecting cellular signaling.

  10. Abnormal secretion of reproductive hormones and antioxidant status involved in quinestrol-induced reproductive toxicity in adult male rat.

    PubMed

    Li, Jian; Wang, Hongwei; Zhang, Jiliang; Zhou, Bianhua; Si, Lifang; Wei, Lan; Li, Xiang

    2014-02-01

    This study aimed to evaluate the effects of quinestrol, a synthetic oestrogen homologue with reproductive toxicity, on the secretion of reproductive hormones and antioxidant status in adult male rat. Our results showed that quinestrol exposure significantly decreased the weight of the testis, epididymides, seminal vesicle, and prostate, as well as the sperm counts in the cauda epididymis of rats. Quinestrol significantly reduced the size of seminiferous tubules and the total number of spermatogenic cells. Serum testosterone, follitropin, and lutropin were also significantly reduced in a dose-related manner after quinestrol exposure. Meanwhile, the activity of superoxide dismutase, glutathione peroxidase, and total antioxide capacity significantly decreased, whereas the malondialdehyde and nitric oxide concentrations significantly increased in the testes. These findings revealed that endocrine disorders of reproductive hormones and oxidative stress may be involved in reproductive toxicity induced by quinestrol in adult male rats. PMID:24183492

  11. Arsenic induced overexpression of inflammatory cytokines based on the human urothelial cell model in vitro and urinary secretion of individuals chronically exposed to arsenic.

    PubMed

    Liu, Shengnan; Sun, Qingshan; Wang, Fei; Zhang, Lin; Song, Yingli; Xi, Shuhua; Sun, Guifan

    2014-11-17

    Chronic persistent inflammation could play an important role in the pathogenesis of some malignancies, and inflammation is a critical factor for bladder cancer development. In this study, we measured urine levels of transforming growth factor-α (TGF-α), tumor necrosis factor-α (TNF-α), and IL-8 in arsenic exposure workers and expressions of inflammatory cytokines in human urothelial cells in vivo and in vitro. We found the concentrations of IL-8, TNF-α, and TGF-α presented in urine were significantly elevated in the high urinary arsenic workers compared with the low urinary arsenic workers. Multiple regression analysis showed that the urinary IL-8 level was significantly positively associated with urinary iAs concentration after adjusting for the confounding effects of age, employed years, body mass index (BMI), smoking, alcohol, and seafood consumption in recent 3 days. Urinary TNF-α and TGF-α levels were also significantly positively associated with urinary iAs concentration, and SMI. TGF-α level was negatively associated with age after adjusting for the confounding effects. Consistent with the results in vivo, mRNA expressions of TNF-α, TGF-α, and IL-8 and protein expressions of TGF-α, TGF-β1, and IL-8 were significantly elevated in SV-HUC-1 cells after exposure to lower concentrations of arsenite for 24h as compared to the control group. These data indicated that arsenic increased the secretion of inflammatory factors and IL-8, TNF-α, and TGF-α expression may be a useful biomarker of the effect of arsenic exposure. PMID:25257954

  12. Expression of the calcium sensing receptor in human peripheral blood T lymphocyte and its contribution to cytokine secretion through MAPKs or NF-κB pathways.

    PubMed

    Li, Tingting; Sun, Mingrui; Yin, Xin; Wu, Chunli; Wu, Qiuyue; Feng, Shanli; Li, Hong; Luan, Ying; Wen, Jie; Yan, Lixin; Zhao, Binhui; Xu, Changqing; Sun, Yihua

    2013-04-01

    The calcium-sensing receptor (CaSR) has been reported to play an important role in many tissues and organs. However, studies about the expression and function of CaSR in T lymphocytes are still not very lucid. In this study, we investigated the above-mentioned issues using RT-PCR, immunofluorescence staining, Western blotting, and the ELISA techniques. We found that the CaSR protein was expressed, and mainly located in the membrane in the normal human peripheral blood T lymphocytes. GdCl(3) (an agonist of CaSR) increased the dose-dependency of the CaSR expression, which was abolished by NPS2390 (an inhibitor of CaSR). GdCl(3) and Ca(2+) increased the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 (one subgroup of MAPKs) and P65 (subunit of NF-κB),but, they had no significant effects on the JNK and P38 subgroups of MAPKs. Meantime, GdCl(3) and Ca(2+) stimulated both the IL-6 and TNF-β releases and their mRNA expressions. However, these effects of GdCl(3) and Ca(2+) were inhibited by NPS2390, U0126 (MAPKs pathway inhibitor) or Bay-11-7082 (NF-κB pathway inhibitor). These results suggested that CaSR was functionally expressed in the T cells, and the activated CaSR contributed to the cytokine secretion through the partial MAPK and NF-κB pathways.

  13. Arsenic induced overexpression of inflammatory cytokines based on the human urothelial cell model in vitro and urinary secretion of individuals chronically exposed to arsenic.

    PubMed

    Liu, Shengnan; Sun, Qingshan; Wang, Fei; Zhang, Lin; Song, Yingli; Xi, Shuhua; Sun, Guifan

    2014-11-17

    Chronic persistent inflammation could play an important role in the pathogenesis of some malignancies, and inflammation is a critical factor for bladder cancer development. In this study, we measured urine levels of transforming growth factor-α (TGF-α), tumor necrosis factor-α (TNF-α), and IL-8 in arsenic exposure workers and expressions of inflammatory cytokines in human urothelial cells in vivo and in vitro. We found the concentrations of IL-8, TNF-α, and TGF-α presented in urine were significantly elevated in the high urinary arsenic workers compared with the low urinary arsenic workers. Multiple regression analysis showed that the urinary IL-8 level was significantly positively associated with urinary iAs concentration after adjusting for the confounding effects of age, employed years, body mass index (BMI), smoking, alcohol, and seafood consumption in recent 3 days. Urinary TNF-α and TGF-α levels were also significantly positively associated with urinary iAs concentration, and SMI. TGF-α level was negatively associated with age after adjusting for the confounding effects. Consistent with the results in vivo, mRNA expressions of TNF-α, TGF-α, and IL-8 and protein expressions of TGF-α, TGF-β1, and IL-8 were significantly elevated in SV-HUC-1 cells after exposure to lower concentrations of arsenite for 24h as compared to the control group. These data indicated that arsenic increased the secretion of inflammatory factors and IL-8, TNF-α, and TGF-α expression may be a useful biomarker of the effect of arsenic exposure.

  14. Cetuximab Reconstitutes Pro-Inflammatory Cytokine Secretions and Tumor-Infiltrating Capabilities of sMICA-Inhibited NK Cells in HNSCC Tumor Spheroids

    PubMed Central

    Klöss, Stephan; Chambron, Nicole; Gardlowski, Tanja; Weil, Sandra; Koch, Joachim; Esser, Ruth; Pogge von Strandmann, Elke; Morgan, Michael A.; Arseniev, Lubomir; Seitz, Oliver; Köhl, Ulrike

    2015-01-01

    Immunosuppressive factors, such as soluble major histocompatibility complex class I chain-related peptide A (sMICA) and transforming growth factor beta 1 (TGF-β1), are involved in tumor immune escape mechanisms (TIEMs) exhibited by head and neck squamous cell carcinomas (HNSCCs) and may represent opportunities for therapeutic intervention. In order to overcome TIEMs, we investigated the antibody-dependent cellular cytotoxicity (ADCC), cytokine release and retargeted tumor infiltration of sMICA-inhibited patient NK cells expressing Fcγ receptor IIIa (FcγRIIIa, CD16a) in the presence of cetuximab, an anti-epidermal growth factor receptor (HER1) monoclonal antibody (mAb). Compared to healthy controls, relapsed HNSCC patients (n = 5), not currently in treatment revealed decreased levels of circulating regulatory NK cell subsets in relation to increased cytotoxic NK cell subpopulations. Elevated sMICA and TGF-β1 plasma levels correlated with diminished TNFα and IFN-γ release and decreased NKG2D (natural killer group 2 member D)-dependent killing of HNSCC cells by NK cells. Incubation of IL-2-activated patient NK cells with patient plasma containing elevated sMICA or sMICA analogs (shed MICA and recombinant MICA) significantly impaired NKG2D-mediated killing by down-regulation of NKG2D surface expression. Of note, CD16 surface expression levels, pro-apoptotic and activation markers, and viability of patient and healthy donor NK cell subpopulations were not affected by this treatment. Accordingly, cetuximab restored killing activity of sMICA-inhibited patient NK cells against cetuximab-coated primary HNSCC cells via ADCC in a dose-dependent manner. Rapid reconstitution of anti-tumor recognition and enhanced tumor infiltration of treated NK cells was monitored by 24 h co-incubation of HNSCC tumor spheroids with cetuximab (1 μg/ml) and was characterized by increased IFN-γ and TNFα secretion. This data show that the impaired NK cell-dependent tumor

  15. Inhibition of Viability, Proliferation, Cytokines Secretion, Surface Antigen Expression, and Adipogenic and Osteogenic Differentiation of Adipose-Derived Stem Cells by Seven-Day Exposure to 0.5 T Static Magnetic Fields.

    PubMed

    Wang, Jian; Xiang, Bo; Deng, Jixian; Freed, Darren H; Arora, Rakesh C; Tian, Ganghong

    2016-01-01

    After seven-day exposure to 0.5-Tesla Static Magnetic Field (SMF), Adipose-derived Stem Cells (ASCs) and those labeled by superparamagnetic iron oxide (SPIO) nanoparticles were examined for viability by methyl thiazol tetrazolium (MTT) assay, proliferation by cell counting and bromodeoxyuridine (BrdU) incorporation, DNA integrity by single cell gel electrophoresis, surface antigen by flow cytometry analysis, and the expression of cytokines and genetic markers by reverse transcription-PCR and underwent adipogenic and osteogenic differentiation assessed by quantifying related specific genes expression. The SMF slightly reduced cell viability and proliferation and inhibited the expression of CD49d, CD54, and CD73 but did not damage DNA integrity. The SMF slightly downregulated the expression of cytokines including Vascular Endothelial Growth Factor (VEGF), Insulin-like Growth Factor-1 (IGF-1), Transforming Growth Factor Beta 1 (TGF-β1), genetic markers comprising Stem Cell Antigen-1 (Sca1), Octamer-4 (Oct-4), ATP-binding Cassette Subfamily B Member 1 (ABCB1), adipogenic marker genes containing Lipoprotein Lipase (LPL), Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ), and osteogenic marker genes including Secreted Phosphor-protein 1 (SPP1) and Osterix (OSX). Exposure to 0.5 T SMF for seven days inhibited viability, proliferation, surface antigen expression, cytokine secretion, stem cell genetic marker expression, and adipogenic and osteogenic differentiation but did not affect the DNA integrity in ASCs with or without SPIO labeling. PMID:26880984

  16. Inhibition of Viability, Proliferation, Cytokines Secretion, Surface Antigen Expression, and Adipogenic and Osteogenic Differentiation of Adipose-Derived Stem Cells by Seven-Day Exposure to 0.5 T Static Magnetic Fields

    PubMed Central

    Wang, Jian; Xiang, Bo; Deng, Jixian; Freed, Darren H.; Arora, Rakesh C.; Tian, Ganghong

    2016-01-01

    After seven-day exposure to 0.5-Tesla Static Magnetic Field (SMF), Adipose-derived Stem Cells (ASCs) and those labeled by superparamagnetic iron oxide (SPIO) nanoparticles were examined for viability by methyl thiazol tetrazolium (MTT) assay, proliferation by cell counting and bromodeoxyuridine (BrdU) incorporation, DNA integrity by single cell gel electrophoresis, surface antigen by flow cytometry analysis, and the expression of cytokines and genetic markers by reverse transcription-PCR and underwent adipogenic and osteogenic differentiation assessed by quantifying related specific genes expression. The SMF slightly reduced cell viability and proliferation and inhibited the expression of CD49d, CD54, and CD73 but did not damage DNA integrity. The SMF slightly downregulated the expression of cytokines including Vascular Endothelial Growth Factor (VEGF), Insulin-like Growth Factor-1 (IGF-1), Transforming Growth Factor Beta 1 (TGF-β1), genetic markers comprising Stem Cell Antigen-1 (Sca1), Octamer-4 (Oct-4), ATP-binding Cassette Subfamily B Member 1 (ABCB1), adipogenic marker genes containing Lipoprotein Lipase (LPL), Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ), and osteogenic marker genes including Secreted Phosphor-protein 1 (SPP1) and Osterix (OSX). Exposure to 0.5 T SMF for seven days inhibited viability, proliferation, surface antigen expression, cytokine secretion, stem cell genetic marker expression, and adipogenic and osteogenic differentiation but did not affect the DNA integrity in ASCs with or without SPIO labeling. PMID:26880984

  17. Cytokines in psoriasis

    PubMed Central

    Baliwag, Jaymie; Barnes, Drew H.; Johnston, Andrew

    2015-01-01

    Psoriasis is a common inflammatory skin disease with an incompletely understood etiology. The disease is characterized by red, scaly and well-demarcated skin lesions formed by the hyperproliferation of epidermal keratinocytes. This hyperproliferation is driven by cytokines secreted by activated resident immune cells, an infiltrate of T cells, dendritic cells and cells of the innate immune system, as well as the keratinocytes themselves. Psoriasis has a strong hereditary character and has a complex genetic background. Genome-wide association studies have identified polymorphisms within or near a number of genes encoding cytokines, cytokine receptors or elements of their signal transduction pathways, further implicating these cytokines in the psoriasis pathomechanism. A considerable number of inflammatory cytokines have been shown to be elevated in lesional psoriasis skin, and the serum concentrations of a subset of these also correlate with psoriasis disease severity. The combined effects of the cytokines found in psoriasis lesions likely explain most of the clinical features of psoriasis, such as the hyperproliferation of keratinocytes, increased neovascularization and skin inflammation. Thus, understanding which cytokines play a pivotal role in the disease process can suggest potential therapeutic targets. A number of cytokines have been therapeutically targeted with success, revolutionizing treatment of this disease. Here we review a number of key cytokines implicated in the pathogenesis of psoriasis. PMID:25585875

  18. MicroRNA-146a-5p Negatively Regulates Pro-Inflammatory Cytokine Secretion and Cell Activation in Lipopolysaccharide Stimulated Human Hepatic Stellate Cells through Inhibition of Toll-Like Receptor 4 Signaling Pathways

    PubMed Central

    Chen, Yuhan; Zeng, Zhaochong; Shen, Xiaoyun; Wu, Zhifeng; Dong, Yinying; Cheng, Jason Chia-Hsien

    2016-01-01

    Lipopolysaccharide (LPS)/toll-like receptor 4 (TLR4) signaling pathway is demonstrated to be involved in the hepatic fibrosis. MicroRNA (miR)-146a-5p is a key regulator of the innate immune response. The functional significance of miR-146a-5p during the LPS/TLR4 mediated hepatic fibrosis process remains unclear. In this study, we found that TLR4 and α-smooth muscle actin (α-SMA) were up-regulated and miR-146a-5p was down-regulated in human hepatic stellate cell (HSC) line LX2 after LPS stimulation. Overexpression of miR-146a-5p inhibited LPS induced pro-inflammatory cytokines secretion through down-regulating the expression levels of TLR-4, IL-1 receptor-associated kinase 1 (IRAK1), TNF receptor associated factor-6 (TRAF6) and phosphorylation of nuclear factor-kappa B (NF-κB). Knockdown of IRAK1 and TRAF6 also suppressed pro-inflammatory cytokine production by inhibiting NF-κB phosphorylation. In addition, miR-146a-5p mimic blocked LPS induced TRAF6 dependent c-Jun N-terminal kinase (JNK) and Smad2 activation as well as α-SMA production. Taken together, these results suggest that miR-146a-5p suppresses pro-inflammatory cytokine secretion and cell activation of HSC through inhibition of TLR4/NF-κB and TLR4/TRAF6/JNK pathway. PMID:27399683

  19. IL-17-producing CD8+ T lymphocytes from psoriasis skin plaques are cytotoxic effector cells that secrete Th17-related cytokines.

    PubMed

    Ortega, Consuelo; Fernández-A, Silvia; Carrillo, Juan M; Romero, Pilar; Molina, Ignacio J; Moreno, José C; Santamaría, Manuel

    2009-08-01

    IL-17-producing CD4+ T lymphocytes (Th17) are currently considered relevant participants in the pathogenesis of psoriasis skin lesions. However, little is known about the potential role of IL-17-producing CD8+ T cells, which are also present at the psoriatic plaque. We have addressed the functional characterization of this CD8+ subtype of T lymphocytes from psoriasis patients. Our results show that CD8+IL-17+ cells from psoriasis-inflamed skin tissue produce TNF-alpha and IFN-gamma (Th1-related cytokines) as well as IL-17, IL-21, and IL-22 (Th17-related cytokines) efficiently. A significant up-regulation of the RORC transcription factor is also observed. These cells are refractory to Tregs but show a proliferative response to anti-CD3/CD28 stimulation that is enhanced by IL-12 and IL-15. Blocking of TNF-alpha activity inhibits TCR-mediated activation and IL-17 production. CD8+IL-17+ T cells are cytotoxic cells that display TCR/CD3-mediated cytotoxic abilities to kill target cells. Thus, CD8+IL-17+ T cells share some key features with Th17 cells and exhibit remarkable differential abilities attributable to the CD8+ lineage of T lymphocytes, adding new insights into the functional resources of IL-17-producing cells from human epidermis that could be of potential interest to our understanding of the pathogenesis of psoriasis.

  20. C-reactive protein impairs angiogenic functions and decreases the secretion of arteriogenic chemo-cytokines in human endothelial progenitor cells.

    PubMed

    Suh, Wonhee; Kim, Koung Li; Choi, Jin-Ho; Lee, Young-Sam; Lee, Jae-Young; Kim, Jeong-Min; Jang, Hyung-Suk; Shin, In-Soon; Lee, Jung-Sun; Byun, Jonghoe; Jeon, Eun-Seok; Kim, Duk-Kyung

    2004-08-13

    C-reactive protein (CRP), a predictor of future cardiovascular diseases, has been reported to damage the vascular wall by inducing endothelial dysfunction and inflammation. This proatherogenic CRP was speculated to have a role in attenuating angiogenic functions of human endothelial progenitor cells (EPCs), possibly impairing vascular regeneration and increasing cardiovascular vulnerability to ischemic injury. Herein, we investigated the direct effect of CRP on angiogenic activity and gene expression in human EPCs. Incubation of EPCs with human recombinant CRP significantly inhibited EPC migration in response to vascular endothelial growth factor, possibly by decreasing the expression of endothelial nitric oxide synthase and subsequent nitric oxide production. In addition, CRP-treated EPCs showed the reduced adhesiveness onto an endothelial cell monolayer. When assayed for the gene expression of arteriogenic chemo-cytokines, CRP substantially decreased their expression levels in EPC, in part due to the upregulation of suppressors of cytokine signaling proteins. These results suggest that CRP directly attenuates the angiogenic and possibly arteriogenic functions of EPCs. This CRP-induced EPC dysfunction may impair the vascular regenerative capacity of EPCs, thereby leading to increased risk of cardiovascular diseases.

  1. CD46 activation regulates miR-150-mediated control of GLUT1 expression and cytokine secretion in human CD4+ T cells

    PubMed Central

    King, Ben C.; Esguerra, Jonathan L. S.; Golec, Ewelina; Eliasson, Lena; Kemper, Claudia; Blom, Anna M.

    2015-01-01

    CD46 is a cell surface complement inhibitor widely expressed in human tissues, in contrast to mice, where expression is limited to the testes. In humans, it has been identified as an important T cell costimulatory receptor, and patients deficient in CD46 or its endogenous ligands are unable to mount effective Th1 T cell responses. Stimulation of human CD4+ T cells with CD3 and CD46 also leads to the differentiation of a ‘switched’ Th1 population, which shuts down IFN-γ secretion and upregulates IL-10, and is believed to be important for negative feedback regulation of the Th1 response. We show here that CD46 costimulation leads to amplified microRNA expression changes in human CD4+ T cells, with associated increases in activation more potent than that mediated by the ‘classic’ costimulator CD28. Blockade of cell-surface CD46 inhibited CD28-mediated costimulation, identifying autocrine CD46 signaling as downstream of CD28. We also identify a downregulation of microRNA-150 in CD46-costimulated T cells, and identify the glucose transporter-1 (GLUT1) encoding transcript SLC2A1 as a target of microRNA-150 regulation, connecting microRNA-150 with modulation of glucose uptake. We also investigated microRNA expression profiles of CD46-induced ‘switched’ IL-10-secreting Th1 T cells and found increased expression of microRNA-150, compared to IFN-γ-secreting Th1 cells. Knockdown of microRNA-150 led to a reduction in IL-10 but not IFN-γ. CD46 therefore controls both Th1 activation and regulation via a miRNA-150-dependent mechanism. PMID:26746193

  2. Extra-ocular muscle cells from patients with Graves' ophthalmopathy secrete α (CXCL10) and β (CCL2) chemokines under the influence of cytokines that are modulated by PPARγ.

    PubMed

    Antonelli, Alessandro; Ferrari, Silvia Martina; Corrado, Alda; Franceschini, Stefano Sellari; Gelmini, Stefania; Ferrannini, Ele; Fallahi, Poupak

    2014-11-01

    To our knowledge, no study has evaluated the involvement of T helper (Th)1- and Th2-chemokines in extra-ocular muscle (EOM) myopathy in "patients with thyroid-associated ophthalmopathy" (TAO-p). We tested the effects of interferon (IFN)γ and tumor necrosis factor (TNF)α stimulation, and of increasing concentrations of peroxisome proliferator-activated receptor (PPAR)γ agonists (pioglitazone or rosiglitazone; 0.1 μM-20 μM), on Th1-chemokine [C-X-C motif ligand (CXCL)10] and Th2-chemokine [C-C motif ligand (CCL)2] secretion in primary EOM cultures from TAO-p vs. control myoblasts. Moreover, we evaluated serum CXCL10 and CCL2 in active TAO-p with prevalent EOM involvement (EOM-p) vs. those with prevalent orbital fat expansion (OF-p). Serum CXCL10 was higher in OF-p and EOM-p vs. controls, while serum CCL2 was not significantly different in controls, or in OF-p and EOM-p. We showed the expression of PPARγ in EOM cells. In primary EOM cultures from TAO-p: a) CXCL10 was undetectable in the supernatant, IFNγ dose-dependently induced it, whereas TNFα did not; b) EOM produced basally low amounts of CCL2, TNFα dose-dependently induced it, whereas IFNγ did not; c) the combination of TNFα and IFNγ had a significant synergistic effect on CXCL10 and CCL2 secretion; and d) PPARγ agonists have an inhibitory role on the modulation of CXCL10, while they stimulate CCL2 secretion. EOM participates in the self-perpetuation of inflammation by releasing both Th1 (CXCL10) and Th2 (CCL2) chemokines under the influence of cytokines, in TAO. PPARγ agonist activation plays an inhibitory role on CXCL10, but stimulates the release of CCL2.

  3. Overexpression of the Saccharomyces cerevisiae mannosylphosphodolichol synthase-encoding gene in Trichoderma reesei results in an increased level of protein secretion and abnormal cell ultrastructure.

    PubMed

    Kruszewska, J S; Butterweck, A H; Kurzatkowski, W; Migdalski, A; Kubicek, C P; Palamarczyk, G

    1999-06-01

    Production of extracellular proteins plays an important role in the physiology of Trichoderma reesei and has potential industrial application. To improve the efficiency of protein secretion, we overexpressed in T. reesei the DPM1 gene of Saccharomyces cerevisiae, encoding mannosylphosphodolichol (MPD) synthase, under homologous, constitutively acting expression signals. Four stable transformants, each with different copy numbers of tandemly integrated DPM1, exhibited roughly double the activity of MPD synthase in the respective endoplasmic reticulum membrane fraction. On a dry-weight basis, they secreted up to sevenfold-higher concentrations of extracellular proteins during growth on lactose, a carbon source promoting formation of cellulases. Northern blot analysis showed that the relative level of the transcript of cbh1, which encodes the major cellulase (cellobiohydrolase I [CBH I]), did not increase in the transformants. On the other hand, the amount of secreted CBH I and, in all but one of the transformants, intracellular CBH I was elevated. Our results suggest that posttranscriptional processes are responsible for the increase in CBH I production. The carbohydrate contents of the extracellular proteins were comparable in the wild type and in the transformants, and no hyperglycosylation was detected. Electron microscopy of the DPM1-amplified strains revealed amorphous structure of the cell wall and over three times as many mitochondria as in the control. Our data indicate that molecular manipulation of glycan biosynthesis in Trichoderma can result in improved protein secretion.

  4. Effect of a four-week exercise program on the secretion of IFN-γ, TNF-α, IL-2 and IL-6 cytokines in elite Taekwondo athletes

    PubMed Central

    Kaya, Oktay

    2016-01-01

    The aim of the present study was to examine how a 4-week exercise program affects the serum levels of certain cytokines in Taekwondo athletes. The study involved 10 elite male Taekwondo athletes (mean age, 20.67±0.24 years; mean weight, 65.45±1.69 kg) who were studying at the Physical Education and Sports High School of Selçuk University (Konya, Turkey) in June 2014. The subjects were involved in a Taekwondo exercise program on every weekday for 4 weeks. The subjects were also engaged in an exercise to exhaustion session twice; once before starting the 4-week exercise program and once upon completion of the program. Blood samples were collected from the subjects in four rounds: During rest, upon fatigue, and before and after the 4-week exercise program. These samples were analyzed to establish the serum levels of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin (IL)-2 and IL-6 using enzyme-linked immunosorbent assay test kits. Pre- and post-exercise program, the IFN-γ and TNF-α levels did not show any significant difference. When compared with the pre-exercise levels, serum IL-2 levels of the subjects were found to be elevated after the 4-week exercise program. The highest serum IL-6 values were established after the subjects were exercised to fatigue before the exercise program was initiated (P<0.05). The 4-week exercise program resulted in a decrease in IL-6 levels (P<0.05). The findings of the study indicate that a 4-week exercise program did not result in significant changes in IFN-γ and TNF-α levels, but led to an increase in IL-2 levels. The notable finding of the present study is that a 4-week exercise program reduces cellular immune functions and, thus, the levels of IL-6, which negatively influences performance. PMID:27588179

  5. Dectin-1-mediated Signaling Leads to Characteristic Gene Expressions and Cytokine Secretion via Spleen Tyrosine Kinase (Syk) in Rat Mast Cells*

    PubMed Central

    Kimura, Yukihiro; Chihara, Kazuyasu; Honjoh, Chisato; Takeuchi, Kenji; Yamauchi, Shota; Yoshiki, Hatsumi; Fujieda, Shigeharu; Sada, Kiyonao

    2014-01-01

    Dectin-1 recognizes β-glucan and plays important roles for the antifungal immunity through the activation of spleen tyrosine kinase (Syk) in dendritic cells or macrophages. Recently, expression of Dectin-1 was also identified in human and mouse mast cells, although its physiological roles were largely unknown. In this report, rat mast cell line RBL-2H3 was analyzed to investigate the molecular mechanism of Dectin-1-mediated activation and responses of mast cells. Treatment of cells with Dectin-1-specific agonist curdlan induced tyrosine phosphorylation of cellular proteins and the interaction of Dectin-1 with the Src homology 2 domain of Syk. These responses depended on tyrosine phosphorylation of the hemi-immunoreceptor tyrosine-based activation motif in the cytoplasmic tail of Dectin-1, whereas they were independent of the γ-subunit of high-affinity IgE receptor. DNA microarray and real-time PCR analyses showed that Dectin-1-mediated signaling stimulated gene expression of transcription factor Nfkbiz and inflammatory cytokines, such as monocyte chemoattractant protein-1, IL-3, IL-4, IL-13, and tumor necrosis factor (TNF)-α. The response was abrogated by pretreatment with Syk inhibitor R406. These results suggest that Syk is critical for Dectin-1-mediated activation of mast cells, although the signaling differs from that triggered by FcϵRI activation. In addition, these gene expressions induced by curdlan stimulation were specifically observed in mast cells, suggesting that Dectin-1-mediated signaling of mast cells offers new insight into the antifungal immunity. PMID:25246527

  6. Simultaneous Exposure to Escherichia coli Heat-Labile and Heat-Stable Enterotoxins Increases Fluid Secretion and Alters Cyclic Nucleotide and Cytokine Production by Intestinal Epithelial Cells

    PubMed Central

    Read, Lisa T.; Hahn, Rachel W.; Thompson, Carli C.; Bauer, David L.; Norton, Elizabeth B.

    2014-01-01

    Enterotoxigenic Escherichia coli (ETEC) is a significant cause of diarrheal disease and death, especially in children in developing countries. ETEC causes disease by colonizing the small intestine and producing heat-labile toxin (LT), heat-stable toxin (ST), or both LT and ST (LT+ST). The majority of ETEC strains produce both ST and LT. Despite the prevalence of LT+ST-producing organisms, few studies have examined the physiologic or immunologic consequences of simultaneous exposure to these two potent enterotoxins. In the current report, we demonstrate that when LT and ST are both present, they increase water movement into the intestinal lumen over and above the levels observed with either toxin alone. As expected, cultured intestinal epithelial cells increased their expression of intracellular cyclic GMP (cGMP) when treated with ST and their expression of intracellular cyclic AMP (cAMP) when treated with LT. When both toxins were present, cGMP levels but not cAMP levels were synergistically elevated compared with the levels of expression caused by the corresponding single-toxin treatment. Our data also demonstrate that the levels of inflammatory cytokines produced by intestinal epithelial cells in response to LT are significantly reduced in animals exposed to both enterotoxins. These findings suggest that there may be complex differences between the epithelial cell intoxication and, potentially, secretory outcomes induced by ETEC strains expressing LT+ST compared with strains that express LT or ST only. Our results also reveal a novel mechanism wherein ST production may reduce the hosts' ability to mount an effective innate or adaptive immune response to infecting organisms. PMID:25287923

  7. Tumor suppression in mice lacking GABARAP, an Atg8/LC3 family member implicated in autophagy, is associated with alterations in cytokine secretion and cell death

    PubMed Central

    Salah, F S; Ebbinghaus, M; Muley, V Y; Zhou, Z; Al-Saadi, K R D; Pacyna-Gengelbach, M; O'Sullivan, G A; Betz, H; König, R; Wang, Z-Q; Bräuer, R; Petersen, I

    2016-01-01

    GABARAP belongs to an evolutionary highly conserved gene family that has a fundamental role in autophagy. There is ample evidence for a crosstalk between autophagy and apoptosis as well as the immune response. However, the molecular details for these interactions are not fully characterized. Here, we report that the ablation of murine GABARAP, a member of the Atg8/LC3 family that is central to autophagosome formation, suppresses the incidence of tumor formation mediated by the carcinogen DMBA and results in an enhancement of the immune response through increased secretion of IL-1β, IL-6, IL-2 and IFN-γ from stimulated macrophages and lymphocytes. In contrast, TGF-β1 was significantly reduced in the serum of these knockout mice. Further, DMBA treatment of these GABARAP knockout mice reduced the cellularity of the spleen and the growth of mammary glands through the induction of apoptosis. Gene expression profiling of mammary glands revealed significantly elevated levels of Xaf1, an apoptotic inducer and tumor-suppressor gene, in knockout mice. Furthermore, DMBA treatment triggered the upregulation of pro-apoptotic (Bid, Apaf1, Bax), cell death (Tnfrsf10b, Ripk1) and cell cycle inhibitor (Cdkn1a, Cdkn2c) genes in the mammary glands. Finally, tumor growth of B16 melanoma cells after subcutaneous inoculation was inhibited in GABARAP-deficient mice. Together, these data provide strong evidence for the involvement of GABARAP in tumorigenesis in vivo by delaying cell death and its associated immune-related response. PMID:27124579

  8. Tumor suppression in mice lacking GABARAP, an Atg8/LC3 family member implicated in autophagy, is associated with alterations in cytokine secretion and cell death.

    PubMed

    Salah, F S; Ebbinghaus, M; Muley, V Y; Zhou, Z; Al-Saadi, K R D; Pacyna-Gengelbach, M; O'Sullivan, G A; Betz, H; König, R; Wang, Z-Q; Bräuer, R; Petersen, I

    2016-01-01

    GABARAP belongs to an evolutionary highly conserved gene family that has a fundamental role in autophagy. There is ample evidence for a crosstalk between autophagy and apoptosis as well as the immune response. However, the molecular details for these interactions are not fully characterized. Here, we report that the ablation of murine GABARAP, a member of the Atg8/LC3 family that is central to autophagosome formation, suppresses the incidence of tumor formation mediated by the carcinogen DMBA and results in an enhancement of the immune response through increased secretion of IL-1β, IL-6, IL-2 and IFN-γ from stimulated macrophages and lymphocytes. In contrast, TGF-β1 was significantly reduced in the serum of these knockout mice. Further, DMBA treatment of these GABARAP knockout mice reduced the cellularity of the spleen and the growth of mammary glands through the induction of apoptosis. Gene expression profiling of mammary glands revealed significantly elevated levels of Xaf1, an apoptotic inducer and tumor-suppressor gene, in knockout mice. Furthermore, DMBA treatment triggered the upregulation of pro-apoptotic (Bid, Apaf1, Bax), cell death (Tnfrsf10b, Ripk1) and cell cycle inhibitor (Cdkn1a, Cdkn2c) genes in the mammary glands. Finally, tumor growth of B16 melanoma cells after subcutaneous inoculation was inhibited in GABARAP-deficient mice. Together, these data provide strong evidence for the involvement of GABARAP in tumorigenesis in vivo by delaying cell death and its associated immune-related response. PMID:27124579

  9. Giardia duodenalis Arginine Deiminase Modulates the Phenotype and Cytokine Secretion of Human Dendritic Cells by Depletion of Arginine and Formation of Ammonia

    PubMed Central

    Banik, Stefanie; Renner Viveros, Pablo; Seeber, Frank; Klotz, Christian; Ignatius, Ralf

    2013-01-01

    Depletion of arginine is a recognized strategy that pathogens use to evade immune effector mechanisms. Depletion depends on microbial enzymes such as arginases, which are considered virulence factors. The effect is mostly interpreted as being a consequence of successful competition with host enzymes for the substrate. However, both arginases and arginine deiminases (ADI) have been associated with pathogen virulence. Both deplete arginine, but their reaction products differ. An ADI has been implicated in the virulence of Giardia duodenalis, an intestinal parasite that infects humans and animals, causing significant morbidity. Dendritic cells (DC) play a critical role in host defense and also in a murine G. duodenalis infection model. The functional properties of these innate immune cells depend on the milieu in which they are activated. Here, the dependence of the response of these cells on arginine was studied by using Giardia ADI and lipopolysaccharide-stimulated human monocyte-derived DC. Arginine depletion by ADI significantly increased tumor necrosis factor alpha and decreased interleukin-10 (IL-10) and IL-12p40 secretion. It also reduced the upregulation of surface CD83 and CD86 molecules, which are involved in cell-cell interactions. Arginine depletion also reduced the phosphorylation of S6 kinase in DC, suggesting the involvement of the mammalian target of rapamycin signaling pathway. The changes were due to arginine depletion and the formation of reaction products, in particular, ammonium ions. Comparison of NH4+ and urea revealed distinct immunomodulatory activities of these products of deiminases and arginases, respectively. The data suggest that a better understanding of the role of arginine-depleting pathogen enzymes for immune evasion will have to take enzyme class and reaction products into consideration. PMID:23589577

  10. Giardia duodenalis arginine deiminase modulates the phenotype and cytokine secretion of human dendritic cells by depletion of arginine and formation of ammonia.

    PubMed

    Banik, Stefanie; Renner Viveros, Pablo; Seeber, Frank; Klotz, Christian; Ignatius, Ralf; Aebischer, Toni

    2013-07-01

    Depletion of arginine is a recognized strategy that pathogens use to evade immune effector mechanisms. Depletion depends on microbial enzymes such as arginases, which are considered virulence factors. The effect is mostly interpreted as being a consequence of successful competition with host enzymes for the substrate. However, both arginases and arginine deiminases (ADI) have been associated with pathogen virulence. Both deplete arginine, but their reaction products differ. An ADI has been implicated in the virulence of Giardia duodenalis, an intestinal parasite that infects humans and animals, causing significant morbidity. Dendritic cells (DC) play a critical role in host defense and also in a murine G. duodenalis infection model. The functional properties of these innate immune cells depend on the milieu in which they are activated. Here, the dependence of the response of these cells on arginine was studied by using Giardia ADI and lipopolysaccharide-stimulated human monocyte-derived DC. Arginine depletion by ADI significantly increased tumor necrosis factor alpha and decreased interleukin-10 (IL-10) and IL-12p40 secretion. It also reduced the upregulation of surface CD83 and CD86 molecules, which are involved in cell-cell interactions. Arginine depletion also reduced the phosphorylation of S6 kinase in DC, suggesting the involvement of the mammalian target of rapamycin signaling pathway. The changes were due to arginine depletion and the formation of reaction products, in particular, ammonium ions. Comparison of NH(4)(+) and urea revealed distinct immunomodulatory activities of these products of deiminases and arginases, respectively. The data suggest that a better understanding of the role of arginine-depleting pathogen enzymes for immune evasion will have to take enzyme class and reaction products into consideration.

  11. Tumor-induced senescent T cells promote the secretion of pro-inflammatory cytokines and angiogenic factors by human monocytes/macrophages through a mechanism that involves Tim-3 and CD40L

    PubMed Central

    Ramello, M C; Tosello Boari, J; Canale, F P; Mena, H A; Negrotto, S; Gastman, B; Gruppi, A; Acosta Rodríguez, E V; Montes, C L

    2014-01-01

    Solid tumors are infiltrated by immune cells where macrophages and senescent T cells are highly represented. Within the tumor microenvironment, a cross-talk between the infiltrating cells may occur conditioning the characteristic of the in situ immune response. Our previous work showed that tumors induce senescence of T cells, which are powerful suppressors of lympho-proliferation. In this study, we report that Tumor-Induced Senescent (TIS)-T cells may also modulate monocyte activation. To gain insight into this interaction, CD4+ or CD8+TIS-T or control-T cells were co-incubated with autologous monocytes under inflammatory conditions. After co-culture with CD4+ or CD8+TIS-T cells, CD14+ monocytes/macrophages (Mo/Ma) exhibit a higher expression of CD16+ cells and a reduced expression of CD206. These Mo/Ma produce nitric oxide and reactive oxygen species; however, TIS-T cells do not modify phagocyte capacity of Mo/Ma. TIS-T modulated-Mo/Ma show a higher production of pro-inflammatory cytokines (TNF, IL-1β and IL-6) and angiogenic factors (MMP-9, VEGF-A and IL-8) and a lower IL-10 and IP-10 secretion than monocytes co-cultured with controls. The mediator(s) present in the supernatant of TIS-T cell/monocyte-macrophage co-cultures promote(s) tubulogenesis and tumor-cell survival. Monocyte-modulation induced by TIS-T cells requires cell-to-cell contact. Although CD4+ shows different behavior from CD8+TIS-T cells, blocking mAbs against T-cell immunoglobulin and mucin protein 3 and CD40 ligand reduce pro-inflammatory cytokines and angiogenic factors production, indicating that these molecules are involved in monocyte/macrophage modulation by TIS-T cells. Our results revealed a novel role for TIS-T cells in human monocyte/macrophage modulation, which may have deleterious consequences for tumor progression. This modulation should be considered to best tailor the immunotherapy against cancer. PMID:25375372

  12. Tumor-induced senescent T cells promote the secretion of pro-inflammatory cytokines and angiogenic factors by human monocytes/macrophages through a mechanism that involves Tim-3 and CD40L.

    PubMed

    Ramello, M C; Tosello Boari, J; Canale, F P; Mena, H A; Negrotto, S; Gastman, B; Gruppi, A; Acosta Rodríguez, E V; Montes, C L

    2014-01-01

    Solid tumors are infiltrated by immune cells where macrophages and senescent T cells are highly represented. Within the tumor microenvironment, a cross-talk between the infiltrating cells may occur conditioning the characteristic of the in situ immune response. Our previous work showed that tumors induce senescence of T cells, which are powerful suppressors of lympho-proliferation. In this study, we report that Tumor-Induced Senescent (TIS)-T cells may also modulate monocyte activation. To gain insight into this interaction, CD4+ or CD8+TIS-T or control-T cells were co-incubated with autologous monocytes under inflammatory conditions. After co-culture with CD4+ or CD8+TIS-T cells, CD14+ monocytes/macrophages (Mo/Ma) exhibit a higher expression of CD16+ cells and a reduced expression of CD206. These Mo/Ma produce nitric oxide and reactive oxygen species; however, TIS-T cells do not modify phagocyte capacity of Mo/Ma. TIS-T modulated-Mo/Ma show a higher production of pro-inflammatory cytokines (TNF, IL-1β and IL-6) and angiogenic factors (MMP-9, VEGF-A and IL-8) and a lower IL-10 and IP-10 secretion than monocytes co-cultured with controls. The mediator(s) present in the supernatant of TIS-T cell/monocyte-macrophage co-cultures promote(s) tubulogenesis and tumor-cell survival. Monocyte-modulation induced by TIS-T cells requires cell-to-cell contact. Although CD4+ shows different behavior from CD8+TIS-T cells, blocking mAbs against T-cell immunoglobulin and mucin protein 3 and CD40 ligand reduce pro-inflammatory cytokines and angiogenic factors production, indicating that these molecules are involved in monocyte/macrophage modulation by TIS-T cells. Our results revealed a novel role for TIS-T cells in human monocyte/macrophage modulation, which may have deleterious consequences for tumor progression. This modulation should be considered to best tailor the immunotherapy against cancer.

  13. Autophagy and cytokines.

    PubMed

    Harris, James

    2011-11-01

    Autophagy is a highly conserved homoeostatic mechanism for the lysosomal degradation of cytosolic constituents, including long-lived macromolecules, organelles and intracellular pathogens. Autophagosomes are formed in response to a number of environmental stimuli, including amino acid deprivation, but also by both host- and pathogen-derived molecules, including toll-like receptor ligands and cytokines. In particular, IFN-γ, TNF-α, IL-1, IL-2, IL-6 and TGF-β have been shown to induce autophagy, while IL-4, IL-10 and IL-13 are inhibitory. Moreover, autophagy can itself regulate the production and secretion of cytokines, including IL-1, IL-18, TNF-α, and Type I IFN. This review discusses the potentially pivotal roles of autophagy in the regulation of inflammation and the coordination of innate and adaptive immune responses.

  14. Abnormal lipid rafts related ganglioside expression and signaling in T lymphocytes in immune thrombocytopenia patients.

    PubMed

    Zhang, Xian; Zhang, Donglei; Liu, Wenjie; Li, Huiyuan; Fu, Rongfeng; Liu, Xiaofan; Xue, Feng; Yang, Renchi

    2016-01-01

    Aberrant T lymphocytes signaling is considered to play a crucial role in the abnormal immune state of primary immune thrombocytopenia (ITP). Lipid raft has been verified to engage in the T cell receptor (TCR)-mediated T lymphocytes signal transduction. Whether lipid raft-associated T cells signal transduction has impact on the pathogenesis of ITP is still unconfirmed. In this study, we aimed to reveal the abnormality in structure and function of lipid rafts (LRs) in CD4(+) and CD8(+) T lymphocytes of patients with ITP. Our results showed that there was an increased lipid raft aggregation in ITP patients, while this kind of increase would not be influenced by platelet counts or therapeutic regimes. Stimulation by anti-CD3/CD28 monoclonal antibodies promoted enhanced lipid raft clustering in T lymphocytes of ITP patients compared with negative controls. Methyl-β-cyclodextrin (MβCD) could block the abnormal lipid raft aggregation and disrupt the TCR-mediated T cells proliferation and cytokines secretion, including both proinflammatory cytokines and anti-inflammatory cytokines. The spontaneous activation of T lymphocytes from ITP patients might be due to the elevated co-localization of protein tyrosine phosphatase (PTP) CD45 and lipid rafts in patients' CD4(+) and CD8(+) T lymphocytes. These findings suggest that the autoactivation of T lymphocytes from ITP patients may lead to the abnormality in lipid raft structure and raft-anchored proteins, and the changes conversely promote the TCR-mediated T cells activation of ITP patients.

  15. Assessing the presence of abnormal regulation of cortisol secretion by membrane hormone receptors: in vivo and in vitro studies in patients with functioning and non-functioning adrenal adenoma.

    PubMed

    Dall'Asta, C; Ballarè, E; Mantovani, G; Ambrosi, B; Spada, A; Barbetta, L; Colombo, P; Travaglini, P; Loli, P; Beck-Peccoz, P

    2004-08-01

    Regulation of cortisol secretion by aberrant hormone receptors may play a role in the pathogenesis of ACTH-independent Cushing's syndrome. In this study, the topic was evaluated by combining in vivo and in vitro approaches. Cortisol responses to various stimuli (standard meal, GnRH + TRH, cisapride, vasopressin, glucagon) were assessed in 6 patients with clinical or subclinical adrenal Cushing's syndrome, and non-functioning adrenal adenoma in two cases. Abnormal responses were observed in three patients with Cushing's syndrome; one patient showed a gastric inhibitory polypeptide (GIP)-dependent cortisol rise after meal, together with responses after GnRH and cisapride; the second patient showed an LH-dependent cortisol response to GnRH, and in the third cortisol rose after cisapride. The pattern of receptor expression performed by RT-PCR showed that while GIP-R was only expressed in tumor from the responsive patient, 5-hydroxytryptamine type 4 receptor and LH-R were also present in normal adrenal tissues and tissues from non-responsive patients. Interestingly, an activating mutation of Gsalpha gene was identified in one of these tumors. Therefore, cortisol responses to agents operating via Gs protein coupled receptors (in one case associated with Gsalpha mutation) were found in Cushing's patients, while these responses were absent in the others. The finding of receptor expression in normal and non-responsive tumors suggests that different mechanisms are probably involved in inducing in vivo cortisol responses. PMID:15326569

  16. Cytokine-induced killer cell therapy-associated idiopathic thrombocytopenic purpura: rare but noteworthy.

    PubMed

    Fu, Xiaomin; Zhang, Yong; Gao, Quanli; Lin, Jizhen; Zhang, Qinxian; Xu, Benling; Song, Yongping

    2016-09-01

    Idiopathic thrombocytopenic purpura (ITP) is characterized by a diminished platelet count, an autoimmune condition with antibodies against platelets and an increased tendency to bleed. The association between ITP and solid tumors is uncommon. Cytokine-induced killer (CIK) cell therapy is a well tolerated and promising cancer treatment with minimal toxicity. For the first time, CIK cell therapy was reported to be followed by ITP. The mechanism through which CIK induces ITP remains unclear. Imbalanced ratio of Th cells, decreased numbers or impaired function of Treg cells and excessive secretion of cytokines inducing abnormal activation of B cells may be among the possible reasons. Therefore, a better understanding of this rare condition will require further investigation of these cases. PMID:27485074

  17. Meiotic abnormalities

    SciTech Connect

    1993-12-31

    Chapter 19, describes meiotic abnormalities. These include nondisjunction of autosomes and sex chromosomes, genetic and environmental causes of nondisjunction, misdivision of the centromere, chromosomally abnormal human sperm, male infertility, parental age, and origin of diploid gametes. 57 refs., 2 figs., 1 tab.

  18. Cytokine Reduction in the Treatment of Joint Conditions

    PubMed Central

    Martel-Pelletier, J.; Otterness, I. G.; Pelletier, J.-P.

    1994-01-01

    The destruction of joints caused by rheumatoid arthritis and osteoarthritis is characterized by an imbalance of enzyme catalysed cartilage breakdown and regeneration. A complex cytokine network perpetuates joint conditions by direct regulation of metalloproteases, by indirect recruitment of cells that secrete degradative enzymes, and by inhibition of reparative processes. The destructive action of cytokines such as interleukin-1, interleukin-6 and tumour necrosis factor-α can be modulated at multiple points associated either with cytokine production or with cytokine action. Potential agents for cytokine reduction include selective anti-cytokine antibodies, anticytokine receptor antibodies, cytokine receptor antagonist proteins, and soluble and chimeric cytokine receptor molecules. Pharmacologic regulation of IL-1 and TNFα remain primary targets for treatment of arthritis, and results of early clinical trials are promising. However, the results of long-term clinical trials will be required to support the value of anti-cytokine therapy in treatment of arthritis. PMID:18472950

  19. Craniofacial Abnormalities

    MedlinePlus

    ... of the skull and face. Craniofacial abnormalities are birth defects of the face or head. Some, like cleft ... palate, are among the most common of all birth defects. Others are very rare. Most of them affect ...

  20. Chromosome Abnormalities

    MedlinePlus

    ... decade, newer techniques have been developed that allow scientists and doctors to screen for chromosomal abnormalities without using a microscope. These newer methods compare the patient's DNA to a normal DNA ...

  1. Walking abnormalities

    MedlinePlus

    ... include: Arthritis of the leg or foot joints Conversion disorder (a psychological disorder) Foot problems (such as a ... injuries. For an abnormal gait that occurs with conversion disorder, counseling and support from family members are strongly ...

  2. Nail abnormalities

    MedlinePlus

    Beau's lines; Fingernail abnormalities; Spoon nails; Onycholysis; Leukonychia; Koilonychia; Brittle nails ... Just like the skin, the fingernails tell a lot about your health: ... the fingernail. These lines can occur after illness, injury to ...

  3. Current status and challenges of cytokine pharmacology

    PubMed Central

    Zídek, Z; Anzenbacher, P; Kmoníčková, E

    2009-01-01

    The major concern of pharmacology about cytokines has originated from plentiful data showing association between gross changes in their production and pathophysiological processes. Despite the enigmatic role of cytokines in diseases, a number of them have become a subject of cytokine and anti-cytokine immunotherapies. Production of cytokines can be influenced by many endogenous and exogenous stimuli including drugs. Cells of the immune system, such as macrophages and lymphocytes, are richly endowed with receptors for the mediators of physiological functions, such as biogenic amines, adenosine, prostanoids, steroids, etc. Drugs, agonists or antagonists of these receptors can directly or indirectly up- and down-regulate secretion of cytokines and expression of cytokine receptors. Vice versa, cytokines interfere with drug pharmacokinetics and pharmacodynamics through the interactions with cytochrome P450 and multiple drug resistance proteins. The aim of the review is to encourage more intensive studies in these fields of cytokine pharmacology. It also outlines major areas of searching promising candidates for immunotherapeutic interventions. PMID:19371342

  4. Role of adipose secreted factors and kisspeptin in the metabolic control of gonadotropin secretion and puberty

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Factors secreted by adipose tissue continue to be discovered. Evidence indicates a strong link between neural influences and adipocyte expression and secretion of a wide array of cytokines, neurotrophic factors, growth factors, binding proteins, and neuropeptides. These “adipokines” are linked to im...

  5. Cytokine mRNA quantification in histologically normal canine duodenal mucosa by real-time RT-PCR.

    PubMed

    Peters, I R; Helps, C R; Calvert, E L; Hall, E J; Day, M J

    2005-01-10

    CD4(+) T helper cells are important for the regulation of immune responses in the intestinal mucosa and they exert their effects through the secretion of pro-inflammatory and immunomodulatory cytokines. Human patients with inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis have alterations in the normal intestinal cytokine profile. These cytokine abnormalities have been shown at both the protein and messenger RNA (mRNA) level. The role that mucosal cytokines play in the pathogenesis of canine IBD has only been investigated using semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) analysis of gut tissue, as cytokine antisera are not available for this species. Real-time RT-PCR has been recognised to be a more accurate and sensitive method of quantifying mRNA transcripts, so in this study TaqMan real-time RT-PCR assays for the quantification of mRNA encoding IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-18, IFN-gamma, TNF-alpha and TGF-beta in canine intestinal mucosa were developed. The amount of these templates was quantified in normal canine duodenal mucosa (n = 8). IL-18, TGF-beta and TNF-alpha were found to be the most abundant transcripts, with IL-10 and IFN-gamma present at levels approximately 10-fold less. IL-2, IL-4, IL-5, IL-6 and IL-12 were the least abundant templates, with some RNA samples having no detectable mRNA copies. The methods developed in this study will form the basis of further work investigating the expression of mRNA encoding cytokines in mucosa from dogs with chronic enteropathies. In addition, these real-time PCR assays can also be used for the quantification of canine cytokine mRNA in other diseases.

  6. Fructus sophorae attenuates secretion of proinflammatory mediators and cytokines through the modulation of NF-κB and MAPK signaling pathways in LPS-stimulated RAW 264.7 macrophages.

    PubMed

    Choi, Yung Hyun; Kang, Hye-Joo

    2016-07-01

    This study investigated the inhibitory effects and underlying mechanisms of fructus sophorae, the dried ripe fruit of Styphnolobium japonicum (L.) Schott, on the production of proinflammatory molecules in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. The results indicated that pretreatment with noncytotoxic concentrations of fructus sophorae extract (FSE) significantly inhibited the release of the proinflammatory mediators nitric oxide (NO) and prostaglandin E(2), which were associated with the downregulation of both mRNA and protein for inducible NO synthase and cyclooxygenase-2, respectively, in LPS-challenged RAW 264.7 cells. FSE also blocked the LPS-induced expression of the proinflammatory cytokines interleukin (IL)-6 and IL-1β. Furthermore, the results showed that FSE efficiently attenuated the LPS-induced nuclear translocation of nuclear factor-kappa B (NF-κB) and phosphorylation of the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) but not p38 MAPK. These results suggest that FSE exhibits anti-inflammatory activity by inhibiting proinflammatory mediators and cytokines through the inactivation of NF-κB, ERK and JNK, and it may offer therapeutic potential for treating inflammatory diseases accompanied with macrophage activation. PMID:27045671

  7. Dengue-2 and yellow fever 17DD viruses infect human dendritic cells, resulting in an induction of activation markers, cytokines and chemokines and secretion of different TNF-α and IFN-α profiles.

    PubMed

    Gandini, Mariana; Reis, Sonia Regina Nogueira Ignacio; Torrentes-Carvalho, Amanda; Azeredo, Elzinandes Leal; Freire, Marcos da Silva; Galler, Ricardo; Kubelka, Claire Fernandes

    2011-08-01

    Flaviviruses cause severe acute febrile and haemorrhagic infections, including dengue and yellow fever and the pathogenesis of these infections is caused by an exacerbated immune response. Dendritic cells (DCs) are targets for dengue virus (DENV) and yellow fever virus (YF) replication and are the first cell population to interact with these viruses during a natural infection, which leads to an induction of protective immunity in humans. We studied the infectivity of DENV2 (strain 16681), a YF vaccine (YF17DD) and a chimeric YF17D/DENV2 vaccine in monocyte-derived DCs in vitro with regard to cell maturation, activation and cytokine production. Higher viral antigen positive cell frequencies were observed for DENV2 when compared with both vaccine viruses. Flavivirus-infected cultures exhibited dendritic cell activation and maturation molecules. CD38 expression on DCs was enhanced for both DENV2 and YF17DD, whereas OX40L expression was decreased as compared to mock-stimulated cells, suggesting that a T helper 1 profile is favoured. Tumor necrosis factor (TNF)-α production in cell cultures was significantly higher in DENV2-infected cultures than in cultures infected with YF17DD or YF17D/DENV. In contrast, the vaccines induced higher IFN-α levels than DENV2. The differential cytokine production indicates that DENV2 results in TNF induction, which discriminates it from vaccine viruses that preferentially stimulate interferon expression. These differential response profiles may influence the pathogenic infection outcome.

  8. Ephedrine hydrochloride inhibits PGN-induced inflammatory responses by promoting IL-10 production and decreasing proinflammatory cytokine secretion via the PI3K/Akt/GSK3β pathway.

    PubMed

    Zheng, Yuejuan; Yang, Yang; Li, Yuhu; Xu, Limin; Wang, Yi; Guo, Ziyi; Song, Haiyan; Yang, Muyi; Luo, Beier; Zheng, Aoxiang; Li, Ping; Zhang, Yan; Ji, Guang; Yu, Yizhi

    2013-07-01

    Approaches for controlling inflammatory responses and reducing the mortality rate of septic patients remain clinically ineffective; new drugs need to be identified that can induce anti-inflammatory responses. Ephedrine hydrochloride (EH) is a compound that is widely used in cardiovascular diseases, especially to treat hypotension caused by either anesthesia or overdose of antihypertensive drugs. In this study, we reported that EH also plays an important role in the control of the inflammatory response. EH increased IL-10 and decreased proinflammatory cytokine (IL-6, tumor-necrosis factor (TNF)-α, IL-12 and IL-1β) expression in primary peritoneal macrophages and Raw264.7 cells treated with peptidoglycan (PGN), a Gram-positive cell wall component. The anti-inflammatory role of EH was also demonstrated in an experimental mouse model of peritonitis induced by intraperitoneal PGN injection. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway was found to be responsible for the EH-mediated increase in IL-10 production and decrease in IL-6 expression. Therefore, our results illustrated that EH can help maintain immune equilibrium and diminish host damage by balancing the production of pro- and anti-inflammatory cytokines after PGN challenge. EH may be a new potential anti-inflammatory drug that can be useful for treating severe invasive Gram-positive bacterial infection.

  9. Involvement of Bruton's Tyrosine Kinase in FcεRI-dependent Mast Cell Degranulation and Cytokine Production

    PubMed Central

    Hata, Daisuke; Kawakami, Yuko; Inagaki, Naoki; Lantz, Chris S.; Kitamura, Toshio; Khan, Wasif N.; Maeda-Yamamoto, Mari; Miura, Toru; Han, Wei; Hartman, Stephen E.; Yao, Libo; Nagai, Hiroichi; Goldfeld, Anne E.; Alt, Frederick W.; Galli, Stephen J.; Witte, Owen N.; Kawakami, Toshiaki

    1998-01-01

    We investigated the role of Bruton's tyrosine kinase (Btk) in FcεRI-dependent activation of mouse mast cells, using xid and btk null mutant mice. Unlike B cell development, mast cell development is apparently normal in these btk mutant mice. However, mast cells derived from these mice exhibited significant abnormalities in FcεRI-dependent function. xid mice primed with anti-dinitrophenyl monoclonal IgE antibody exhibited mildly diminished early-phase and severely blunted late-phase anaphylactic reactions in response to antigen challenge in vivo. Consistent with this finding, cultured mast cells derived from the bone marrow cells of xid or btk null mice exhibited mild impairments in degranulation, and more profound defects in the production of several cytokines, upon FcεRI cross-linking. Moreover, the transcriptional activities of these cytokine genes were severely reduced in FcεRI-stimulated btk mutant mast cells. The specificity of these effects of btk mutations was confirmed by the improvement in the ability of btk mutant mast cells to degranulate and to secrete cytokines after the retroviral transfer of wild-type btk cDNA, but not of vector or kinase-dead btk cDNA. Retroviral transfer of Emt (= Itk/Tsk), Btk's closest relative, also partially improved the ability of btk mutant mast cells to secrete mediators. Taken together, these results demonstrate an important role for Btk in the full expression of FcεRI signal transduction in mast cells. PMID:9547335

  10. Human umbilical cord-derived mesenchymal stem cells suppress proliferation of PHA-activated lymphocytes in vitro by inducing CD4(+)CD25(high)CD45RA(+) regulatory T cell production and modulating cytokine secretion.

    PubMed

    Yang, Hongna; Sun, Jinhua; Li, Yan; Duan, Wei-Ming; Bi, Jianzhong; Qu, Tingyu

    2016-04-01

    Bone marrow-derived mesenchymal stem cells (MSCs) are promising candidate cells for therapeutic application in autoimmune diseases due to their immunomodulatory properties. Unused human umbilical cords (UC) offer an abundant and noninvasive source of MSCs without ethical issues and are emerging as a valuable alternative to bone marrow tissue for producing MSCs. We thus investigated the immunomodulation effect of umbilical cord-derived MSCs (UC-MSCs) on human peripheral blood mononuclear cells (PBMCs), T cells in particular, in a co-culture system. We found that UC-MSCs efficiently suppressed the proliferation of phytohaemagglutinin (PHA)-stimulated PBMCs (p<0.01). Kinetic analysis revealed that UC-MSCs primarily inhibited the division of generation 3 (G3) and 4 (G4) of PBMCs. In addition, UC-MSCs augmented the expression of CD127(+) and CD45RA(+) but reduced the expression of CD25(+) in PBMCs stimulated by PHA (p<0.05). Furthermore, UC-MSCs inhibited PHA-resulted increase in the frequency of CD4(+)CD25(+)CD127(low/-) Tregs significantly (p<0.01) but augmented PHA-resulted increase in the frequency of CD4(+)CD25(high)CD45RA(+) Tregs to about three times in PBMCs. The levels of anti-inflammatory cytokines, PEG2, TGF-β, and IL-10 were greatly up-regulated, accompanied by a significant down-regulation of pro-inflammatory IFN-γ in the co-culture (p<0.01). Our results showed that UC-MSCs are able to suppress mitogen-induced PBMC activation and proliferation in vitro by altering T lymphocyte phenotypes, increasing the frequency of CD4(+)CD25(high)CD45RA(+) Tregs, and modulating the associated cytokine production. Further studies are warranted to investigate the therapeutic potential of UC-MSCs in immunologically-diseased conditions.

  11. PD-1 Expression and Cytokine Secretion Profiles of Mycobacterium tuberculosis-Specific CD4+ T-Cell Subsets; Potential Correlates of Containment in HIV-TB Co-Infection.

    PubMed

    Pollock, Katrina M; Montamat-Sicotte, Damien J; Grass, Lisa; Cooke, Graham S; Kapembwa, Moses S; Kon, Onn M; Sampson, Robert D; Taylor, Graham P; Lalvani, Ajit

    2016-01-01

    HIV co-infection is an important risk factor for tuberculosis (TB) providing a powerful model in which to dissect out defective, protective and dysfunctional Mycobacterium tuberculosis (MTB)-specific immune responses. To identify the changes induced by HIV co-infection we compared MTB-specific CD4+ responses in subjects with active TB and latent TB infection (LTBI), with and without HIV co-infection. CD4+ T-cell subsets producing interferon-gamma (IFN-γ), interleukin-2 (IL-2) and tumour necrosis factor-alpha (TNF-α) and expressing CD279 (PD-1) were measured using polychromatic flow-cytometry. HIV-TB co-infection was consistently and independently associated with a reduced frequency of CD4+ IFN-γ and IL-2-dual secreting T-cells and the proportion correlated inversely with HIV viral load (VL). The impact of HIV co-infection on this key MTB-specific T-cell subset identifies them as a potential correlate of mycobacterial immune containment. The percentage of MTB-specific IFN-γ-secreting T-cell subsets that expressed PD-1 was increased in active TB with HIV co-infection and correlated with VL. This identifies a novel correlate of dysregulated immunity to MTB, which may in part explain the paucity of inflammatory response in the face of mycobacterial dissemination that characterizes active TB with HIV co-infection.

  12. Single-Cell Cytokine Profiling to Investigate Cellular Functional Diversity in Hematopoietic Malignancies.

    PubMed

    Chen, Jonathan J; Kwak, Minsuk; Fan, Rong

    2016-01-01

    Single-cell analysis of cytokine production is increasingly recognized as an important method to understand the inflammatory microenvironment and hematopoietic disease state. Certain cytokines are critical to the regulation of lineage specification, and the aberrant production of these cytokines can contribute to lineage reprogramming. Here, we describe of a platform combining subnanoliter microchambers and a high-density antibody barcode array for the study of single-cell cytokine secretions in hematopoietic cancer cell populations. PMID:27581152

  13. Cross-talk between apoptosis and cytokines in the regulation of parasitic infection.

    PubMed

    DosReis, George A; Ribeiro-Gomes, Flavia L; Guillermo, Landi V C; Lopes, Marcela F

    2007-01-01

    Parasitic diseases have worldwide medical and economical impact. Host T lymphocytes and the cytokines they produce determine the outcome of parasitic infections. Programmed cell death by apoptosis is induced in the course of parasitic infections, and affects cytokine production by removing activated effector T and B cells. In addition, engulfment of apoptotic cells promotes the secretion of cytokines that regulate intracellular replication of protozoan parasites. In this review, we discuss how the cross-talk between apoptosis and cytokines regulates parasitic infection.

  14. Hepatitis-related hepatocellular carcinoma: Insights into cytokine gene polymorphisms

    PubMed Central

    Dondeti, Mahmoud Fathy; El-Maadawy, Eman Anwar; Talaat, Roba Mohamed

    2016-01-01

    Hepatocellular carcinoma (HCC) is a primary liver cancer, which is one of the most prevalent cancers among humans. Many factors are involved in the liver carcinogenesis as lifestyle and environmental factors. Hepatitis virus infections are now recognized as the chief etiology of HCC; however, the precise mechanism is still enigmatic till now. The inflammation triggered by the cytokine-mediated immune response, was reported to be the closest factor of HCC development. Cytokines are immunoregulatory proteins produced by immune cells, functioning as orchestrators of the immune response. Genes of cytokines and their receptors are known to be polymorphic, which give rise to variations in their genes. These variations have a great impact on the expression levels of the secreted cytokines. Therefore, cytokine gene polymorphisms are involved in the molecular mechanisms of several diseases. This piece of work aims to shed much light on the role of cytokine gene polymorphisms as genetic host factor in hepatitis related HCC. PMID:27570418

  15. Hepatitis-related hepatocellular carcinoma: Insights into cytokine gene polymorphisms.

    PubMed

    Dondeti, Mahmoud Fathy; El-Maadawy, Eman Anwar; Talaat, Roba Mohamed

    2016-08-14

    Hepatocellular carcinoma (HCC) is a primary liver cancer, which is one of the most prevalent cancers among humans. Many factors are involved in the liver carcinogenesis as lifestyle and environmental factors. Hepatitis virus infections are now recognized as the chief etiology of HCC; however, the precise mechanism is still enigmatic till now. The inflammation triggered by the cytokine-mediated immune response, was reported to be the closest factor of HCC development. Cytokines are immunoregulatory proteins produced by immune cells, functioning as orchestrators of the immune response. Genes of cytokines and their receptors are known to be polymorphic, which give rise to variations in their genes. These variations have a great impact on the expression levels of the secreted cytokines. Therefore, cytokine gene polymorphisms are involved in the molecular mechanisms of several diseases. This piece of work aims to shed much light on the role of cytokine gene polymorphisms as genetic host factor in hepatitis related HCC. PMID:27570418

  16. Lipidomic profiling in Crohn's disease: Abnormalities in phosphatidylinositols, with preservation of ceramide, phosphatidylcholine and phosphatidylserine composition

    PubMed Central

    Sewell, Gavin W.; Hannun, Yusuf A.; Han, Xianlin; Koster, Grielof; Bielawski, Jacek; Goss, Victoria; Smith, Philip J.; Rahman, Farooq Z.; Vega, Roser; Bloom, Stuart L.; Walker, Ann P.; Postle, Anthony D.; Segal, Anthony W.

    2012-01-01

    Crohn's disease is a chronic inflammatory condition largely affecting the terminal ileum and large bowel. A contributing cause is the failure of an adequate acute inflammatory response as a result of impaired secretion of pro-inflammatory cytokines by macrophages. This defective secretion arises from aberrant vesicle trafficking, misdirecting the cytokines to lysosomal degradation. Aberrant intestinal permeability is also well-established in Crohn's disease. Both the disordered vesicle trafficking and increased bowel permeability could result from abnormal lipid composition. We thus measured the sphingo- and phospholipid composition of macrophages, using mass spectrometry and stable isotope labelling approaches. Stimulation of macrophages with heat-killed Escherichia coli resulted in three main changes; a significant reduction in the amount of individual ceramide species, an altered composition of phosphatidylcholine, and an increased rate of phosphatidylcholine synthesis in macrophages. These changes were observed in macrophages from both healthy control individuals and patients with Crohn's disease. The only difference detected between control and Crohn's disease macrophages was a reduced proportion of newly-synthesised phosphatidylinositol 16:0/18:1 over a defined time period. Shotgun lipidomics analysis of macroscopically non-inflamed ileal biopsies showed a significant decrease in this same lipid species with overall preservation of sphingolipid, phospholipid and cholesterol composition. PMID:22728312

  17. TNF receptor-associated factor-3 signaling mediates activation of p38 and Jun N-terminal kinase, cytokine secretion, and Ig production following ligation of CD40 on human B cells.

    PubMed

    Grammer, A C; Swantek, J L; McFarland, R D; Miura, Y; Geppert, T; Lipsky, P E

    1998-08-01

    CD40 engagement induces a variety of functional outcomes following association with adaptor molecules of the TNF receptor-associated factor (TRAF) family. Whereas TRAF2, -5, and -6 initiate NF-kappaB activation, the outcomes of TRAF3-initiated signaling are less characterized. To delineate CD40-induced TRAF3-dependent events, Ramos B cells stably transfected with a dominant negative TRAF3 were stimulated with membranes expressing recombinant CD154/CD40 ligand. In the absence of TRAF3 signaling, activation of p38 and control of Ig production were abrogated, whereas Jun N-terminal kinase activation and secretion of IL-10, lymphotoxin-alpha, and TNF-alpha were partially blocked. By contrast, induction of apoptosis, activation of NF-kappaB, generation of granulocyte-macrophage CSF, and up-regulation of CD54, MHC class II, and CD95 were unaffected by the TRAF3 dominant negative. Together, these results indicate that TRAF3 initiates independent signaling pathways via p38 and JNK that are associated with specific functional outcomes.

  18. Lysophosphatidic acid increases proximal tubule cell secretion of profibrotic cytokines PDGF-B and CTGF through LPA2- and Gαq-mediated Rho and αvβ6 integrin-dependent activation of TGF-β.

    PubMed

    Geng, Hui; Lan, Rongpei; Singha, Prajjal K; Gilchrist, Annette; Weinreb, Paul H; Violette, Shelia M; Weinberg, Joel M; Saikumar, Pothana; Venkatachalam, Manjeri A

    2012-10-01

    After ischemia-reperfusion injury (IRI), kidney tubules show activated transforming growth factor β (TGF-β) signaling and increased expression of profibrotic peptides, platelet-derived growth factor-B (PDGF-B) and connective tissue growth factor (CTGF). If tubule repair after IRI is incomplete, sustained paracrine activity of these peptides can activate interstitial fibroblast progenitors and cause fibrosis. We show that lysophosphatidic acid (LPA), a ubiquitous phospholipid that is increased at sites of injury and inflammation, signals through LPA2 receptors and Gαq proteins of cultured proximal tubule cells to transactivate latent TGF-β in a Rho/Rho-kinase and αvβ6 integrin-dependent manner. Active TGF-β peptide then initiates signaling to increase the production and secretion of PDGF-B and CTGF. In a rat model of IRI, increased TGF-β signaling that was initiated early during reperfusion did not subside during recovery, but progressively increased, causing tubulointerstitial fibrosis. This was accompanied by correspondingly increased LPA2 and β6 integrin proteins and elevated tubule expression of TGF-β1, together with PDGF-B and CTGF. Treatment with a pharmacological TGF-β type I receptor antagonist suppressed TGF-β signaling, decreased the expression of β6 integrin, PDGF-B, and CTGF, and ameliorated fibrosis. We suggest that LPA-initiated autocrine signaling is a potentially important mechanism that gives rise to paracrine profibrotic signaling in injured kidney tubule cells.

  19. Cytokines in Radiobiological Responses: A Review

    PubMed Central

    Schaue, Dörthe; Kachikwu, Evelyn L.; McBride, William H.

    2013-01-01

    Cytokines function in many roles that are highly relevant to radiation research. This review focuses on how cytokines are structurally organized, how they are induced by radiation, and how they orchestrate mesenchymal, epithelial and immune cell interactions in irradiated tissues. Pro-inflammatory cytokines are the major components of immediate early gene programs and as such can be rapidly activated after tissue irradiation. They converge with the effects of ionizing radiation in that both generate free radicals including reactive oxygen and nitrogen species (ROS/RNS). “Self” molecules secreted or released from cells after irradiation feed the same paradigm by signaling for ROS and cytokine production. As a result, multilayered feedback control circuits can be generated that perpetuate the radiation tissue damage response. The pro-inflammatory phase persists until such times as perceived challenges to host integrity are eliminated. Antioxidant, anti-inflammatory cytokines then act to restore homeostasis. The balance between pro-inflammatory and anti-inflammatory forces may shift to and fro for a long time after radiation exposure, creating waves as the host tries to deal with persisting pathogenesis. Individual cytokines function within socially interconnected groups to direct these integrated cellular responses. They hunt in packs and form complex cytokine networks that are nested within each other so as to form mutually reinforcing or antagonistic forces. This yin-yang balance appears to have redox as a fulcrum. Because of their social organization, cytokines appear to have a considerable degree of redundancy and it follows that an elevated level of a specific cytokine in a disease situation or after irradiation does not necessarily implicate it causally in pathogenesis. In spite of this, “driver” cytokines are emerging in pathogenic situations that can clearly be targeted for therapeutic benefit, including in radiation settings. Cytokines can greatly

  20. [Endocrine abnormalities in HIV infections].

    PubMed

    Verges, B; Chavanet, P; Desgres, J; Kisterman, J P; Waldner, A; Vaillant, G; Portier, H; Brun, J M; Putelat, R

    The finding of endocrine gland lesions at pathological examination in AIDS and reports of several cases of endocrine disease in patients with this syndrome have prompted us to study endocrine functions in 63 patients (51 men, 12 women) with HIV-1 infection. According to the Center for Disease Control (CDC) classification system, 13 of these patients were stage CDC II, 27 stage CDC III and 23 stage CDC IV. We explored the adrenocortical function (ACTH, immediate tetracosactrin test) and the thyroid function (free T3 and T4 levels, TRH on TSH test) in all 63 patients. The hypothalamic-pituitary-gonadal axis (testosterone levels, LHRH test) and prolactin secretion (THR test) were explored in the 51 men. The results obtained showed early peripheral testicular insufficiency at stage CDC II and early pituitary gland abnormalities with hypersecretion of ACTH and prolactin also at stage CDC II. On the other hand, adrenocortical and pituitary abnormalities were not frequently found. The physiopathology of the endocrine abnormalities observed in HIV-1-infected patients remains unclear, but one may suspect that it involves interleukin-1 since this protein factor has recently been shown to stimulate the corticotropin-releasing hormone secretion and to act directly on the glycoprotein capsule of the virus (gp 120) whose structure is similar to that of some neurohormones.

  1. Interleukin-1 Family Cytokines in Liver Diseases

    PubMed Central

    Tsutsui, Hiroko; Cai, Xianbin; Hayashi, Shuhei

    2015-01-01

    The gene encoding IL-1 was sequenced more than 30 years ago, and many related cytokines, such as IL-18, IL-33, IL-36, IL-37, IL-38, IL-1 receptor antagonist (IL-1Ra), and IL-36Ra, have since been identified. IL-1 is a potent proinflammatory cytokine and is involved in various inflammatory diseases. Other IL-1 family ligands are critical for the development of diverse diseases, including inflammatory and allergic diseases. Only IL-1Ra possesses the leader peptide required for secretion from cells, and many ligands require posttranslational processing for activation. Some require inflammasome-mediated processing for activation and release, whereas others serve as alarmins and are released following cell membrane rupture, for example, by pyroptosis or necroptosis. Thus, each ligand has the proper molecular process to exert its own biological functions. In this review, we will give a brief introduction to the IL-1 family cytokines and discuss their pivotal roles in the development of various liver diseases in association with immune responses. For example, an excess of IL-33 causes liver fibrosis in mice via activation and expansion of group 2 innate lymphoid cells to produce type 2 cytokines, resulting in cell conversion into pro-fibrotic M2 macrophages. Finally, we will discuss the importance of IL-1 family cytokine-mediated molecular and cellular networks in the development of acute and chronic liver diseases. PMID:26549942

  2. [Cytokines and allergic response].

    PubMed

    Guenounou, M

    1998-01-01

    Allergic reactions are under the control of several events that occur sequentially following allergen exposure, recognition by the immune system, IgE production and their interaction with effector cells bearing Fc epsilon receptors. The lymphocyte activation in response to allergens determines the intensity and the nature of the immune response. Cytokines produced by T (and non-T) cells are involved in the polarized development of the specific immune response. In particular, type 1 and type 2 cytokines are responsible for the control of the different steps during allergic reactions. Th2 cytokines and particularly IL4 are responsible for switching the immunoglobulin synthesis by B cells to IgE production. They also play a key role in the activation of effector cells that occurs following allergen interaction with fixed specific IgE and participate to the local inflammatory reaction. Cytokine profile determination appears to represent a helpful laboratory parameter in the understanding of the mechanisms underlying allergic diseases. The development of new technological tools may allow the use of cell activation parameters, and cytokine profiles determination in clinical biology. This review aims to analyze the involvement of the cytokine network in the mechanisms leading to IgE production and the involvement of cytokines in effector mechanisms of allergic reactions. It also analyses the potential use of cytokine profile determination for diagnosis purpose and survey of immune desensitization of allergic diseases.

  3. Circulating monocytes are not the major source of plasma cytokines in patients with sepsis.

    PubMed

    Gille-Johnson, Patrik; Smedman, Christian; Gudmundsdotter, Lindvi; Somell, Anna; Nihlmark, Kopek; Paulie, Staffan; Andersson, Jan; Gårdlund, Bengt

    2012-12-01

    In sepsis, large quantities of inflammatory cytokines are released into the bloodstream. The cellular source of these cytokines is unclear, and we have here investigated to what extent circulating cells in blood contributed to this production. We used the enzyme-linked immunospot technique to study the spontaneous as well as the lipopolysaccharide (LPS)-induced secretion of the proinflammatory cytokines interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), granulocyte-macrophage colony-stimulating factor, IL-1β, IL-12p40, and the anti-inflammatory cytokine IL-10 from whole-blood cells. The study comprised 32 septic patients (24 with septic shock) and 30 healthy controls. Despite significantly increased plasma cytokine levels in the septic patients, the number of spontaneous cytokine-secreting cells was small or nonexistent and did not differ between the two groups. Lipopolysaccharide stimulation of cells from the same samples triggered substantially increased numbers of cytokine-producing cells in both patients and controls. However, although the numbers of IL-6- and tumor necrosis factor α-secreting monocytes were very similar in both groups, significantly fewer IL-1β-, IL-10-, IL-12p40-, and granulocyte-macrophage colony-stimulating factor-secreting monocytes were seen in samples from septic patients as compared with healthy controls. The reduced number of cytokine-secreting cells in response to LPS stimulation correlated with disease severity, as expressed by Sequential Organ Failure Assessment score and the stage of sepsis. In summary, circulating leukocytes did not appear to be responsible for the increased plasma levels of cytokines observed in sepsis. A selective sepsis-induced downregulation of cytokine secretion in response to LPS underscores the complexity of cytokine regulation in sepsis.

  4. Antiresistin RNA Oligonucleotide Ameliorates Diet-Induced Nonalcoholic Fatty Liver Disease in Mice through Attenuating Proinflammatory Cytokines.

    PubMed

    Tan, Yi; Jin, Xing Liang; Lao, Weiguo; Kim, Jane; Xiao, Linda; Qu, Xianqin

    2015-01-01

    The aim of this study was to determine whether inhibition of resistin by a synthetic antiresistin RNA (oligonucleotide) oligo ameliorates metabolic and histological abnormalities in nonalcoholic fatty liver disease (NAFLD) induced by high-fat diet (HFD) in mice. The antiresistin RNA oligo and a scrambled control oligo (25 mg/kg of body weight) were i.p. injected to HFD mice. Serum metabolic parameters and hepatic enzymes were measured after 4-week treatment. The treatment significantly reduced epididymal fat and attenuated the elevated serum resistin, cholesterol, triglycerides, glucose, and insulin with an improved glucose tolerance test. Antiresistin RNA oligo also normalized serum AST and ALT levels with improved pathohistology of NAFLD. Immunoblotting and qRT-PCR revealed that decreased protein and mRNA expression of resistin in fat and liver tissues of the treated mice were associated with reduction of adipose TNF-α and IL-6 expression and secretion into circulation. mRNA and protein expression of hepatic phosphoenolpyruvate carboxykinase (PEPCK) and sterol regulatory element-binding protein-1c (SREBP-1c) were also significantly decreased in the treated mice. Our results suggest that resistin may exacerbate NAFLD in metabolic syndrome through upregulating inflammatory cytokines and hepatic PEPCK and SREBP-1c. Antiresistin RNA oligo ameliorated metabolic abnormalities and histopathology of NAFLD through attenuating proinflammatory cytokines.

  5. [Rheumatoid arthritis and cytokines].

    PubMed

    Kaneko, Shunta; Kondo, Yuya; Yokosawa, Masahiro; Sumida, Takayuki

    2016-06-01

    The cytokines are an important substance involved in the immune reaction and maintenance of homeostasis. An imbalance in the cytokine network may lead to inflammation and autoimmune diseases such as rheumatoid arthritis (RA). RA is an autoimmune and systemic inflammatory disorder characterized by synovial inflammation, destruction of cartilage and bone and systemic manifestations. The pro-inflammatory cytokines such as tumor necrosis factor α (TNFα), interleukin-1 (IL-1), IL-6 and IL-17 induce the inflammation of the joints and destruction of bone and cartilage via activation of macrophages, fibroblast like synoviocytes (FLS), helper T (Th) cells and osteoclasts. Recently, the available therapeutic agents that target these cytokines have excellent clinical effects in RA patients.

  6. [Immunostimulating drugs and cytokines].

    PubMed

    Lehners, Nicola; Goldschmidt, Hartmut; Raab, Marc S

    2011-11-01

    Cytokines are essential regulators of hematopoesis and the immune system. Genetic engineering of recombinant cytokines has facilitated their implementation in many clinical areas. In the field of oncology the granulopoetic human growth factors G-CSF and GM-CSF are of particular importance. They can be applied to prevent chemotherapy induced neutropenia. Furthermore, they allow for mobilization of hematopoetic stem cells in order to obtain peripheral blood stem cell transplants. Another class of cytokines, the interferons, possess immunomodulating, antiproliferative, and antiviral properties. While the significance of interferon alfa as an antitumor agent is dwindling, it still plays a very important role in the therapy of chronic hepatitis b and c. Interferon beta is successfully used to treat multiple sclerosis. Among the heterogenous group of interleukines in particular interleukin 2 has reached clinical practice as an immunostimulating agent in the therapy of metastatic renal cell carcinoma. Many other cytokines have yet to undergo clinical trials.

  7. Cytokines and acute pancreatitis.

    PubMed

    Brady, M; Christmas, S; Sutton, R; Neoptolemos, J; Slavin, J

    1999-07-01

    Cytokines have been shown to play a pivotal role in multiple organ dysfunction, a major cause of death in severe acute pancreatitis. Moreover, the two-hit hypothesis of the cytokine-induced systemic inflammatory response syndrome explains the variable individual response to severe acute pancreatitis and the impact of secondary events such as sepsis or therapeutic intervention. Many experimental anti-cytokine therapies have been administered following induction of experimental pancreatitis, and have proved to be therapeutic. Patients with severe pancreatitis present early because of pain. Clearly then a window for therapeutic intervention is available between onset of symptoms and peak pro-inflammatory cytokine expression. It is this fundamental observation that convinces many in the field that the treatment of AP will be one of the first clinical successes for novel drugs or therapy that seek to modulate the inflammatory response.

  8. Jerusalem of cytokines.

    PubMed

    Levi, B Z; Sica, A; Müller-Newen, G; Takahashi, N; Vandenbeele, P; Fish, E

    1999-06-01

    The Second Joint Meeting of the International Cytokine Society and the International Society for Interferon and Cytokine Research was held on October 25-30, 1998 in Jerusalem, Israel. The nature of this Joint Meeting dictated that it was intensive and covered topics that included receptor-ligand interactions, signal transduction, transcriptional regulation, antiviral action and apoptotic pathways induced by cytokines such as interferons, interleukines and chemokines. Their roles in infectious diseases and cancers were considered. This overview is by no mean comprehensive and covers only part of the many topics and subjects that were presented in the many plenary talks, symposia and poster sessions. The meeting was held in an excellent scientific atmosphere, that was probably affected by the "divine presence" in Jerusalem, and special thanks for the excellent organization are owed to Drs. Kaempfer, Revel, Wallach and Witz.

  9. Infanticide secrets

    PubMed Central

    Barr, Jennieffer A.; Beck, Cheryl T.

    2008-01-01

    ABSTRACT OBJECTIVE To explore thoughts of infanticide that did not lead to the act among mothers with postpartum depression. DESIGN A phenomenologic hermeneutic study in which women were invited to share their experiences of having thoughts of infanticide. SETTING Community setting in a large metropolitan city, Brisbane, Australia. PARTICIPANTS Fifteen women who had been diagnosed as clinically depressed with postpartum onset whose babies were 12 months of age or younger. METHOD Audiotaped, in-depth interviews were transcribed verbatim. Thematic analysis commenced immediately after the first interview, and data collection continued until saturation was achieved. A questioning approach that reflected hermeneutics was facilitated by use of journals by the researchers. MAIN FINDINGS Six themes emerged from the data: imagined acts of infanticide, the experience of horror, distorted sense of responsibility, consuming negativity, keeping secrets, and managing the crisis. CONCLUSION Women who experienced nonpsychotic depression preferred not to disclose their thoughts of infanticide to health professionals, including trusted general practitioners or psychiatrists. These women were more likely to mention their suicidal thoughts than their infanticidal thoughts in order to obtain health care. General practitioners and other health professionals should directly ask about whether a woman has been experiencing thoughts of harming herself or her baby, regardless of the reason why she has presented. PMID:19074717

  10. Helper T cells and atherosclerosis: the cytokine web

    PubMed Central

    Baidya, S; Zeng, Q

    2005-01-01

    There is growing evidence regarding the importance of inflammation in the pathogenesis of atherosclerosis and its ultimate progression to the clinical syndromes. Recently there has been an increasing interest in the role of helper T (Th) cells in atherosclerosis. The Th cells act with the macrophages and the dendritic cells via the various cytokines in bringing about a variety of changes thus leading to the progression of atherosclerosis. Atherosclerotic lesions have been seen to have increased expression of type 1 helper T (TH1) cells together with increased levels of the Th1 related cytokines. It is mainly the cytokines involved with Th1 functioning that seem to show a prominent effect, with the whole process centred around interferon gamma, making it seem like every pathway and the cytokines involved lead to a final common pathway of interferon gamma secretion; the increase or decrease of which dictates the progression of atherosclerosis and its final manifestation as the clinical syndromes. PMID:16344296

  11. Interleukin-16 stimulates the expression and production of pro-inflammatory cytokines by human monocytes

    PubMed Central

    Mathy, N L; Scheuer, W; Lanzendörfer, M; Honold, K; Ambrosius, D; Norley, S; Kurth, R

    2000-01-01

    Interleukin-16 (IL-16) acts as a chemoattractant for CD4+ cells, as a modulator of T-cell activation, and plays a key role in asthma. This report describes the cytokine-inducing effects of IL-16 on total peripheral blood mononuclear cells (PBMC) and PBMC subpopulations. While CD4+ T lymphocytes did not secrete cytokines in response to rhIL-16, CD14+ CD4+ monocytes and maturing macrophages secrete IL-1β, IL-6, IL-15 and tumour necrosis factor-α (TNF-α) upon rhIL-16 stimulation. The mRNA species for these four cytokines were detected as early as 4 hr post-stimulation, with protein being secreted by 24 hr. Secretion of IL-1β and IL-6 by total PBMC was dose dependent, with maximal secretion being observed using 50 ng/ml rhIL-16. However, for IL-15 or TNF-α maximal secretion by total PBMC occurred with all concentrations between 5 ng/ml to 500 ng/ml rhIL-16. Purified monocytes/macrophages secreted maximal concentrations of all four cytokines in the presence of 500 ng/ml rhIL-16, except for monocytes where maximal secretion of IL-15 was, interestingly, observed with only 50 ng/ml rhIL-16. The use of higher concentrations of rhIL-16 (1000 ng/ml) inhibited secretion of all four cytokines. While these IL-16-induced cytokines are likely to be involved in the immune system's response to antigen, the data suggest that IL-16 may play a key role in initiating and/or sustaining an inflammatory response. PMID:10809960

  12. Altered cytokine network in gestational diabetes mellitus affects maternal insulin and placental-fetal development.

    PubMed

    Wedekind, Lauren; Belkacemi, Louiza

    2016-01-01

    Pregnancy is characterized by an altered inflammatory profile, compared to the non-pregnant state with an adequate balance between pro-and anti-inflammatory cytokines needed for normal development. Cytokines are small secreted proteins expressed mainly in immunocompetent cells in the reproductive system. From early developmental stages onward, the secretory activity of placenta cells clearly contributes to increase local as well as systemic levels of cytokines. The placental production of cytokines may affect mother and fetus independently. In turn because of this unique position at the maternal fetal interface, the placenta is also exposed to the regulatory influence of cytokines from maternal and fetal circulations, and hence, may be affected by changes in any of these. Gestational diabetes mellitus (GDM) is associated with an overall alteration of the cytokine network. This review discusses the changes that occur in cytokines post GDM and their negative effects on maternal insulin and placental-fetal development. PMID:27230834

  13. Signaling of Cytokines is Important in Regulation of GnRH Neurons

    PubMed Central

    Wolfe, Andrew

    2016-01-01

    Cytokines encompass a broad class of peptides that mediate signals in a broad range of physiological situations including inflammation, infection, and obesity. The cytokine receptor-associated tyrosine kinase, Jak2, is one of the most important proteins mediating cytokine signaling pathway activation. Recently, our group has demonstrated that Jak2 signaling in the gonadotropin-releasing hormone (GnRH) neuron plays a critical role in fertility in males and females, implicating cytokine activation of the neuron in GnRH neuronal development and function. To date, the specific cytokine(s) essential for activating Jak2 during neuroendocrine development are not known. In this article, we review the evidence for the role of several class 1 cytokines in regulating GnRH neuronal development, GnRH secretion, and GnRH expression. PMID:22161498

  14. Divergent T-Cell Cytokine Patterns in Inflammatory Arthritis

    NASA Astrophysics Data System (ADS)

    Simon, A. K.; Seipelt, E.; Sieper, J.

    1994-08-01

    A major immunoregulatory mechanism in inflammatory infections and allergic diseases is the control of the balance of cytokines secreted by Th1/Th2 subsets of T helper (Th) cells. This might also be true in autoimmune diseases; a Th2 pattern that prevents an effective immune response in infections with intracellular bacteria may favor immunosuppression in autoimmune diseases. The pattern of cytokine expression was compared in the synovial tissue from patients with a typical autoimmune disease, rheumatoid arthritis, and with a disorder with similar synovial pathology but driven by persisting exogenous antigen, reactive arthritis. We screened 12 rheumatoid and 9 reactive arthritis synovial tissues by PCR and in situ hybridization for their expression of T-cell cytokines. The cytokine pattern differs significantly between the two diseases; rheumatoid arthritis samples express a Th1-like pattern whereas in reactive arthritis interferon γ expression is accompanied by that of interleukin 4. Studying the expression of cytokines by in situ hybridization confirmed the results found by PCR; they also show an extremely low frequency of cytokine-transcribing cells. In a double-staining experiment, it was demonstrated that interleukin 4 is made by CD4 cells. These experiments favor the possibility of therapeutic intervention in inflammatory rheumatic diseases by means of inhibitory cytokines.

  15. B cell abnormalities in systemic lupus erythematosus

    PubMed Central

    2003-01-01

    Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease characterized by the differentiation of short- and long-lived immunoglobulin secreting plasma cells that secrete pathogenic autoantibodies. Ectopic germinal centers and plasma cells secreting autoantibodies have been observed in lupus nephritis kidneys. Candidate genetic susceptibility loci for SLE include genes that affect differentiation and survival of plasma cells, such as those that influence activation, proliferation, cytokine and chemokine secretion/responsiveness, and apoptosis of the T and B cells that are involved in humoral immunity generated in germinal centers, as well as genes that are involved in presentation and clearance of apoptotic material and autoantigens by antigen presenting cells and other phagocytes. Emerging data have demonstrated that B lymphocytes are active participants in humoral immune responses that lead to T-dependent and T-independent differentiation of immunoglobulin-secreting plasma cells by homotypic CD154–CD40 interactions as well as continued stimulation by B cell activating factor through B cell maturation antigen, B cell activating factor receptor and transmembrane activater. PMID:15180894

  16. B cell abnormalities in systemic lupus erythematosus.

    PubMed

    Grammer, Amrie C; Lipsky, Peter E

    2003-01-01

    Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease characterized by the differentiation of short- and long-lived immunoglobulin secreting plasma cells that secrete pathogenic autoantibodies. Ectopic germinal centers and plasma cells secreting autoantibodies have been observed in lupus nephritis kidneys. Candidate genetic susceptibility loci for SLE include genes that affect differentiation and survival of plasma cells, such as those that influence activation, proliferation, cytokine and chemokine secretion/responsiveness, and apoptosis of the T and B cells that are involved in humoral immunity generated in germinal centers, as well as genes that are involved in presentation and clearance of apoptotic material and autoantigens by antigen presenting cells and other phagocytes. Emerging data have demonstrated that B lymphocytes are active participants in humoral immune responses that lead to T-dependent and T-independent differentiation of immunoglobulin-secreting plasma cells by homotypic CD154-CD40 interactions as well as continued stimulation by B cell activating factor through B cell maturation antigen, B cell activating factor receptor and transmembrane activater.

  17. Structural and Topographic Dynamics of Pulmonary Histopathology and Local Cytokine Profiles in Paracoccidioides brasiliensis Conidia-Infected Mice

    PubMed Central

    Cruz, Oswaldo G.; Restrepo, Angela; Cano, Luz Elena; Lenzi, Henrique Leonel

    2011-01-01

    Background Paracoccidioidomycosis (PCM), an endemic systemic mycosis caused by the fungus Paracoccidioides brasiliensis (Pb), usually results in severe lung damage in patients. Methods and Findings Considering the difficulties to sequentially study the infection in humans, this work was done in mice inoculated intranasally with infective Pb-conidia. Lungs of control and Pb-infected mice were studied after 2-hours, 4, 8, 12 and 16-weeks post-infection (p.i) in order to define histopathologic patterns of pulmonary lesions, multiplex-cytokine profiles and their dynamics during the course of this mycosis. Besides the nodular/granulomatous lesions previously informed, results revealed additional non-formerly described lung abnormalities, such as periarterial sheath inflammation and pseudotumoral masses. The following chronologic stages occurring during the course of the experimental infection were defined: Stage one (2-hours p.i): mild septal infiltration composed by neutrophils and macrophages accompanied by an intense “cytokine burst” represented by significant increases in IL-1α, IL-1β, IL-4, IL-5, IL-6, IL-10, IL12p70, IL-13, IL-17, Eotaxin, G-CSF, MCP1, MIP1α, GM-CSF, IFN-γ, MIP1β and TNFα levels. Stage two (4-weeks p.i): presence of nodules, evidence of incipient periarterial- and intense but disperse parenchymal- inflammation, abnormalities that continued to be accompanied by hyper-secretion of those cytokines and chemokines mentioned in the first stage of infection. Stages three and four (8 and 12-weeks p.i.): fungal proliferation, inflammation and collagenesis reached their highest intensity with particular involvement of the periarterial space. Paradoxically, lung cytokines and chemokines were down-regulated with significant decreases in IL-2,IL-3,IL-5,IL-9,IL-13,IL-15,GM-CSF,IFN-γ,MIP1β and TNFα. Stage five (16-weeks p.i.): inflammation decreased becoming limited to the pseudotumoral masses and was accompanied by a “silent” cytokine response

  18. [Cytokines, endothelial dysfunction, and insulin resistance].

    PubMed

    de Carvalho, Maria Helena C; Colaço, André Luiz; Fortes, Zuleica Bruno

    2006-04-01

    Endothelial dysfunction is associated with several vascular conditions as atherosclerosis, hypertension, hyperlipidemia and diabetes mellitus. In all these conditions insulin resistance (IR) is present. Cytokines are low molecular weight proteins with several endocrine and metabolic functions that participate of inflammation and immune response. Several of these cytokines are independent risk factors for cerebrovascular and coronary artery disease. The major sources of cytokines (adipokines) are the visceral and subcutaneous adipose tissues. Thus, increased adipose tissue mass is associated with alteration in adipokine production as over expression of tumor necrosis factor alpha, interleukin 6, plasminogen activator inhibitor 1, and under expression of adiponectin in adipocite tissue. The pro-inflammatory status associated with these changes provides a potential link between IR and endothelial dysfunction, the early stage in the atherosclerotic process, in obese individuals, and type 2 diabetic patients. Reduction of adipose tissue mass through weight reduction in association with exercise reduces TNF-alpha, IL-6, and PAI-1, increases adiponectin, and is associated with improved insulin sensitivity and endothelial function. This review will focus on the evidence for regulation of endothelial function by insulin and the adypokines such as adyponectin, leptin, resistin, IL-6 and TNF-alpha. Interaction between insulin signaling and adypokines will be discussed, as well as the concept that aberrant adypokine secretion in IR and/or obesity impairs endothelial function and contributes further to reduce insulin sensitivity.

  19. Coordinate cytokine regulatory sequences

    DOEpatents

    Frazer, Kelly A.; Rubin, Edward M.; Loots, Gabriela G.

    2005-05-10

    The present invention provides CNS sequences that regulate the cytokine gene expression, expression cassettes and vectors comprising or lacking the CNS sequences, host cells and non-human transgenic animals comprising the CNS sequences or lacking the CNS sequences. The present invention also provides methods for identifying compounds that modulate the functions of CNS sequences as well as methods for diagnosing defects in the CNS sequences of patients.

  20. [Cytokines and the liver].

    PubMed

    Kershenobich, D; Borovoy, J; Guevara, L; Male, R; Alcocer, J

    1990-07-01

    The cytokines are proteins synthetized by lymphoid and monocyte/macrophage system cells in response to a wide variety of infectious stimulus, featuring bacterial endotoxins. These proteins have immunoregulatory effects and have been implicated in inflammation and fibrosis. In this review we refer to the interleukin-1, interleukin-6 and tumor necrosis factor because of their elevated basal levels in acute and chronic hepatopaties and in response to lipopolisacharide mainly in alcoholic liver disease. PMID:19256129

  1. Insulin and Glucagon Secretion In Vitro

    NASA Technical Reports Server (NTRS)

    Rajan, Arun S.

    1998-01-01

    Long-duration space flight is associated with many physiological abnormalities in astronauts. In particular, altered regulation of the hormones insulin and glucagon may contribute to metabolic disturbances such as increased blood sugar levels, which if persistently elevated result in toxic effects. These changes are also observed in the highly prevalent disease diabetes, which affects 16 million Americans and consumes over $100 billion in annual healthcare costs. By mimicking the microgravity environment of space in the research laboratory using a NASA-developed bioreactor, one can study the physiology of insulin and glucagon secretion and determine if there are alterations in these cellular processes. The original specific objectives of the project included: (1) growing ('cell culture') of pancreatic islet beta and alpha cells that secrete insulin and glucagon respectively, in the NASA bioreactor; (2) examination of the effects of microgravity on insulin and glucagon secretion; and (3) study of molecular mechanisms of insulin and glucagon secretion if altered by microgravity.

  2. The role of cytokines in skin aging.

    PubMed

    Borg, M; Brincat, S; Camilleri, G; Schembri-Wismayer, P; Brincat, M; Calleja-Agius, J

    2013-10-01

    Cutaneous aging is one of the major noticeable menopausal complications that most women want to fight in their quest for an eternally youthful skin appearance. It may contribute to some maladies that occur in aging which, despite not being life-threatening, affect the well-being, psychological state and quality of life of aged women. Skin aging is mainly affected by three factors: chronological aging, decreased levels of estrogen after menopause, and environmental factors. Aged skin is characterized by a decrease in collagen content and skin thickness which result in dry, wrinkled skin that is easily bruised and takes a longer time to heal. Cytokines play a crucial role in the manifestation of these features of old skin. The pro-inflammatory cytokine tumor necrosis factor-alpha inhibits collagen synthesis and enhances collagen degradation by increasing the production of MMP-9. It also lowers the skin immunity and thus increases the risk of cutaneous infections in old age. Deranged levels of several interleukins and interferons also affect the aging process. The high level of CCN1 protein in aged skin gives dermal fibroblasts an 'age-associated secretory phenotype' that causes abnormal homeostasis of skin collagen and leads to the loss of the function and integrity of skin. Further research is required especially to establish the role of cytokines in the treatment of cutaneous aging.

  3. Cytokine Therapies in Neurological Disease.

    PubMed

    Azodi, Shila; Jacobson, Steven

    2016-07-01

    Cytokines are a heterogeneous group of glycoproteins that coordinate physiological functions. Cytokine deregulation is observed in many neurological diseases. This article reviews current research focused on human clinical trials of cytokine and anticytokine therapies in the treatment of several neurological disease including stroke, neuromuscular diseases, neuroinfectious diseases, demyelinating diseases, and neurobehavioral diseases. This research suggests that cytokine therapy applications may play an important role in offering new strategies for disease modulation and treatment. Further, this research provides insights into the causal link between cytokine deregulation and neurological diseases. PMID:27388288

  4. Curcumin regulates airway epithelial cell cytokine responses to the pollutant cadmium.

    PubMed

    Rennolds, Jessica; Malireddy, Smitha; Hassan, Fatemat; Tridandapani, Susheela; Parinandi, Narasimham; Boyaka, Prosper N; Cormet-Boyaka, Estelle

    2012-01-01

    Cadmium is a toxic metal present in the environment and its inhalation can lead to pulmonary disease such as lung cancer and chronic obstructive pulmonary disease. These lung diseases are characterized by chronic inflammation. Here we show that exposure of human airway epithelial cells to cadmium promotes a polarized apical secretion of IL-6 and IL-8, two pivotal pro-inflammatory cytokines known to play an important role in pulmonary inflammation. We also determined that two distinct pathways controlled secretion of these proinflammatory cytokines by human airway epithelial cells as cadmium-induced IL-6 secretion occurs via an NF-κB dependent pathway, whereas IL-8 secretion involves the Erk1/2 signaling pathway. Interestingly, the natural antioxidant curcumin could prevent both cadmium-induced IL-6 and IL-8 secretion by human airway epithelial cells. In conclusion, curcumin could be used to prevent airway inflammation due to cadmium inhalation.

  5. A Possible Change Process of Inflammatory Cytokines in the Prolonged Chronic Stress and Its Ultimate Implications for Health

    PubMed Central

    Tian, Rui; Hou, Gonglin; Li, Dan; Yuan, Ti-Fei

    2014-01-01

    Sustained stress triggers series of changes in the brain and the body. At the early stage of stress, the activated hypothalamus-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) axis can upregulate the levels of glucocorticoid (GCs) and catecholamines (CAs), respectively, and then they in turn inhibit the secretion of proinflammatory cytokines directly or indirectly while promoting the secretion of anti-inflammatory cytokines. At the prolonged stage, the sustained activated HPA demonstrates cortisol-resistance. At the same time, the inflammation related transcription pathway, such as nuclear-factor kappa-B (NF-κB) signaling, may be inhibited. Additionally, the inflammatory cytokines mediate a negative feedback regulation on themselves. Collectively, these regulations may increase the proinflammatory cytokines while decreasing the anti-inflammatory cytokines. This may further activate NF-κB and increase the proinflammation cytokines, which in turn reduce the inflammatory responses, contributing to various diseases. PMID:24995360

  6. Tooth - abnormal shape

    MedlinePlus

    Hutchinson incisors; Abnormal tooth shape; Peg teeth; Mulberry teeth; Conical teeth ... The appearance of normal teeth varies, especially the molars. ... conditions. Specific diseases can affect tooth shape, tooth ...

  7. The Role of Cytokines and Chemokines in Filovirus Infection

    PubMed Central

    Bixler, Sandra L.; Goff, Arthur J.

    2015-01-01

    Ebola- and marburgviruses are highly pathogenic filoviruses and causative agents of viral hemorrhagic fever. Filovirus disease is characterized by a dysregulated immune response, severe organ damage, and coagulation abnormalities. This includes modulation of cytokines, signaling mediators that regulate various components of the immune system as well as other biological processes. Here we examine the role of cytokines in filovirus infection, with an emphasis on understanding how these molecules affect development of the antiviral immune response and influence pathology. These proteins may present targets for immune modulation by therapeutic agents and vaccines in an effort to boost the natural immune response to infection and/or reduce immunopathology. PMID:26512687

  8. Cytokines (interleukin-9, IL-17, IL-22, IL-25 and IL-33) and asthma

    PubMed Central

    Farahani, Rahim; Sherkat, Roya; Hakemi, Mazdak Ganjalikhani; Eskandari, Nahid; Yazdani, Reza

    2014-01-01

    Asthma is a reversible airway obstruction that is characterized by constriction of airway smooth muscle, hyper secretion of mucus, edema and airway hyper responsiveness (AHR), mucus secretion and thickening of the basement membrane underlying the airway epithelium. During the process of airway inflammation, complex interactions of innate and adaptive immune cells as well as structural cells and their cytokines have many important roles. It was believed that airway inflammation is orchestrated by allergen specific T helper (Th) 2 cells, which recruit and accumulate in the lungs and produce a range of different effector cytokines. However, more recent studies have revealed the potential collaboration of other helper T cells and their cytokines in this process. Th17 cell may have a role in severe asthma and chronic obstructive pulmonary disease (COPD). Interleukin (IL)-9-producing subset called Th9 cell, Th22 cells which primarily secrete IL-22, IL-13 and tumor necrosis factor-α and Th25 cells via producing IL-25 are believed to be important for initiating allergic reactions and developing airway inflammation. Cytokines are important in asthma and play a critical role in orchestrating the allergic inflammatory response, although the precise role of each cytokine remains to be determined. The aim of this review is to summarize the current knowledge about the possible roles of newly identified helper T cells derived cytokines (IL-9, 17, 22, 25 and IL-33) in asthma. The potential therapeutic applications emerging from the roles of these cytokines will be discussed as well. PMID:24949298

  9. Suppression of Proinflammatory Cytokines in Functionalized Fullerene-Exposed Dermal Keratinocytes

    DOE PAGES

    Gao, Jun; Wang, Hsing-Lin; Iyer, Rashi

    2010-01-01

    Initial experiments using differentially functionalized fullerenes, CD-, hexa-, and tris-, suggested a properties dependent effect on cytotoxic and proliferative responses in human skin keratinocytes. In the present study we investigated the cytokine secretion profile of dermal epithelial cells exposed to functionalized fullerenes. Keratinocyte-derived cytokines affect homing and trafficking of normal and malignant epidermal immune as well as nonimmune cells in vivo. These cytokines are critical for regulating activation, proliferation, and differentiation of epidermal cells. Our results indicate that tris- (size range <100 nm) significantly reduces inflammatory cytokine release in a dose- and time-dependent manner. In contrast CD- demonstrated a relatively pro-inflammatorymore » cytokine response, while hexa- did not significantly perturb cytokine responses. Physical and chemical characterizations of these engineered nanomaterials suggest that the disparate biological responses observed may potentially be a function of the aggregation properties of these fullerenes.« less

  10. Flavonoids as Cytokine Modulators: A Possible Therapy for Inflammation-Related Diseases

    PubMed Central

    Leyva-López, Nayely; Gutierrez-Grijalva, Erick P.; Ambriz-Perez, Dulce L.; Heredia, J. Basilio

    2016-01-01

    High levels of cytokines, such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α and IL-6, are associated with chronic diseases like rheumatoid arthritis, asthma, atherosclerosis, Alzheimer’s disease and cancer; therefore cytokine inhibition might be an important target for the treatment of these diseases. Most drugs used to alleviate some inflammation-related symptoms act by inhibiting cyclooxygenases activity or by blocking cytokine receptors. Nevertheless, these drugs have secondary effects when used on a long-term basis. It has been mentioned that flavonoids, namely quercetin, apigenin and luteolin, reduce cytokine expression and secretion. In this regard, flavonoids may have therapeutical potential in the treatment of inflammation-related diseases as cytokine modulators. This review is focused on current research about the effect of flavonoids on cytokine modulation and the description of the way these compounds exert their effect. PMID:27294919

  11. Cytokines and the hypothalamic-pituitary-adrenal axis.

    PubMed

    Hermus, A R; Sweep, C G

    1990-12-20

    After administration of the cytokines interleukin 1 (IL1), tumor necrosis factor (TNF), interleukin 2 and interleukin 6 to laboratory animals or humans, plasma levels of glucocorticoids are elevated. This effect is mediated by activation of the hypothalamic-pituitary unit. IL1 and TNF inhibit aldosterone production by rat adrenocortical cells in vitro and stimulate renin release by rat renal cortical cells. Administration of IL1 or TNF in rats suppresses hypothalamic-pituitary-thyroid function, whereas IL1 acts at the level of the brain and the gonads to interfere with gonadotropin and sex steroid secretion. During stimulation of the immune system (e.g. during infectious diseases), peculiar alterations in hormone secretion occur (hypercortisolism, hyperreninemic hypoaldosteronism, euthyroid sick syndrome, hypogonadism). The role of cytokines in these alterations remains to be established.

  12. Autophagy Protects against Colitis by the Maintenance of Normal Gut Microflora and Secretion of Mucus*

    PubMed Central

    Tsuboi, Koichiro; Nishitani, Mayo; Takakura, Atsushi; Imai, Yasuyuki; Komatsu, Masaaki; Kawashima, Hiroto

    2015-01-01

    Genome-wide association studies of inflammatory bowel diseases identified susceptible loci containing an autophagy-related gene. However, the role of autophagy in the colon, a major affected area in inflammatory bowel diseases, is not clear. Here, we show that colonic epithelial cell-specific autophagy-related gene 7 (Atg7) conditional knock-out (cKO) mice showed exacerbation of experimental colitis with more abundant bacterial invasion into the colonic epithelium. Quantitative PCR analysis revealed that cKO mice had abnormal microflora with an increase of some genera. Consistently, expression of antimicrobial or antiparasitic peptides such as angiogenin-4, Relmβ, intelectin-1, and intelectin-2 as well as that of their inducer cytokines was significantly reduced in the cKO mice. Furthermore, secretion of colonic mucins that function as a mucosal barrier against bacterial invasion was also significantly diminished in cKO mice. Taken together, our results indicate that autophagy in colonic epithelial cells protects against colitis by the maintenance of normal gut microflora and secretion of mucus. PMID:26149685

  13. Autophagy Protects against Colitis by the Maintenance of Normal Gut Microflora and Secretion of Mucus.

    PubMed

    Tsuboi, Koichiro; Nishitani, Mayo; Takakura, Atsushi; Imai, Yasuyuki; Komatsu, Masaaki; Kawashima, Hiroto

    2015-08-14

    Genome-wide association studies of inflammatory bowel diseases identified susceptible loci containing an autophagy-related gene. However, the role of autophagy in the colon, a major affected area in inflammatory bowel diseases, is not clear. Here, we show that colonic epithelial cell-specific autophagy-related gene 7 (Atg7) conditional knock-out (cKO) mice showed exacerbation of experimental colitis with more abundant bacterial invasion into the colonic epithelium. Quantitative PCR analysis revealed that cKO mice had abnormal microflora with an increase of some genera. Consistently, expression of antimicrobial or antiparasitic peptides such as angiogenin-4, Relmβ, intelectin-1, and intelectin-2 as well as that of their inducer cytokines was significantly reduced in the cKO mice. Furthermore, secretion of colonic mucins that function as a mucosal barrier against bacterial invasion was also significantly diminished in cKO mice. Taken together, our results indicate that autophagy in colonic epithelial cells protects against colitis by the maintenance of normal gut microflora and secretion of mucus.

  14. Structurally abnormal human autosomes

    SciTech Connect

    1993-12-31

    Chapter 25, discusses structurally abnormal human autosomes. This discussion includes: structurally abnormal chromosomes, chromosomal polymorphisms, pericentric inversions, paracentric inversions, deletions or partial monosomies, cri du chat (cat cry) syndrome, ring chromosomes, insertions, duplication or pure partial trisomy and mosaicism. 71 refs., 8 figs.

  15. [Cytokines in bone diseases. Cytokine and postmenopausal osteoporosis].

    PubMed

    Inada, Masaki; Miyaura, Chisato

    2010-10-01

    Bone resorption is regulated by various cytokines. In postmenopausal osteoporosis, bone loss due to estrogen deficiency is closely related to the production of bone-resorbing cytokine. Especially, the increased production of IL-1, IL-6 and TNF-α could induce the expression of RANKL in bone tissues to enhance osteoclastogenesis. Relationship between estrogen deficiency and various cytokines is important to clarify the pathogenesis of postmenopausal osteoporosis.

  16. Secreted Lymphotoxin-α Is Essential for the Control of an Intracellular Bacterial Infection

    PubMed Central

    Roach, Daniel R.; Briscoe, Helen; Saunders, Bernardette; France, Malcolm P.; Riminton, Sean; Britton, Warwick J.

    2001-01-01

    Although the essential role of tumor necrosis factor (TNF) in the control of intracellular bac-terial infection is well established, it is uncertain whether the related cytokines lymphotoxin-α (LTα3) and lymphotoxin-β (LTβ) have independent roles in this process. Using C57Bl/6 mice in which the genes for these cytokines have been disrupted, we have examined the relative contribution of secreted LTα3 and membrane-bound LTβ in the host response to aerosol Mycobacterium tuberculosis infection. To overcome the lack of peripheral lymph nodes in LTα−/− and LTβ−/− mice, bone marrow chimeric mice were constructed. LTα−/− chimeras, which lack both secreted LTα3 and membrane-bound LTβ (LTα1β2 and LTα2β1), were highly susceptible and succumbed 5 wk after infection. LTβ−/− chimeras, which lack only the membrane-bound LTβ, controlled the infection in a comparable manner to wild-type (WT) chimeric mice. T cell responses to mycobacterial antigens and macrophage responses in LTα−/− chimeras were equivalent to those of WT chimeras, but in LTα−/− chimeras, granuloma formation was abnormal. LTα−/− chimeras recruited normal numbers of T cells into their lungs, but the lymphocytes were restricted to perivascular and peribronchial areas and were not colocated with macrophages in granulomas. Therefore, LTα3 is essential for the control of pulmonary tuberculosis, and its critical role lies not in the activation of T cells and macrophages per se but in the local organization of the granulomatous response. PMID:11208864

  17. MicroRNA-Regulated Proinflammatory Cytokines in Sarcopenia

    PubMed Central

    Fan, Jingjing; Kou, Xianjuan; Yang, Yi; Chen, Ning

    2016-01-01

    Sarcopenia has been defined as the aging-related disease with the declined mass, strength, and function of skeletal muscle, which is the major cause of frailty and falls in elders. The activation of inflammatory signal pathways due to diseases and aging is suggested to reveal the critical impact on sarcopenia. Several proinflammatory cytokines, especially interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), play crucial roles in modulation of inflammatory signaling pathway during the aging-related loss of skeletal muscle. MicroRNAs (miRNAs) have emerged as the important regulators for the mass and functional maintenance of skeletal muscle through regulating gene expression of proinflammatory cytokines. In this paper, we have systematically discussed regulatory mechanisms of miRNAs for the expression and secretion of inflammatory cytokines during sarcopenia, which will provide some novel targets and therapeutic strategies for controlling aging-related atrophy of skeletal muscle and corresponding chronic inflammatory diseases. PMID:27382188

  18. Morphological abnormalities among lampreys

    USGS Publications Warehouse

    Manion, Patrick J.

    1967-01-01

    The experimental control of the sea lamprey (Petromyzon marinus) in the Great Lakes has required the collection of thousands of lampreys. Representatives of each life stage of the four species of the Lake Superior basin were examined for structural abnormalities. The most common aberration was the presence of additional tails. The accessory tails were always postanal and smaller than the normal tail. The point of origin varied; the extra tails occurred on dorsal, ventral, or lateral surfaces. Some of the extra tails were misshaped and curled, but others were normal in shape and pigment pattern. Other abnormalities in larval sea lampreys were malformed or twisted tails and bodies. The cause of the structural abnormalities is unknown. The presence of extra caudal fins could be genetically controlled, or be due to partial amputation or injury followed by abnormal regeneration. Few if any lampreys with structural abnormalities live to sexual maturity.

  19. Human placental trophoblasts express the immunosuppressive cytokine IL-35.

    PubMed

    Mao, Haiting; Gao, Wenjuan; Ma, Chao; Sun, Jintang; Liu, Jia; Shao, Qianqian; Song, Bingfeng; Qu, Xun

    2013-07-01

    Studies of maternal-fetal tolerance focus on defining mechanisms for establishment of immunological privilege within the uterus during pregnancy. Fetal trophoblasts play a key role in maternal tolerance, in part through cytokines production. As a novel inhibitory cytokine, IL-35 is produced by Foxp3(+) regulatory T cells (Tregs) and mediates maximal suppression of Tregs. The purpose of the study is to analyze the expression of IL-35 in first-trimester human placental trophoblasts. IL-35 expression was detected at both protein and mRNA levels by immunohistochemical staining and quantitative real-time PCR method, respectively and secretion of IL-35 was measured by ELISA assay. Our results demonstrated that human trophoblasts constitutively expressed IL-35. Ebi3 and p35 (two subunits of IL-35) mRNA was shown to be co-expressed in trophoblast cells. Moreover, large amounts of secreted IL-35 were detected in the supernatants of trophoblast cells. But we did not detect the constitutive expression of IL-35 in decidual stromal cells. Our findings confirmed for the first time that first-trimester human trophoblast cells expressed and secreted IL-35, which might contribute to their suppressive capacity to maternal immune cells. Therefore, IL-35 may be an important factor of the cytokine network regulating local immune responses during human pregnancy.

  20. TLR signals posttranscriptionally regulate the cytokine trafficking mediator sortilin

    PubMed Central

    Yabe-Wada, Toshiki; Matsuba, Shintaro; Takeda, Kazuya; Sato, Tetsuya; Suyama, Mikita; Ohkawa, Yasuyuki; Takai, Toshiyuki; Shi, Haifeng; Philpott, Caroline C.; Nakamura, Akira

    2016-01-01

    Regulating the transcription, translation and secretion of cytokines is crucial for controlling the appropriate balance of inflammation. Here we report that the sorting receptor sortilin plays a key role in cytokine production. We observed interactions of sortilin with multiple cytokines including IFN-α, and sortilin depletion in plasmacytoid dendritic cells (pDCs) led to a reduction of IFN-α secretion, suggesting a pivotal role of sortilin in the exocytic trafficking of IFN-α in pDCs. Moreover, sortilin mRNA was degraded posttranscriptionally upon stimulation with various TLR ligands. Poly-rC-binding protein 1 (PCBP1) recognized the C-rich element (CRE) in the 3′ UTR of sortilin mRNA, and depletion of PCBP1 enhanced the degradation of sortilin transcripts, suggesting that PCBP1 can act as a trans-acting factor to stabilize sortilin transcripts. The nucleotide-binding ability of PCBP1 was impaired by zinc ions and alterations of intracellular zinc affect sortilin expression. PCBP1 may therefore control the stability of sortilin transcripts by sensing intracellular zinc levels. Collectively, our findings provide insights into the posttranslational regulation of cytokine production through the posttranscriptional control of sortilin expression by TLR signals. PMID:27220277

  1. Modulation of Cytokine Network in the Comorbidity of Schizophrenia and Tuberculosis.

    PubMed

    Cai, Lei; Yang, Yu-Hong; He, Lin; Chou, Kuo-Chen

    2016-01-01

    Schizophrenia is a severe complex disabling disease that has impaired about 1% of the total population. It is widely recognized that schizophrenia is caused by the abnormal immune system. However, the current genome-wide association study (GWAS) of schizophrenia did not identify any cytokine molecules except genes in the major histocompatibility complex (MHC) region, suggesting that new strategies are needed to find out the effects of cytokines during the development of Schizophrenia. Recently, increasing evidences have found the comorbidity of schizophrenia with tuberculosis. To narrow down the scope of cytokines and reveal the core culprit, we first systematically review the common cytokines between these two diseases, followed by summarizing the core cytokines' interaction and modulation. The findings thus obtained may provide useful insights into the pathogeneses of both schizophrenia and tuberculosis from the angle of cytokines.

  2. Adaptive interactions between cytokines and the hypothalamic-pituitary-gonadal axis.

    PubMed

    Cannon, J G

    1998-09-29

    Circulating and tissue concentrations of pyrogenic cytokines, especially interleukin (IL)-1 beta, vary temporally through the menstrual cycle and pregnancy. The secretion of these cytokines in vitro by isolated human mononuclear cells is significantly influenced by exogenous gonadal steroids and gonadotropins. Reciprocally, cytokines influence gonadotropin secretion by the pituitary and steroidogenesis by the ovaries and testes. Several hypotheses have been advanced regarding the adaptive value of these interrelationships. Cytokine-induced synthesis of proteolytic enzymes and extracellular matrix proteins may be important for the tissue remodeling necessary for ovulation, implantation, and delivery. Tolerance of the fetal allograft may require downregulation of cytotoxic effector cells and reciprocal upregulation of humoral and nonspecific host defenses. The inhibitory influence of IL-1 beta on the luteinizing hormone surge may prevent inopportune conception, and the abortive influences of tumor necrosis factor-alpha and gamma interferon may terminate pregnancy during periods of infection.

  3. Abnormal uterine bleeding.

    PubMed

    Jennings, J C

    1995-11-01

    Physicians who care for female patients cannot avoid the frequent complaint of abnormal uterine bleeding. Knowledge of the disorders that cause this problem can prevent serious consequences in many patients and improve the quality of life for many others. The availability of noninvasive and minimally invasive diagnostic studies and minimally invasive surgical treatment has revolutionized management of abnormal uterine bleeding. Similar to any other disorder, the extent to which a physician manages abnormal uterine bleeding depends on his or her own level of comfort. When limitations of either diagnostic or therapeutic capability are encountered, consultation and referral should be used to the best interest of patients.

  4. Differential regulation of monocyte cytokine release by αV and β2 integrins that bind CD23

    PubMed Central

    Edkins, Adrienne L; Borland, Gillian; Acharya, Mridu; Cogdell, Richard J; Ozanne, Bradford W; Cushley, William

    2012-01-01

    The human soluble CD23 (sCD23) protein displays highly pleiotropic cytokine-like activity. Monocytic cells express the sCD23-binding integrins αVβ3, αVβ5, αMβ2 and αXβ2, but it is unclear which of these four integrins most acutely regulates sCD23-driven cytokine release. The hypothesis that ligation of different sCD23-binding integrins promoted release of distinct subsets of cytokines was tested. Lipopolysaccharide (LPS) and sCD23 promoted release of distinct groups of cytokines from the THP-1 model cell line. The sCD23-driven cytokine release signature was characterized by elevated amounts of RANTES (CCL5) and a striking increase in interleukin-8 (IL-8; CXCL8) secretion, but little release of macrophage inflammatory protein 1β (MIP-1β; CCL4). Antibodies to αVβ3 or αXβ2 both promoted IL-8 release, consistent with the sCD23-driven pattern, but both also evoked strong MIP-1β secretion; simultaneous ligation of these two integrins further increased cytokine secretion but did not alter the pattern of cytokine output. In both model cell lines and primary tissue, integrin-mediated cytokine release was more pronounced in immature monocyte cells than in mature cells. The capacity of anti-integrin monoclonal antibodies to elicit a cytokine release response is epitope-dependent and also reflects the differentiation state of the cell. Although a pattern of cytokine release identical to that provoked by sCD23 could not be elicited with any individual anti-integrin monoclonal antibody, αXβ2 and αVβ3 appear to regulate IL-8 release, a hallmark feature of sCD23-driven cytokine secretion, more acutely than αMβ2 or αVβ5. PMID:22348662

  5. Recent advances in cytokines in cutaneous and systemic lupus erythematosus.

    PubMed

    Mikita, Naoya; Ikeda, Takaharu; Ishiguro, Mariko; Furukawa, Fukumi

    2011-09-01

    Lupus erythematosus (LE) includes a broad spectrum of diseases from a cutaneous-limited type to a systemic type. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease which affects multiple organs. Cutaneous lupus erythematosus (CLE) includes skin symptoms seen in SLE and cutaneous-limited LE. Although immune abnormalities, as well as heritable, hormonal and environmental factors, are involved in the pathology of LE, the actual pathogenesis is still unclear. Recently, the involvement of various cytokines has been shown in the pathogenesis of LE. Moreover, some trials with biological agents targeted specific cytokines are also ongoing for SLE. In this article, we review the contributions of major cytokines such as interferon, tumor necrosis factor-α and interleukin-18 to LE, especially SLE and CLE.

  6. Macrophage cytokine response to particles and lipopolysaccharide in vitro.

    PubMed

    Daniels, A U; Barnes, F H; Charlebois, S J; Smith, R A

    2000-03-15

    Several investigators have suggested that biologic molecules adsorbed onto particles may play a key role in determining macrophage response. Adsorbed endotoxins (bacterial debris) may be of particular importance since they are widely present exogenously and endogenously and adhere strongly to many materials. Murine-transformed peritoneal macrophages (IC-21) were used in this in vitro study. Secretions of IL-1 beta, TNF alpha, and IL-6 were used as a measure of macrophage response to micron-range particles of high-density polyethylene and Co-Cr-Mo alloy, with and without adsorbed lipopolysaccharide (LPS) endotoxin. Little cytokine secretion was measured in response to particles (and to polypropylene experimental chambers) cleaned with ethanol and saline and not exposed to LPS. The lack of macrophage response to cleaned particles has been reported by others and may help reconcile conflicting reports in the literature. Cytokine secretion levels were high in all cases if the chambers (with or without particles) were exposed to LPS (and rinsed to minimize nonbound LPS). Secretion patterns were different with particles present and for polymer versus metal particles. Overall, these results suggest that (1) adsorbed molecules on material surfaces strongly affect macrophage response and (2) particle surface chemistry and microstructure affect the concentration and configuration of adsorbed molecules, further influencing particle interaction with macrophage surface receptors. PMID:10602080

  7. Cytokines and therapeutic oligonucleotides.

    PubMed

    Hartmann, G; Bidlingmaier, M; Eigler, A; Hacker, U; Endres, S

    1997-12-01

    Therapeutic oligonucleotides - short strands of synthetic nucleic acids - encompass antisense and aptamer oligonucleotides. Antisense oligonucleotides are designed to bind to target RNA by complementary base pairing and to inhibit translation of the target protein. Antisense oligonucleotides enable specific inhibition of cytokine synthesis. In contrast, aptamer oligonucleotides are able to bind directly to specific proteins. This binding depends on the sequence of the oligonucleotide. Aptamer oligonucleotides with CpG motifs can exert strong immunostimulatory effects. Both kinds of therapeutic oligonucleotides - antisense and aptamer oligonucleotides - provide promising tools to modulate immunological functions. Recently, therapeutic oligonucleotides have moved towards clinical application. An antisense oligonucleotide directed against the proinflammatory intercellular adhesion molecule 1 (ICAM-1) is currently being tested in clinical trials for therapy of inflammatory disease. Immunostimulatory aptamer oligonucleotides are in preclinical development for immunotherapy. In the present review we summarize the application of therapeutic oligonucleotides to modulate immunological functions. We include technological aspects as well as current therapeutic concepts and clinical studies.

  8. Combinatorial Cytokine Code Generates Anti-Viral State in Dendritic Cells

    PubMed Central

    Hartmann, Boris M.; Marjanovic, Nada; Nudelman, German; Moran, Thomas M.; Sealfon, Stuart C.

    2014-01-01

    The physiological function of the immune system and the response to therapeutic immunomodulators may be sensitive to combinatorial cytokine micro-environments that shape the responses of specific immune cells. Previous work shows that paracrine cytokines released by virus-infected human dendritic cells (DC) can dictate the maturation state of naïve DCs. To understand the effects of paracrine signaling, we systematically studied the effects of combinations cytokines in this complex mixture in generating an anti-viral state. After naïve DCs were exposed to either IFNβ or to paracrine signaling released by DCs infected by Newcastle disease virus (NDV), microarray analysis revealed a large number of genes that were differently regulated by the DC-secreted paracrine signaling. In order to identify the cytokine mechanisms involved, we identified 20 cytokines secreted by NDV infected DCs for which the corresponding receptor gene is expressed in naïve DCs. By exposing cells to all combinations of 19 cytokines (leave-one-out studies), we identified five cytokines (IFNβ, TNFα, IL-1β, TNFSF15, and IL28) as candidates for regulating DC maturation markers. Subsequent experiments identified IFNβ, TNFα, and IL1β as the major contributors to this anti-viral state. This finding was supported by infection studies in vitro, by T-cell activation studies and by in vivo infection studies in mouse. Combination of cytokines can cause response states in DCs that differ from those achieved by the individual cytokines alone. These results suggest that the cytokine microenvironment may act via a combinatorial code to direct the response state of specific immune cells. Further elucidation of this code may provide insight into responses to infection and neoplasia as well as guide the development of combinatorial cytokine immunomodulation for infectious, autoimmune, and immunosurveillance-related diseases. PMID:24616721

  9. "Jeopardy" in Abnormal Psychology.

    ERIC Educational Resources Information Center

    Keutzer, Carolin S.

    1993-01-01

    Describes the use of the board game, Jeopardy, in a college level abnormal psychology course. Finds increased student interaction and improved application of information. Reports generally favorable student evaluation of the technique. (CFR)

  10. Abnormal Uterine Bleeding

    MedlinePlus

    ... Abnormal uterine bleeding is any bleeding from the uterus (through your vagina) other than your normal monthly ... or fibroids (small and large growths) in the uterus can also cause bleeding. Rarely, a thyroid problem, ...

  11. Abnormal Uterine Bleeding FAQ

    MedlinePlus

    ... as cancer of the uterus, cervix, or vagina • Polycystic ovary syndrome How is abnormal bleeding diagnosed? Your health care ... before the fetus can survive outside the uterus. Polycystic Ovary Syndrome: A condition characterized by two of the following ...

  12. Preserved ex vivo inflammatory status and cytokine responses in naturally long-lived mice

    PubMed Central

    Arranz, Lorena; Lord, Janet M.

    2010-01-01

    Preserved immune cell function has been reported in mice that achieve extreme longevity. Since cytokines are major modulators of immune responses, we aimed to determine the levels of 21 cytokines secreted ex vivo by peritoneal leukocytes cultured under basal- and mitogen- (conconavalin A (ConA) and LPS) stimulated conditions in middle-aged (44 ± 4 weeks), old (69 ± 4 weeks), very old (92 ± 4 weeks), and extreme long-lived (125 ± 4 weeks) ICR (CD1) female mice. The secretion of cytokines was measured by multiplex luminometry. Increased basal levels of proinflammatory IL-1β, IL-6, IL-12 (p70), IFN-γ, and TNF-α were seen in the old and very old animals, accompanied by decreased IL-10. In contrast, the extreme long-lived mice maintained the overall cytokine profile of middle-aged mice, though the basal secretion of IL-2, IL-9, IL-10, IL-13, and IL-12 (p40) was raised. Under LPS- and/or ConA-stimulated conditions, leukocytes from old and very old animals showed a significantly impaired response with respect to secretion of Th1 cytokines IL-3, IL-12p70, IFN-γ, and TNF-α; Th2 cytokines IL-6, IL-4, IL-10, and IL-13; and the regulatory cytokines IL-2, IL-5, and IL-17. Extreme long-lived mice preserved the middle-aged-like cytokine profile, with the most striking effect seen for the IL-2 response to ConA, which was minimal in the old and very old mice but increased with respect to the middle-aged level in extreme long-lived mice. Chemokine responses in regard to KC, MCP-1, MIP1β, and RANTES were more variable, though similar secretion of LPS-induced KC and MCP-1 and ConA-induced MCP-1, MIP-1β, and RANTES was found in long-lived and middle-aged mice. Thus, extreme long-lived animals showed only a minimal inflammatory profile, much lower than the old and very old groups and also lower than the middle-aged, which is likely mediated by the increase of anti-inflammatory cytokines such as IL-10. This was coupled to a robust response to immune stimuli

  13. Predictive value of cytokines for developing complications after polytrauma

    PubMed Central

    Dekker, Anne-Britt E; Krijnen, Pieta; Schipper, Inger B

    2016-01-01

    AIM: To investigate posttraumatic cytokine alterations and their value for predicting complications and mortality in polytraumatized patients. METHODS: Studies on the use of specific cytokines to predict the development of complications and mortality were identified in MEDLINE, EMBASE, Web of Science and the Cochrane Library. Of included studies, relevant data were extracted and study quality was scored. RESULTS: Forty-two studies published between 1988 and 2015 were identified, including 28 cohort studies and 14 “nested” case-control studies. Most studies investigated the cytokines interleukin (IL)-6, IL-8, IL-10 and tumor necrosis factor (TNF-α). IL-6 seems related to muliorgan dysfunction syndrome, multiorgan failure (MOF) and mortality; IL-8 appears altered in acute respiratory distress syndrome, MOF and mortality; IL-10 alterations seem to precede sepsis and MOF; and TNF-α seems related to MOF. CONCLUSION: Cytokine secretion patterns appear to be different for patients developing complications when compared to patients with uneventful posttraumatic course. More research is needed to strengthen the evidence for clinical relevance of these cytokines.

  14. Effects of cytokines on potassium channels in renal tubular epithelia.

    PubMed

    Nakamura, Kazuyoshi; Komagiri, You; Kubokawa, Manabu

    2012-02-01

    Renal tubular potassium (K(+)) channels play important roles in the formation of cell-negative potential, K(+) recycling, K(+) secretion, and cell volume regulation. In addition to these physiological roles, it was reported that changes in the activity of renal tubular K(+) channels were involved in exacerbation of renal cell injury during ischemia and endotoxemia. Because ischemia and endotoxemia stimulate production of cytokines in immune cells and renal tubular cells, it is possible that cytokines would affect K(+) channel activity. Although the regulatory mechanisms of renal tubular K(+) channels have extensively been studied, little information is available about the effects of cytokines on these K(+) channels. The first report was that tumor necrosis factor acutely stimulated the single channel activity of the 70 pS K(+) channel in the rat thick ascending limb through activation of tyrosine phosphatase. Recently, it was also reported that interferon-γ (IFN-γ) and interleukin-1β (IL-1β) modulated the activity of the 40 pS K(+) channel in cultured human proximal tubule cells. IFN-γ exhibited a delayed suppression and an acute stimulation of K(+) channel activity, whereas IL-1β acutely suppressed the channel activity. Furthermore, these cytokines suppressed gene expression of the renal outer medullary potassium channel. The renal tubular K(+) channels are functionally coupled to the coexisting transporters. Therefore, the effects of cytokines on renal tubular transporter activity should also be taken into account, when interpreting their effects on K(+) channel activity. PMID:22042037

  15. Predictive value of cytokines for developing complications after polytrauma

    PubMed Central

    Dekker, Anne-Britt E; Krijnen, Pieta; Schipper, Inger B

    2016-01-01

    AIM: To investigate posttraumatic cytokine alterations and their value for predicting complications and mortality in polytraumatized patients. METHODS: Studies on the use of specific cytokines to predict the development of complications and mortality were identified in MEDLINE, EMBASE, Web of Science and the Cochrane Library. Of included studies, relevant data were extracted and study quality was scored. RESULTS: Forty-two studies published between 1988 and 2015 were identified, including 28 cohort studies and 14 “nested” case-control studies. Most studies investigated the cytokines interleukin (IL)-6, IL-8, IL-10 and tumor necrosis factor (TNF-α). IL-6 seems related to muliorgan dysfunction syndrome, multiorgan failure (MOF) and mortality; IL-8 appears altered in acute respiratory distress syndrome, MOF and mortality; IL-10 alterations seem to precede sepsis and MOF; and TNF-α seems related to MOF. CONCLUSION: Cytokine secretion patterns appear to be different for patients developing complications when compared to patients with uneventful posttraumatic course. More research is needed to strengthen the evidence for clinical relevance of these cytokines. PMID:27652210

  16. Hepatotoxicants induce cytokine imbalance in response to innate immune system.

    PubMed

    Goto, Shima; Deguchi, Jiro; Nishio, Naoki; Nomura, Naruaki; Funabashi, Hitoshi

    2015-06-01

    In recent years, attention has been paid to innate immune systems as mechanisms to initiate or promote drug-induced liver injury (DILI). Kupffer cells are hepatic resident macrophages and might be involved in the pathogenesis of DILI by release of pro- and anti-inflammatory mediators such as cytokines, chemokines, reactive oxygen species, and/or nitric oxides. The purpose of this study was to investigate alterations in mediator levels induced by hepatotoxic compounds in isolated Kupffer cells and discuss the relation between balance of each cytokine or chemokine and potential of innate immune-mediated DILI. Primary cultured rat Kupffer cells were treated with hepatotoxic (acetaminophen, troglitazone, trovafloxacin) or non-hepatotoxic (pioglitazone, levofloxacin) compounds with or without lipopolysaccharide (LPS). After 24 hr treatment, cell supernatants were collected and various levels of mediators released by Kupffer cells were examined. Although hepatotoxicants had no effect on the LPS-induced tumor necrosis factor-alpha (TNF-α) secretion, they enhanced the release of pro-inflammatory cytokine interleukin-1 beta (IL-1β) and suppressed the anti-inflammatory cytokines interleukin-6 (IL-6) and interleukin-10 (IL-10) induced by LPS. These cytokine shifts were not associated with switching the phenotypes of M1 and M2 macrophages in Kupffer cells. In conclusion, the present study suggested that the levels of some specific cytokines are affected by DILI-related drugs with LPS stimulation, and imbalance between pro- and anti-inflammatory cytokines, induced by the up-regulation of IL-1β and the down-regulation of IL-6 or IL-10, plays a key role in innate immune-mediated DILI. PMID:25972199

  17. Monocyte Subpopulations from Pre-Eclamptic Patients Are Abnormally Skewed and Exhibit Exaggerated Responses to Toll-Like Receptor Ligands

    PubMed Central

    Al-ofi, Ebtisam

    2012-01-01

    The leading cause of pregnancy-associated mortality and morbidity is pre-eclampsia (PE). Although information regarding the etiology of this disease is scant, its pathophysiology is characterized by abnormal placentation, endothelial dysfunction as well as an exaggerated inflammatory response. Clinical evidence also indicates that the abundance of many immune cells at the feto-maternal interface and in the circulation of PE patients is abnormal, when compared with normal pregnant (NP) controls. In addition, the phenotype and function of some of these cells is altered. To further characterize the systemic effects of PE on circulating cells, we analyzed monocytic subpopulations in NP and PE patients by flow cytometry. We found that non-classical CD14lowCD16+ monocytes are significantly increased in women with PE and they display irregular expression of several chemokine receptors and antigen presentation molecules. The most striking phenotypic difference among the cell surface molecules was the marked upregulation of TLR4 expression, where both CD14highCD16+ and CD14lowCD16+ monocytes demonstrated higher levels than their NP counterparts. Stimulation of PE monocytes with TLR ligands resulted in profound secretion of various cytokines in comparison with NP controls. These data suggest that PE monocytes are hyper-responsive to TLR ligands and this may contribute to exacerbation of the disease. PMID:22848746

  18. Curcumin regulates airway epithelial cell cytokine responses to the pollutant cadmium

    SciTech Connect

    Rennolds, Jessica; Malireddy, Smitha; Hassan, Fatemat; Tridandapani, Susheela; Parinandi, Narasimham; Boyaka, Prosper N.; Cormet-Boyaka, Estelle

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer Cadmium induces secretion of IL-6 and IL-8 by two distinct pathways. Black-Right-Pointing-Pointer Cadmium increases NAPDH oxidase activity leading to Erk activation and IL-8 secretion. Black-Right-Pointing-Pointer Curcumin prevents cadmium-induced secretion of both IL-6 and IL-8 by airway cells. Black-Right-Pointing-Pointer Curcumin could be use to suppress lung inflammation due to cadmium inhalation. -- Abstract: Cadmium is a toxic metal present in the environment and its inhalation can lead to pulmonary disease such as lung cancer and chronic obstructive pulmonary disease. These lung diseases are characterized by chronic inflammation. Here we show that exposure of human airway epithelial cells to cadmium promotes a polarized apical secretion of IL-6 and IL-8, two pivotal pro-inflammatory cytokines known to play an important role in pulmonary inflammation. We also determined that two distinct pathways controlled secretion of these proinflammatory cytokines by human airway epithelial cells as cadmium-induced IL-6 secretion occurs via an NF-{kappa}B dependent pathway, whereas IL-8 secretion involves the Erk1/2 signaling pathway. Interestingly, the natural antioxidant curcumin could prevent both cadmium-induced IL-6 and IL-8 secretion by human airway epithelial cells. In conclusion, curcumin could be used to prevent airway inflammation due to cadmium inhalation.

  19. Gastric emptying abnormal in duodenal ulcer

    SciTech Connect

    Holt, S.; Heading, R.C.; Taylor, T.V.; Forrest, J.A.; Tothill, P.

    1986-07-01

    To investigate the possibility that an abnormality of gastric emptying exists in duodenal ulcer and to determine if such an abnormality persists after ulcer healing, scintigraphic gastric emptying measurements were undertaken in 16 duodenal ulcer patients before, during, and after therapy with cimetidine; in 12 patients with pernicious anemia, and in 12 control subjects. No difference was detected in the rate or pattern of gastric emptying in duodenal ulcer patients before and after ulcer healing with cimetidine compared with controls, but emptying of the solid component of the test meal was more rapid during treatment with the drug. Comparison of emptying patterns obtained in duodenal ulcer subjects during and after cimetidine treatment with those obtained in pernicious anemia patients and controls revealed a similar relationship that was characterized by a tendency for reduction in the normal differentiation between the emptying of solid and liquid from the stomach. The similarity in emptying patterns in these groups of subjects suggests that gastric emptying of solids may be influenced by changes in the volume of gastric secretion. The failure to detect an abnormality of gastric emptying in duodenal ulcer subjects before and after ulcer healing calls into question the widespread belief that abnormally rapid gastric emptying is a feature with pathogenetic significance in duodenal ulcer disease.

  20. The SNARE Machinery in Mast Cell Secretion.

    PubMed

    Lorentz, Axel; Baumann, Anja; Vitte, Joana; Blank, Ulrich

    2012-01-01

    Mast cells are known as inflammatory cells which exert their functions in allergic and anaphylactic reactions by secretion of numerous inflammatory mediators. During an allergic response, the high-affinity IgE receptor, FcεRI, becomes cross-linked by receptor-bound IgE and antigen resulting in immediate release of pre-synthesized mediators - stored in granules - as well as in de novo synthesis of various mediators like cytokines and chemokines. Soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptors (SNARE) proteins were found to play a central role in regulating membrane fusion events during exocytosis. In addition, several accessory regulators like Munc13, Munc18, Rab GTPases, secretory carrier membrane proteins, complexins, or synaptotagmins were found to be involved in membrane fusion. In this review we summarize our current knowledge about the SNARE machinery and its mechanism of action in mast cell secretion.

  1. The SNARE Machinery in Mast Cell Secretion

    PubMed Central

    Lorentz, Axel; Baumann, Anja; Vitte, Joana; Blank, Ulrich

    2012-01-01

    Mast cells are known as inflammatory cells which exert their functions in allergic and anaphylactic reactions by secretion of numerous inflammatory mediators. During an allergic response, the high-affinity IgE receptor, FcεRI, becomes cross-linked by receptor-bound IgE and antigen resulting in immediate release of pre-synthesized mediators – stored in granules – as well as in de novo synthesis of various mediators like cytokines and chemokines. Soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptors (SNARE) proteins were found to play a central role in regulating membrane fusion events during exocytosis. In addition, several accessory regulators like Munc13, Munc18, Rab GTPases, secretory carrier membrane proteins, complexins, or synaptotagmins were found to be involved in membrane fusion. In this review we summarize our current knowledge about the SNARE machinery and its mechanism of action in mast cell secretion. PMID:22679448

  2. Authentication Without Secrets

    SciTech Connect

    Pierson, Lyndon G.; Robertson, Perry J.

    2015-11-01

    This work examines a new approach to authentication, which is the most fundamental security primitive that underpins all cyber security protections. Current Internet authentication techniques require the protection of one or more secret keys along with the integrity protection of the algorithms/computations designed to prove possession of the secret without actually revealing it. Protecting a secret requires physical barriers or encryption with yet another secret key. The reason to strive for "Authentication without Secret Keys" is that protecting secrets (even small ones only kept in a small corner of a component or device) is much harder than protecting the integrity of information that is not secret. Promising methods are examined for authentication of components, data, programs, network transactions, and/or individuals. The successful development of authentication without secret keys will enable far more tractable system security engineering for high exposure, high consequence systems by eliminating the need for brittle protection mechanisms to protect secret keys (such as are now protected in smart cards, etc.). This paper is a re-release of SAND2009-7032 with new figures numerous edits.

  3. [Hair shaft abnormalities].

    PubMed

    Itin, P H; Düggelin, M

    2002-05-01

    Hair shaft disorders may lead to brittleness and uncombable hair. In general the hair feels dry and lusterless. Hair shaft abnormalities may occur as localized or generalized disorders. Genetic predisposition or exogenous factors are able to produce and maintain hair shaft abnormalities. In addition to an extensive history and physical examination the most important diagnostic examination to analyze a hair shaft problem is light microscopy. Therapy of hair shaft disorders should focus to the cause. In addition, minimizing traumatic influences to hair shafts, such as dry hair with an electric dryer, permanent waves and dyes is important. A short hair style is more suitable for such patients with hair shaft disorders.

  4. Inflammatory cytokines in pediatric obstructive sleep apnea

    PubMed Central

    Huang, Yu-Shu; Guilleminault, Christian; Hwang, Fang-Ming; Cheng, Chuan; Lin, Cheng-Hui; Li, Hsueh-Yu; Lee, Li-Ang

    2016-01-01

    Abstract Pediatric obstructive sleep apnea (OSA) is associated with chronic systemic inflammation and with cognitive impairments. This study aimed to investigate the status of proinflammatory cytokines, particularly interleukin 17 (IL-17) and interleukin 23 (IL-23) and cognition in pediatric OSA. Controls and OSA children participated in the study. Exclusion criteria were adenotonsillectomy, heart, neurological and severe psychiatric diseases, craniofacial syndromes, and obesity. Polysomnogram was followed by serum testing for inflammatory markers and neurocognitive tests such as continuous performance task (CPT) and Wisconsin card sorting test, questionnaires, analyses of plasma high-sensitivity C-reactive protein (HS-CRP), tumor necrosis factor alpha (TNF-α), interleukin 1 (IL-1), interleukin 6 (IL-6), IL-17, and IL-23. Seventy-nine, 4 to 12-year-old subjects in 2 groups ended the study: 47 nonobese OSA children (mean age = 7.84 ± 0.56 years, body mass index [BMI] = 16.95 ± 0.47 kg/m2, BMI z-score = 0.15 ± 0.21, and mean apnea–hypopnea index [AHI] = 9.13 ± 1.67 events/h) and 32 healthy control children (mean age = 7.02 ± 0.65 years, with BMI = 16.55 ± 0.58 kg/m2, BMI z-score = −0.12 ± 0.27, and mean AHI = 0.41 ± 0.07 event/h) were enrolled. Serum cytokine analyses showed significantly higher levels of HS-CRP, IL-17, and IL-23 in OSA children (P = 0.002, P = 0.024, and P = 0.047). Regression test showed significant influence of HS-CRP, TNF-α, IL-6, IL-17, and specifically IL-23, with the continuous performance test and Wisconsin card sorting test. OSA children have abnormal levels of IL-17, an interleukin related to T helper 17 cells, a T helper cell involved in development of autoimmunity and inflammation. This high expression level may contribute to the complications of pediatric OSA; we also found a significant influence of inflammatory cytokines, particularly IL-23, on abnormal neurocognitive testing. PMID

  5. The Function of Fish Cytokines

    PubMed Central

    Zou, Jun; Secombes, Christopher J.

    2016-01-01

    What is known about the biological activity of fish cytokines is reviewed. Most of the functional studies performed to date have been in teleost fish, and have focused on the induced effects of cytokine recombinant proteins, or have used loss- and gain-of-function experiments in zebrafish. Such studies begin to tell us about the role of these molecules in the regulation of fish immune responses and whether they are similar or divergent to the well-characterised functions of mammalian cytokines. This knowledge will aid our ability to determine and modulate the pathways leading to protective immunity, to improve fish health in aquaculture. PMID:27231948

  6. Cytokines in systemic lupus erythematosus.

    PubMed

    Lourenço, Elaine V; La Cava, Antonio

    2009-04-01

    Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies that can form immune complexes and deposit in tissues, causing inflammation and organ damage. There is evidence that interferons and some interleukins can have an active role in the pathogenesis of SLE and can contribute significantly to the immune imbalance in the disease, whereas the role of some cytokines (such as TNF) is still debated. This review discusses the activity of several cytokines in SLE, their effects on the immune cells in relation to the disease pathogenesis, and the promise and limitations of cytokine-based therapies in clinical trials for lupus patients.

  7. Secretion of both IL-2 and IL-4 by tumor cells results in rejection and immunity.

    PubMed

    Strome, S E; Chang, A E; Shu, S; Krauss, J C

    1996-01-01

    The generation of a therapeutic immune response to malignancy is critically dependent on the inherent immunogenicity of the tumor. Our study demonstrates that secretion of both interleukin-2 (IL-2) and IL-4 by a seemingly nonimmunogenic tumor abrogates tumorigenicity, and mice that have rejected the genetically modified tumor are immune to challenges with the parental tumor. The induction of immunity by the IL-2/IL-4-secreting tumor was significantly better than that achieved with the admixture of tumor cells and the classic adjuvant, Corynebacterium parvum. To elicit a primary immune response, the majority of cells needed to secrete both cytokines. Ad-mixture of IL-2-secreting cells with IL-4-secreting cells did not result in tumor cell rejection. The IL-2/IL-4-secreting tumor cells were efficiently rejected in animals immunosuppressed by total body irradiation. Depletion of CD4+ or CD8+ T cells did not abrogate rejection of the tumor cells, but the animals depleted of CD4 cells failed to generate protective immunity. Our study demonstrates that secretion of the combination of IL-2 and IL-4 significantly enhances tumor immunogenicity. The requirement of cells secreting both cytokines suggests an intricate mechanism different from the mere presence of both cytokines at the tumor-inoculation site. PMID:9147701

  8. MTMR3 risk allele enhances innate receptor-induced signaling and cytokines by decreasing autophagy and increasing caspase-1 activation.

    PubMed

    Lahiri, Amit; Hedl, Matija; Abraham, Clara

    2015-08-18

    Inflammatory bowel disease (IBD) is characterized by dysregulated host:microbial interactions and cytokine production. Host pattern recognition receptors (PRRs) are critical in regulating these interactions. Multiple genetic loci are associated with IBD, but altered functions for most, including in the rs713875 MTMR3/HORMAD2/LIF/OSM region, are unknown. We identified a previously undefined role for myotubularin-related protein 3 (MTMR3) in amplifying PRR-induced cytokine secretion in human macrophages and defined MTMR3-initiated mechanisms contributing to this amplification. MTMR3 decreased PRR-induced phosphatidylinositol 3-phosphate (PtdIns3P) and autophagy levels, thereby increasing PRR-induced caspase-1 activation, autocrine IL-1β secretion, NFκB signaling, and, ultimately, overall cytokine secretion. This MTMR3-mediated regulation required the N-terminal pleckstrin homology-GRAM domain and Cys413 within the phosphatase domain of MTMR3. In MTMR3-deficient macrophages, reducing the enhanced autophagy or restoring NFκB signaling rescued PRR-induced cytokines. Macrophages from rs713875 CC IBD risk carriers demonstrated increased MTMR3 expression and, in turn, decreased PRR-induced PtdIns3P and autophagy and increased PRR-induced caspase-1 activation, signaling, and cytokine secretion. Thus, the rs713875 IBD risk polymorphism increases MTMR3 expression, which modulates PRR-induced outcomes, ultimately leading to enhanced PRR-induced cytokines.

  9. MTMR3 risk allele enhances innate receptor-induced signaling and cytokines by decreasing autophagy and increasing caspase-1 activation

    PubMed Central

    Lahiri, Amit; Hedl, Matija; Abraham, Clara

    2015-01-01

    Inflammatory bowel disease (IBD) is characterized by dysregulated host:microbial interactions and cytokine production. Host pattern recognition receptors (PRRs) are critical in regulating these interactions. Multiple genetic loci are associated with IBD, but altered functions for most, including in the rs713875 MTMR3/HORMAD2/LIF/OSM region, are unknown. We identified a previously undefined role for myotubularin-related protein 3 (MTMR3) in amplifying PRR-induced cytokine secretion in human macrophages and defined MTMR3-initiated mechanisms contributing to this amplification. MTMR3 decreased PRR-induced phosphatidylinositol 3-phosphate (PtdIns3P) and autophagy levels, thereby increasing PRR-induced caspase-1 activation, autocrine IL-1β secretion, NFκB signaling, and, ultimately, overall cytokine secretion. This MTMR3-mediated regulation required the N-terminal pleckstrin homology-GRAM domain and Cys413 within the phosphatase domain of MTMR3. In MTMR3-deficient macrophages, reducing the enhanced autophagy or restoring NFκB signaling rescued PRR-induced cytokines. Macrophages from rs713875 CC IBD risk carriers demonstrated increased MTMR3 expression and, in turn, decreased PRR-induced PtdIns3P and autophagy and increased PRR-induced caspase-1 activation, signaling, and cytokine secretion. Thus, the rs713875 IBD risk polymorphism increases MTMR3 expression, which modulates PRR-induced outcomes, ultimately leading to enhanced PRR-induced cytokines. PMID:26240347

  10. Secrets to success.

    PubMed

    Sorrel, Amy Lynn

    2014-02-01

    A new national study reveals what it takes for physician practices to stay financially viable. Several Texas practices, among those rated as "better performers," share their secrets to success. One of those secrets, a physician says, is "hiring good people and getting out of their way." PMID:24500918

  11. Secrets in "The Day of Ahmed's Secret."

    ERIC Educational Resources Information Center

    Duckett, Peter; Knox, Marjorie

    2001-01-01

    Examines images and the written text in the picture book, "The Day of Ahmed's Secret," by Florence Parry Heide and Judith Heide Gilliland. Examines the book in greater detail by looking for issues of authenticity as well as social issues within the book's pictures and written texts. (SG)

  12. Platelet secretion: From haemostasis to wound healing and beyond.

    PubMed

    Golebiewska, Ewelina M; Poole, Alastair W

    2015-05-01

    Upon activation, platelets secrete more than 300 active substances from their intracellular granules. Platelet dense granule components, such as ADP and polyphosphates, contribute to haemostasis and coagulation, but also play a role in cancer metastasis. α-Granules contain multiple cytokines, mitogens, pro- and anti-inflammatory factors and other bioactive molecules that are essential regulators in the complex microenvironment of the growing thrombus but also contribute to a number of disease processes. Our understanding of the molecular mechanisms of secretion and the genetic regulation of granule biogenesis still remains incomplete. In this review we summarise our current understanding of the roles of platelet secretion in health and disease, and discuss some of the hypotheses that may explain how platelets may control the release of its many secreted components in a context-specific manner, to allow platelets to play multiple roles in health and disease.

  13. EFFECT OF CYTOKINE AND PHARMACOGENOMIC GENETIC POLYMORPHISMS IN TRANSPLANTATION

    PubMed Central

    Girnita, Diana M; Burckart, Gilbert; Zeevi, Adriana

    2008-01-01

    Purpose of review Recent investigations related to the polymorphism of genes that affect drug therapy and the polymorphisms of cytokines and growth factors that control immune responses have been associated with outcomes following solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT). This review will provide a current update on the most recent findings and discuss the challenges for developing individualized therapeutic strategies based on clinical and genetic profiles. Recent Findings Single nucleotide polymorphisms (SNPs) of cytokine genes have been shown to have an impact in vitro or in vivo protein secretion, dividing the individuals into High, Low or Intermediate producers for a given molecule. Many studies have been performed to determine the contribution of single cytokine gene SNPs on SOT or HSCT outcomes and the reported results are still controversial. However, analysis of a combination of several cytokines and/or cytokine receptor polymorphisms adjusted for known clinical risk factors and ethnicity have resulted in significant clinical correlations. Furthermore, associations with gene polymorphisms that affect immunosuppressive drug therapy in solid organ transplantation have also been extensively studied. There is a continuous flow of new information regarding functional SNPs that may affect the immune response to the allograft or to drug therapy and their impact on clinical outcomes have yet to be validated in large cohorts SOT or HSCT Summary Consolidating the information that we have on pharmacogenetics and on cytokine genetics to produce patient-oriented individualized drug regimens is an important challenge in transplantation medicine. Using a multi-variant approach based on genetic profile and other relevant clinical factors a score system may be developed to predict the severity of rejection, infection or other complications associated with transplantation. The ultimate goal of these studies is to improve patient

  14. IL25 elicits a multipotent progenitor cell population that promotes TH2 cytokine responses

    Technology Transfer Automated Retrieval System (TEKTRAN)

    CD4+ T helper 2 (TH2) cells secrete interleukin (IL)4, IL5 and IL13, and are required for immunity to gastrointestinal helminth infections. However, TH2 cells also promote chronic inflammation associated with asthma and allergic disorders. The non-haematopoietic-cell-derived cytokines thymic stromal...

  15. Selective suppression of endothelial cytokine production by progesterone receptor.

    PubMed

    Goddard, Lauren M; Ton, Amy N; Org, Tõnis; Mikkola, Hanna K A; Iruela-Arispe, M Luisa

    2013-01-01

    Steroid hormones are well-recognized suppressors of the inflammatory response, however, their cell- and tissue-specific effects in the regulation of inflammation are far less understood, particularly for the sex-related steroids. To determine the contribution of progesterone in the endothelium, we have characterized and validated an in vitro culture system in which human umbilical vein endothelial cells constitutively express human progesterone receptor (PR). Using next generation RNA-sequencing, we identified a selective group of cytokines that are suppressed by progesterone both under physiological conditions and during pathological activation by lipopolysaccharide. In particular, IL-6, IL-8, CXCL2/3, and CXCL1 were found to be direct targets of PR, as determined by ChIP-sequencing. Regulation of these cytokines by progesterone was also confirmed by bead-based multiplex cytokine assays and quantitative PCR. These findings provide a novel role for PR in the direct regulation of cytokine levels secreted by the endothelium. They also suggest that progesterone-PR signaling in the endothelium directly impacts leukocyte trafficking in PR-expressing tissues. PMID:23747964

  16. Micropatterning of Aptamer Beacons to Create Cytokine-Sensing Surfaces.

    PubMed

    Tuleuova, Nazgul; Revzin, Alexander

    2010-12-01

    Aptamer beacons are DNA or RNA probes that bind proteins or small molecules of interest and emit signal directly upon interaction with the target analyte. This paper describes micropatterning of aptamer beacons for detection of IFN-γ-an important inflammatory cytokine. The beacon consisted of a fluorophore-labeled aptamer strand hybridized with a shorter, quencher-carrying complementary strand. Cytokine molecules were expected to displace quenching strands of the beacon, disrupting FRET effect and resulting in fluorescence signal. The glass substrate was first micropatterned with poly(ethylene glycol) (PEG) hydrogel microwells (35 μm diameter individual wells) so as to define sites for attachment of beacon molecules. PEG microwell arrays were then incubated with avidin followed by biotin-aptamer-fluorophore constructs. Subsequent incubation with quencher-carrying complementary strands resulted in formation of DNA duplex and caused quenching of fluorescence due to FRET effect. When exposed to IFN-γ, microwells changed fluorescence from low (quencher hybridized with fluorophore-carrying strand) to high (quenching strand displaced by cytokine molecules). The fluorescence signal was confined to microwells, was changing in real-time and was dependent on the concentration of IFN-γ. In the future, we plan to co-localize aptamer beacons and cells on micropatterned surfaces in order to monitor in real-time cytokine secretion from immune cells in microwells.

  17. Characterization of Adsorbents for Cytokine Removal from Blood in an In Vitro Model

    PubMed Central

    Gabor, Franz; Hartmann, Jens

    2015-01-01

    Introduction. Cytokines are basic targets that have to be removed effectively in order to improve the patient's health status in treating severe inflammation, sepsis, and septic shock. Although there are different adsorbents commercially available, the success of their clinical use is limited. Here, we tested different adsorbents for their effective removal of cytokines from plasma and the resulting effect on endothelial cell activation. Methods. The three polystyrene divinylbenzene (PS-DVB) based adsorbents Amberchrom CG161c and CG300m and a clinically approved haemoperfusion adsorbent (HAC) were studied with regard to cytokine removal in human blood. To induce cytokine release from leucocytes, human blood cells were stimulated with 1 ng/ml LPS for 4 hours. Plasma was separated and adsorption experiments in a dynamic model were performed. The effect of cytokine removal on endothelial cell activation was evaluated using a HUVEC-based cell culture model. The beneficial outcome was assessed by measuring ICAM-1, E-selectin, and secreted cytokines IL-8 and IL-6. Additionally the threshold concentration for HUVEC activation by TNF-α and IL-1β was determined using this cell culture model. Results. CG161c showed promising results in removing the investigated cytokines. Due to its pore size the adsorbent efficiently removed the key factor TNF-α, outperforming the commercially available adsorbents. The CG161c treatment reduced cytokine secretion and expression of cell adhesion molecules by HUVEC which underlines the importance of effective removal of TNF-α in inflammatory diseases. Conclusion. These results confirm the hypothesis that cytokine removal from the blood should approach physiological levels in order to reduce endothelial cell activation. PMID:26770992

  18. Novel cancer vaccines prepared by anchoring cytokines to tumor cells avoiding gene transfection

    NASA Astrophysics Data System (ADS)

    Nizard, Philippe; Gross, David-Alexandre; Chenal, Alexandre; Beaumelle, Bruno; Kosmatopoulos, Konstadinos; Gillet, Daniel

    2002-06-01

    Cytokines have a strong potential for triggering anticancer immunity if released in the tumor microenvironment. Successful vaccines have been engineered using tumor cells genetically modified to secrete the cytokines. Unfortunately, this approach remains difficult and hazardous to perform in the clinic. We describe a new way of combining cytokines with tumor cells to prepare anticancer vaccines. This consists in anchoring recombinant cytokines to the membrane of killed tumor cells. Attachment is mediated by a fragment of diphtheria toxin (T) genetically connected to the cytokine. It is triggered by an acid pH pulse. The method was applied to IL-2, a potent anti-tumor cytokine. IL-2 anchored to the surface of tumor cells by the T anchor retained its IL-2 activity and remained exposed several days. Interestingly, vaccination of mice with these modified tumor cells induced a protective anti-tumor immunity mediated by tumor-specific cytotoxic T lymphocytes. This procedure presents several advantages as compared to the conventional approaches based on the transfection of tumor cells with cytokine genes. It does not require the culture of tumor cells from the patients and eliminates the safety problems connected with viral vectors while allowing the control of the amount of cytokines delivered with the vaccine.

  19. Ex Vivo Innate Immune Cytokine Signature of Enhanced Risk of Relapsing Brucellosis

    PubMed Central

    Feldman, Kristyn E.; Loriaux, Paul M.; Saito, Mayuko; Tuero, Iskra; Villaverde, Homarh; Siva, Tenaya; Gotuzzo, Eduardo; Gilman, Robert H.; Hoffmann, Alexander; Vinetz, Joseph M.

    2013-01-01

    Background Brucellosis, a zoonotic infection caused by one of the Gram-negative intracellular bacteria of the Brucella genus, is an ongoing public health problem in Perú. While most patients who receive standard antibiotic treatment recover, 5–40% suffer a brucellosis relapse. In this study, we examined the ex vivo immune cytokine profiles of recovered patients with a history of acute and relapsing brucellosis. Methodology/Principal Findings Blood was taken from healthy control donors, patients with a history of acute brucellosis, or patients with a history of relapsing brucellosis. Peripheral blood mononuclear cells were isolated and remained in culture without stimulation or were stimulated with a panel of toll-like receptor agonists or heat-killed Brucella melitensis (HKBM) isolates. Innate immune cytokine gene expression and protein secretion were measured by quantitative real-time polymerase chain reaction and a multiplex bead-based immunoassay, respectively. Acute and relapse patients demonstrated consistently elevated cytokine gene expression and secretion levels compared to controls. Notably, these include: basal and stimulus-induced expression of GM-CSF, TNF-α, and IFN-γ in response to LPS and HKBM; basal secretion of IL-6, IL-8, and TNF-α; and HKBM or Rev1-induced secretion of IL-1β, IL-2, GM-CSF, IFN-Υ, and TNF-α. Although acute and relapse patients were largely indistinguishable by their cytokine gene expression profiles, we identified a robust cytokine secretion signature that accurately discriminates acute from relapse patients. This signature consists of basal IL-6 secretion, IL-1β, IL-2, and TNF-α secretion in response to LPS and HKBM, and IFN-γ secretion in response to HKBM. Conclusions/Significance This work demonstrates that informative cytokine variations in brucellosis patients can be detected using an ex vivo assay system and used to identify patients with differing infection histories. Targeted diagnosis of this signature may

  20. Pseudomonas aeruginosa and Its Bacterial Components Influence the Cytokine Response in Thymocytes and Splenocytes

    PubMed Central

    Zimmermann, Corinna; Mausberg, Anne K.; Dehmel, Thomas; Kieseier, Bernd C.; Hartung, Hans-Peter; Hofstetter, Harald H.

    2016-01-01

    Infections with Pseudomonas aeruginosa may cause many different diseases. The spectrum of such infections in general includes inflammation and bacterial sepsis. Hospital-acquired pneumonia, naturally resistant to a wide range of antibiotics, is associated with a particularly high mortality rate in mechanically ventilated patients. The pathogenesis of P. aeruginosa is complex and mediated by several virulence factors, as well as cell-associated factors. We have previously demonstrated that stimulation with different bacteria triggers the cytokine response of thymocytes. In this study, we investigated the effect of P. aeruginosa and its different components on the cytokine production of immature and mature immune cells. We found that the induced cytokine pattern in the thymus and the spleen after infections with P. aeruginosa is primarily mediated by lipopolysaccharide (LPS) of the outer cell membrane, but other components of the bacterium can influence the cytokine secretion as well. Stimulation with heat-killed P. aeruginosa and LPS does not influence the amount of cytokine-producing CD4+ T cells but instead suppresses the emergence of Th17 cells. However, stimulation with P. aeruginosa or its components triggers the interleukin-17 (IL-17) response both in thymocytes and in splenocytes. We conclude that infections with P. aeruginosa affect the cytokine secretion of immature and mature cells and that IL-17 and Th17 cells play only a minor role in the development of pathological systemic inflammatory disease conditions during P. aeruginosa infections. Therefore, other inflammatory immune responses must be responsible for septic reactions of the host. PMID:26902726

  1. Pseudomonas aeruginosa and Its Bacterial Components Influence the Cytokine Response in Thymocytes and Splenocytes.

    PubMed

    Weber, Andreas; Zimmermann, Corinna; Mausberg, Anne K; Dehmel, Thomas; Kieseier, Bernd C; Hartung, Hans-Peter; Hofstetter, Harald H

    2016-05-01

    Infections with Pseudomonas aeruginosa may cause many different diseases. The spectrum of such infections in general includes inflammation and bacterial sepsis. Hospital-acquired pneumonia, naturally resistant to a wide range of antibiotics, is associated with a particularly high mortality rate in mechanically ventilated patients. The pathogenesis of P. aeruginosa is complex and mediated by several virulence factors, as well as cell-associated factors. We have previously demonstrated that stimulation with different bacteria triggers the cytokine response of thymocytes. In this study, we investigated the effect of P. aeruginosa and its different components on the cytokine production of immature and mature immune cells. We found that the induced cytokine pattern in the thymus and the spleen after infections with P. aeruginosa is primarily mediated by lipopolysaccharide (LPS) of the outer cell membrane, but other components of the bacterium can influence the cytokine secretion as well. Stimulation with heat-killed P. aeruginosa and LPS does not influence the amount of cytokine-producing CD4(+) T cells but instead suppresses the emergence of Th17 cells. However, stimulation with P. aeruginosa or its components triggers the interleukin-17 (IL-17) response both in thymocytes and in splenocytes. We conclude that infections with P. aeruginosa affect the cytokine secretion of immature and mature cells and that IL-17 and Th17 cells play only a minor role in the development of pathological systemic inflammatory disease conditions during P. aeruginosa infections. Therefore, other inflammatory immune responses must be responsible for septic reactions of the host.

  2. Morphological abnormalities in elasmobranchs.

    PubMed

    Moore, A B M

    2015-08-01

    A total of 10 abnormal free-swimming (i.e., post-birth) elasmobranchs are reported from The (Persian-Arabian) Gulf, encompassing five species and including deformed heads, snouts, caudal fins and claspers. The complete absence of pelvic fins in a milk shark Rhizoprionodon acutus may be the first record in any elasmobranch. Possible causes, including the extreme environmental conditions and the high level of anthropogenic pollution particular to The Gulf, are briefly discussed.

  3. Omega-3 fatty acids modulate neonatal cytokine response to endotoxin.

    PubMed

    Espiritu, Michael M; Lin, Hong; Foley, Elizabeth; Tsang, Valerie; Rhee, Eunice; Perlman, Jeffrey; Cunningham-Rundles, Susanna

    2016-08-01

    Neonatal immune response is characterized by an uncompensated pro-inflammatory response that can lead to inflammation-related morbidity and increased susceptibility to infection. We investigated the effects of long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) pre-treatment on cytokine secretion to low-concentration endotoxin (lipopolysaccharide, LPS) in THP-1 monocytes and neonatal cord blood (CB) from healthy full-term infants. Pre-treatment of THP-1 cells, with either n-3 PUFA at 25 or 100 μM significantly reduced IL-6, IL-10, and IL-12 secretion while DHA, but not EPA, reduced TNF-α response to LPS. DHA inhibition was stronger compared to EPA and effective at the low concentration. The same concentrations of n-3 PUFAs inhibited IL-12 but not IL-10 cytokine response in whole CB from 9 infants pre-treated for 24 h. To assess clinical relevance for acute response to LPS, the effects of low-concentration DHA at 25 μM or 12.5 μM were assessed before and after LPS exposure of isolated CB mononuclear cells from 20 infants for 1 h. When added before or after LPS, physiologic DHA treatment produced significant concentration-dependent inhibition of TNF-α, IL-6, IL-1β, and IL-8 secretion. The results demonstrate prophylactic and therapeutic modulation of neonatal cytokine response to LPS and provide proof-of-concept that low-concentration administration of n-3 PUFA could attenuate or resolve neonatal inflammatory response.

  4. Chromosome abnormalities in glioma

    SciTech Connect

    Li, Y.S.; Ramsay, D.A.; Fan, Y.S.

    1994-09-01

    Cytogenetic studies were performed in 25 patients with gliomas. An interesting finding was a seemingly identical abnormality, an extra band on the tip of the short arm of chromosome 1, add(1)(p36), in two cases. The abnormality was present in all cells from a patient with a glioblastoma and in 27% of the tumor cells from a patient with a recurrent irradiated anaplastic astrocytoma; in the latter case, 7 unrelated abnormal clones were identified except 4 of those clones shared a common change, -Y. Three similar cases have been described previously. In a patient with pleomorphic astrocytoma, the band 1q42 in both homologues of chromosome 1 was involved in two different rearrangements. A review of the literature revealed that deletion of the long arm of chromosome 1 including 1q42 often occurs in glioma. This may indicate a possible tumor suppressor gene in this region. Cytogenetic follow-up studies were carried out in two patients and emergence of unrelated clones were noted in both. A total of 124 clonal breakpoints were identified in the 25 patients. The breakpoints which occurred three times or more were: 1p36, 1p22, 1q21, 1q25, 3q21, 7q32, 8q22, 9q22, 16q22, and 22q13.

  5. [Congenital foot abnormalities].

    PubMed

    Delpont, M; Lafosse, T; Bachy, M; Mary, P; Alves, A; Vialle, R

    2015-03-01

    The foot may be the site of birth defects. These abnormalities are sometimes suspected prenatally. Final diagnosis depends on clinical examination at birth. These deformations can be simple malpositions: metatarsus adductus, talipes calcaneovalgus and pes supinatus. The prognosis is excellent spontaneously or with a simple orthopedic treatment. Surgery remains outstanding. The use of a pediatric orthopedist will be considered if malposition does not relax after several weeks. Malformations (clubfoot, vertical talus and skew foot) require specialized care early. Clubfoot is characterized by an equine and varus hindfoot, an adducted and supine forefoot, not reducible. Vertical talus combines equine hindfoot and dorsiflexion of the forefoot, which is performed in the midfoot instead of the ankle. Skew foot is suspected when a metatarsus adductus is resistant to conservative treatment. Early treatment is primarily orthopedic at birth. Surgical treatment begins to be considered after walking age. Keep in mind that an abnormality of the foot may be associated with other conditions: malposition with congenital hip, malformations with syndromes, neurological and genetic abnormalities. PMID:25524290

  6. Titanium surface hydrophilicity modulates the human macrophage inflammatory cytokine response.

    PubMed

    Alfarsi, Mohammed A; Hamlet, Stephen M; Ivanovski, Saso

    2014-01-01

    Increased titanium surface hydrophilicity has been shown to accelerate dental implant osseointegration. Macrophages are important in the early inflammatory response to surgical implant placement and influence the subsequent healing response. This study investigated the modulatory effect of a hydrophilic titanium surface on the inflammatory cytokine expression profile in a human macrophage cell line (THP-1). Genes for 84 cytokines, chemokines, and their receptors were analyzed following exposure to (1) polished (SMO), (2) micro-rough sand blasted, acid etched (SLA), and (3) hydrophilic-modified SLA (modSLA) titanium surfaces for 1 and 3 days. By day 3, the SLA surface elicited a pro-inflammatory response compared to the SMO surface with statistically significant up-regulation of 16 genes [Tumor necrosis factor (TNF) Interleukin (IL)-1β, Chemokine (C-C motif) ligand (CCL)-1, 2, 3, 4, 18, 19, and 20, Chemokine (C-X-C motif) ligand (CXCL)-1, 5, 8 and 12, Chemokine (C-C motif) receptor (CCR)-7, Lymphotoxin-beta (LTB), and Leukotriene B4 receptor (LTB4R)]. This effect was countered by the modSLA surface, which down-regulated the expression of 10 genes (TNF, IL-1α and β, CCL-1, 3, 19 and 20, CXCL-1 and 8, and IL-1 receptor type 1), while two were up-regulated (osteopontin and CCR5) compared to the SLA surface. These cytokine gene expression changes were confirmed by decreased levels of corresponding protein secretion in response to modSLA compared to SLA. These results show that a hydrophilic titanium surface can modulate human macrophage pro-inflammatory cytokine gene expression and protein secretion. An attenuated pro-inflammatory response may be an important molecular mechanism for faster and/or improved wound healing.

  7. Influence of Phthalates on Cytokine Production in Monocytes and Macrophages: A Systematic Review of Experimental Trials

    PubMed Central

    Hansen, Juliana Frohnert; Bendtzen, Klaus; Boas, Malene; Frederiksen, Hanne; Nielsen, Claus H.; Rasmussen, Åse Krogh; Feldt-Rasmussen, Ulla

    2015-01-01

    Background Phthalates are a group of endocrine disrupting chemicals suspected to influence the immune system. The aim of this systematic review is to summarise the present knowledge on the influence of phthalates on monocyte and macrophage production and secretion of cytokines, an influence which could affect both pro- and anti-inflammatory abilities of these cells. Strategy and Results A systematic search was performed in Medline, Embase and Toxline in June 2013, last updated 3rd of August 2014. Criteria used to select studies were described and published beforehand online on Prospero (http://www.crd.york.ac.uk/NIHR_PROSPERO, registration number CRD42013004236). In vivo, ex vivo and in vitro studies investigating the influence of phthalates on cytokine mRNA expression and cytokine secretion in animals and humans were included. A total of 11 reports, containing 12 studies, were found eligible for inclusion. In these, a total of four different phthalate diesters, six primary metabolites (phthalate monoesters) and seven different cytokines were investigated. Though all studies varied greatly in study design and species sources, four out of five studies that investigated di-2-ethylhexyl phthalate found an increased tumour necrosis factor-α secretion/production from monocytes or macrophages. A summary of cytokine measurements was not possible since few studies were comparable in study design and due to insufficient reporting of raw data for most of the included studies. Conclusion Results from this review have suggested that at least one phthalate (di-2-ethylhexyl phthalate) has the ability to enhance tumour necrosis factor-α production/secretion from monocytes/macrophages in vitro, but also observed ex vivo. Influence of other phthalates on other cytokines has only been investigated in few studies. Thus, in vitro studies on primary human monocytes/macrophages as well as more in vivo studies are needed to confirm or dispute these findings. PMID:25811352

  8. Abnormal pressures as hydrodynamic phenomena

    USGS Publications Warehouse

    Neuzil, C.E.

    1995-01-01

    So-called abnormal pressures, subsurface fluid pressures significantly higher or lower than hydrostatic, have excited speculation about their origin since subsurface exploration first encountered them. Two distinct conceptual models for abnormal pressures have gained currency among earth scientists. The static model sees abnormal pressures generally as relict features preserved by a virtual absence of fluid flow over geologic time. The hydrodynamic model instead envisions abnormal pressures as phenomena in which flow usually plays an important role. This paper develops the theoretical framework for abnormal pressures as hydrodynamic phenomena, shows that it explains the manifold occurrences of abnormal pressures, and examines the implications of this approach. -from Author

  9. Use of cytokines in infection.

    PubMed

    Aoki, Naoko; Xing, Zhou

    2004-11-01

    Infectious disease remains an ever-growing health concern worldwide due to increasing antibiotic-resistant microbial strains, immune-compromised populations, international traffic and globalisation, and bioterrorism. There exists an urgent need to develop novel prophylactic and therapeutic strategies. In addition to classic antibiotic therapeutics, immune-modulatory molecules such as cytokines or their inhibitors represent a promising form of antimicrobial therapeutics or immune adjuvant used for the purpose of vaccination. These molecules, in the form of either recombinant protein or transgene, exert their antimicrobial effect by enhancing infectious agent-specific immune activation or memory development, or by dampening undesired inflammatory and immune responses resulting from infection and host defence mechanisms. In the last two decades, a number of cytokine therapy-based experimental and clinical trials have been conducted, and some of these efforts have led to the routine clinical use of cytokines. For instance, although IFNs have been used to treat hepatitis C with great success, many other cytokines are yet to be fully evaluated for their antimicrobial potential. This review discusses the biology and therapeutic potential of selected immune modulatory cytokines and their inhibitors, including granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, IFN-gamma, IL-12 and TNF.

  10. Diphenylarsinic Acid Induced Activation of Cultured Rat Cerebellar Astrocytes: Phosphorylation of Mitogen-Activated Protein Kinases, Upregulation of Transcription Factors, and Release of Brain-Active Cytokines.

    PubMed

    Negishi, Takayuki; Matsumoto, Mami; Kojima, Mikiya; Asai, Ryota; Kanehira, Tomoko; Sakaguchi, Fumika; Takahata, Kazuaki; Arakaki, Rina; Aoyama, Yohei; Yoshida, Hikari; Yoshida, Kenji; Yukawa, Kazunori; Tashiro, Tomoko; Hirano, Seishiro

    2016-03-01

    Diphenylarsinic acid (DPAA) was detected as the primary compound responsible for the arsenic poisoning that occurred in Kamisu, Ibaraki, Japan, where people using water from a well that was contaminated with a high level of arsenic developed neurological (mostly cerebellar) symptoms and dysregulation of regional cerebral blood flow. To understand the underlying molecular mechanism of DPAA-induced cerebellar symptoms, we focused on astrocytes, which have a brain-protective function. Incubation with 10 µM DPAA for 96 h promoted cell proliferation, increased the expression of antioxidative stress proteins (heme oxygenase-1 and heat shock protein 70), and induced the release of cytokines (MCP-1, adrenomedullin, FGF2, CXCL1, and IL-6). Furthermore, DPAA overpoweringly increased the phosphorylation of three major mitogen-activated protein kinases (MAPKs) (ERK1/2, p38MAPK, and SAPK/JNK), which indicated MAPK activation, and subsequently induced expression and/or phosphorylation of transcription factors (Nrf2, CREB, c-Jun, and c-Fos) in cultured rat cerebellar astrocytes. Structure-activity relationship analyses of DPAA and other related pentavalent organic arsenicals revealed that DPAA at 10 µM activated astrocytes most effective among organic arsenicals tested at the same dose. These results suggest that in a cerebellum exposed to DPAA, abnormal activation of the MAPK-transcription factor pathway and irregular secretion of these neuroactive, glioactive, and/or vasoactive cytokines in astrocytes can be the direct/indirect cause of functional abnormalities in surrounding neurons, glial cells, and vascular cells: This in turn might lead to the onset of cerebellar symptoms and disruption of cerebral blood flow. PMID:26645585

  11. Change in Plasma Cytokine Levels During Risperidone Treatment in Children with Autism

    PubMed Central

    Choi, Jae Eun; Widjaja, Felicia; Careaga, Milo; Bent, Stephen; Ashwood, Paul

    2014-01-01

    Abstract Background: Atypical antipsychotics decrease irritability in autism. They also affect the cytokine network. Psychological stress, depression, and, possibly, autism spectrum disorder (ASD) are associated with the production of pro-inflammatory cytokines. We sought to determine if risperidone treatment led to changes in plasma cytokine levels. Methods: Forty-five subjects from an open-label study of risperidone treatment of children and adolescents with ASD, ages 4–18 years, had an analysis of 27 different cytokines at baseline and after 8 weeks of treatment using multiplex assays (Millipore) and read on the Luminex 100™ platform. We examined changes in each of the cytokine levels in the entire group, and also compared changes in cytokines in responders versus nonresponders. Results: After 8 weeks of risperidone treatment, 2 of the 27 plasma cytokines showed statistically significant decreases in median levels: Eotaxin (p=0.0003) and monocyte chemoattractant protein-1 (MCP-1) (p=0.0024). Six of the 48 subjects met two criteria for responders to risperidone, and the median values of interleukin (IL)-5 were significantly higher (p=0.005) in the overall responder group than in nonresponders. Conclusions: Two cytokines, eotaxin and MCP-1, which have previously been identified as abnormally elevated in children with autism, decreased during treatment with risperidone. This suggests a possible mechanism of action of risperidone treatment and a balancing of the immune system in affected subjects in this very preliminary study. PMID:24828014

  12. Feeling Abnormal: Simulation of Deviancy in Abnormal and Exceptionality Courses.

    ERIC Educational Resources Information Center

    Fernald, Charles D.

    1980-01-01

    Describes activity in which student in abnormal psychology and psychology of exceptional children classes personally experience being judged abnormal. The experience allows the students to remember relevant research, become sensitized to the feelings of individuals classified as deviant, and use caution in classifying individuals as abnormal.…

  13. Six secrets of champagne

    NASA Astrophysics Data System (ADS)

    Liger-Belair, Gérard

    2015-12-01

    Popping open a bottle of champagne is one of life's great delights, but how much do you really know about the science behind this greatest of wines? Gérard Liger-Belair reveals his six favourite champagne secrets.

  14. Secret quality of love.

    PubMed

    Strachan-Hall, Elaine

    2016-09-01

    Many of us can recite three Donabedian dimensions of the quality of care of structure, process and outcome. Recently, I was introduced to another of Avedis Donabedian's quotes about the 'secret quality of love'. PMID:27581908

  15. Fermented soybeans, Chungkookjang, prevent hippocampal cell death and β-cell apoptosis by decreasing pro-inflammatory cytokines in gerbils with transient artery occlusion

    PubMed Central

    Park, Sunmin; Kim, Da Sol; Moon, Bo Reum

    2015-01-01

    Since Chungkookjang, a short-term fermented soybean, is known to improve glucose metabolism and antioxidant activity, it may prevent the neurological symptoms and glucose disturbance induced by artery occlusion. We investigated the protective effects and mechanisms of traditional (TFC) and standardized Chungkookjang fermented with Bacillus licheniformis (BLFC) against ischemia/reperfusion damage in the hippocampal CA1 region and against hyperglycemia after transient cerebral ischemia in gerbils. Gerbils were subjected to either an occlusion of the bilateral common carotid arteries for 8 min to render them ischemic or a sham operation. Ischemic gerbils were fed either a 40% fat diet containing 10% of either cooked soybean (CSB), TFC, or BLFC for 28 days. Neuronal cell death and cytokine expression in the hippocampus, neurological deficit, serum cytokine levels, and glucose metabolism were measured. TFC and BLFC contained more isoflavonoid aglycones than CSB. Artery occlusion increased the expressions of IL-1β and TNF-α as well as cell death in the hippocampal CA1 region and induced severe neurological symptoms. CSB, TFC, and BLFC prevented the neuronal cell death and the symptoms such as dropped eyelid, bristling hair, reduced muscle tone and flexor reflex, and abnormal posture and walking patterns, and suppressed cytokine expressions. CSB was less effective than TFC and BLFC. Artery occlusion induced glucose intolerance due to decreased insulin secretion and β-cell mass. TFC and BLFC prevented the impairment of glucose metabolism by artery occlusion. Especially TFC and BLFC increased β-cell proliferation and suppressed the β-cell apoptosis by suppressing TNF-α and IL-1β which in turn decreased cleaved caspase-3 that caused apoptosis. In conclusion, TFC and BLFC may prevent and alleviate neuronal cell death in the hippocampal CA1 region and neurological symptoms and poststroke hyperglycemia in gerbils with artery occlusion. This might be associated with

  16. Fermented soybeans, Chungkookjang, prevent hippocampal cell death and β-cell apoptosis by decreasing pro-inflammatory cytokines in gerbils with transient artery occlusion.

    PubMed

    Park, Sunmin; Kim, Da Sol; Kang, Sunna; Moon, Bo Reum

    2016-02-01

    Since Chungkookjang, a short-term fermented soybean, is known to improve glucose metabolism and antioxidant activity, it may prevent the neurological symptoms and glucose disturbance induced by artery occlusion. We investigated the protective effects and mechanisms of traditional (TFC) and standardized Chungkookjang fermented with Bacillus licheniformis (BLFC) against ischemia/reperfusion damage in the hippocampal CA1 region and against hyperglycemia after transient cerebral ischemia in gerbils. Gerbils were subjected to either an occlusion of the bilateral common carotid arteries for 8 min to render them ischemic or a sham operation. Ischemic gerbils were fed either a 40% fat diet containing 10% of either cooked soybean (CSB), TFC, or BLFC for 28 days. Neuronal cell death and cytokine expression in the hippocampus, neurological deficit, serum cytokine levels, and glucose metabolism were measured. TFC and BLFC contained more isoflavonoid aglycones than CSB. Artery occlusion increased the expressions of IL-1β and TNF-α as well as cell death in the hippocampal CA1 region and induced severe neurological symptoms. CSB, TFC, and BLFC prevented the neuronal cell death and the symptoms such as dropped eyelid, bristling hair, reduced muscle tone and flexor reflex, and abnormal posture and walking patterns, and suppressed cytokine expressions. CSB was less effective than TFC and BLFC. Artery occlusion induced glucose intolerance due to decreased insulin secretion and β-cell mass. TFC and BLFC prevented the impairment of glucose metabolism by artery occlusion. Especially TFC and BLFC increased β-cell proliferation and suppressed the β-cell apoptosis by suppressing TNF-α and IL-1β which in turn decreased cleaved caspase-3 that caused apoptosis. In conclusion, TFC and BLFC may prevent and alleviate neuronal cell death in the hippocampal CA1 region and neurological symptoms and poststroke hyperglycemia in gerbils with artery occlusion. This might be associated with

  17. Efficient quantum secret sharing

    NASA Astrophysics Data System (ADS)

    Qin, Huawang; Dai, Yuewei

    2016-05-01

    An efficient quantum secret sharing scheme is proposed, in which the dealer generates some single particles and then uses the operations of quantum-controlled-not and Hadamard gate to encode a determinate secret into these particles. The participants get their shadows by performing the single-particle measurements on their particles, and even the dealer cannot know their shadows. Compared to the existing schemes, our scheme is more practical within the present technologies.

  18. Targeted cytokines for cancer immunotherapy.

    PubMed

    Lode, H N; Reisfeld, R A

    2000-01-01

    Targeting of cytokines into the tumor microenvironment using antibody-cytokine fusion proteins, called immunocytokines, represents a novel approach in cancer immunotherapy. This article summarizes therapeutic efficacy and immune mechanisms involved in targeting interleukin-2 (IL-2) to neuroectodermal tumors using ganglioside GD2-specific antibody-IL-2 fusion protein (ch14.18-IL-2). Treatment of established melanoma metastases with ch14.18-IL-2 resulted in eradication of disease followed by a vaccination effect protecting mice from lethal challenges with wild-type tumor calls. In a syngeneic neuroblastoma model, targeted IL-2 was effective in the amplification of a weak memory immune response previously induced by IL-12 gene therapy using an engineered linear version of this heterodimeric cytokine. These findings show that targeted IL-2 may provide an effective tool in cancer immunotherapy and establish the missing link between T cell-mediated vaccination and objective clinical responses.

  19. Cytokines in Machado Joseph Disease/Spinocerebellar Ataxia 3.

    PubMed

    da Silva Carvalho, Gerson; Saute, Jonas Alex Morales; Haas, Clarissa Branco; Torrez, Vitor Rocco; Brochier, Andressa Wigner; Souza, Gabriele Nunes; Furtado, Gabriel Vasata; Gheno, Tailise; Russo, Aline; Monte, Thais Lampert; Schumacher-Schuh, Artur; D'Avila, Rui; Donis, Karina Carvalho; Castilhos, Raphael Machado; Souza, Diogo Onofre; Saraiva-Pereira, Maria Luiza; Torman, Vanessa Leotti; Camey, Suzi; Portela, Luis Valmor; Jardim, Laura Bannach

    2016-08-01

    The aim of the present study is to describe the serum concentrations of a broad spectrum of cytokines in symptomatic and asymptomatic carriers of Machado Joseph disease (SCA3/MJD) CAG expansions. Molecularly confirmed carriers and controls were studied. Age at onset, disease duration, and clinical scales Scale for the Assessment and Rating of Ataxia (SARA), Neurological Examination Score for Spinocerebellar Ataxias (NESSCA), SCA Functional Index (SCAFI), and Composite Cerebellar Functional Score (CCFS) were obtained from the symptomatic carriers. Serum was obtained from all individuals and a cytokine panel "consisted of" eotaxin, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-α, IFN-γ, interleukin (IL)-1β, IL-1RA, IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17, interferon gamma-induced protein (IP)-10, monocyte chemoattractant protein (MCP)-1, monokine induced by gamma interferon (MIG), macrophage inflammatory protein (MIP)-a, MIP-b, regulated on activation, normal T cell expressed and secreted (RANTES) and tumor necrosis factor (TNF)-α was analyzed. In a subgroup of symptomatic carriers, the cytokine panel was repeated after 360 days. Cytokine distribution among groups was studied by discriminant analysis; changes in serum levels after 360 days were studied by generalized estimation equation. Sixty-six symptomatic carriers, 13 asymptomatic carriers, and 43 controls were studied. No differences in cytokine patterns were found between controls and carriers of the CAG expansions or between controls and symptomatic carriers only. In contrast, eotaxin concentrations were significantly higher in asymptomatic than in symptomatic carriers or in controls (p = 0.001, ANCOVA). Eotaxin did not correlate with age, disease duration, CAG expansion, NESSCA score, and SARA score. Among symptomatic carriers, eotaxin dropped after 360 days (p = 0.039, GEE). SCA3/MJD patients presented a benign pattern of

  20. Intranasal coadministration of Cholera toxin with amoeba lysates modulates the secretion of IgA and IgG antibodies, production of cytokines and expression of pIgR in the nasal cavity of mice in the model of Naegleria fowleri meningoencephalitis.

    PubMed

    Carrasco-Yepez, Maricela; Campos-Rodriguez, Rafael; Lopez-Reyes, Israel; Bonilla-Lemus, Patricia; Rodriguez-Cortes, Antonio Yahve; Contis-Montes de Oca, Arturo; Jarillo-Luna, Adriana; Miliar-Garcia, Angel; Rojas-Hernandez, Saul

    2014-11-01

    The nasal mucosa is the first contact with antigens to induce IgA response. The role of this site has rarely been studied. We have shown than intranasal administration with Naegleria fowleri lysates plus Cholera toxin (CT) increased the protection (survival up to 100%) against N. fowleri infection in mice and apparently antibodies IgA and IgG together with polymorphonuclear (PMN) cells avoid the attachment of N. fowleri to apical side of the nasal epithelium. We also observed that nasal immunization resulted in the induction of antigen-specific IgG subclasses (IgG1 and IgG2a) in nasal washes at days 3 and 9 after the challenge and IgA and IgG in the nasal cavity, compared to healthy and infected mice. We found that immunization with both treatments, N. fowleri lysates plus CT or CT alone, increased the expression of the genes for alpha chain, its receptor (pIgR), and it also increased the expression of the corresponding proteins evidenced by the ∼65 and ∼74kDa bands, respectively. Since the production of pIgR, IgA and IgG antibodies, is up-regulated by some factors, we analyzed the expression of genes for IL-10, IL-6, IFN-γ, TNF-α and IL-1β by using RT-PCR of nasal passages. Immunization resulted in an increased expression of IL-10, IL-6, and IFN-γ cytokines. We also aimed to examine the possible influences of immunization and challenge on the production of inflammatory cytokines (TNF-α and IL-1β). We observed that the stimulus of immunization inhibits the production of TNF-α compared to the infected group where the infection without immunization causes an increase in it. Thus, it is possible that the coexistence of selected cytokines produced by our immunization model may provide a highly effective immunological environment for the production of IgA, IgG and pIgR as well as a strong activation of the PMN in mucosal effector tissue such as nasal passages. PMID:24731967

  1. Intranasal coadministration of Cholera toxin with amoeba lysates modulates the secretion of IgA and IgG antibodies, production of cytokines and expression of pIgR in the nasal cavity of mice in the model of Naegleria fowleri meningoencephalitis.

    PubMed

    Carrasco-Yepez, Maricela; Campos-Rodriguez, Rafael; Lopez-Reyes, Israel; Bonilla-Lemus, Patricia; Rodriguez-Cortes, Antonio Yahve; Contis-Montes de Oca, Arturo; Jarillo-Luna, Adriana; Miliar-Garcia, Angel; Rojas-Hernandez, Saul

    2014-11-01

    The nasal mucosa is the first contact with antigens to induce IgA response. The role of this site has rarely been studied. We have shown than intranasal administration with Naegleria fowleri lysates plus Cholera toxin (CT) increased the protection (survival up to 100%) against N. fowleri infection in mice and apparently antibodies IgA and IgG together with polymorphonuclear (PMN) cells avoid the attachment of N. fowleri to apical side of the nasal epithelium. We also observed that nasal immunization resulted in the induction of antigen-specific IgG subclasses (IgG1 and IgG2a) in nasal washes at days 3 and 9 after the challenge and IgA and IgG in the nasal cavity, compared to healthy and infected mice. We found that immunization with both treatments, N. fowleri lysates plus CT or CT alone, increased the expression of the genes for alpha chain, its receptor (pIgR), and it also increased the expression of the corresponding proteins evidenced by the ∼65 and ∼74kDa bands, respectively. Since the production of pIgR, IgA and IgG antibodies, is up-regulated by some factors, we analyzed the expression of genes for IL-10, IL-6, IFN-γ, TNF-α and IL-1β by using RT-PCR of nasal passages. Immunization resulted in an increased expression of IL-10, IL-6, and IFN-γ cytokines. We also aimed to examine the possible influences of immunization and challenge on the production of inflammatory cytokines (TNF-α and IL-1β). We observed that the stimulus of immunization inhibits the production of TNF-α compared to the infected group where the infection without immunization causes an increase in it. Thus, it is possible that the coexistence of selected cytokines produced by our immunization model may provide a highly effective immunological environment for the production of IgA, IgG and pIgR as well as a strong activation of the PMN in mucosal effector tissue such as nasal passages.

  2. Endocrine abnormalities of obesity.

    PubMed

    Björntorp, P

    1995-09-01

    Studies have shown that patients with central obesity have increased cortisol secretion, probably because they have increased activity of the hypothalamic-pituitary-adrenal (HPA) axis. A high waist-to-hip ratio (WHR) is associated with low production of sex steroids, such as testosterone in men, and a low rate of secretion of growth hormone. High levels of cortisol and insulin combined with low levels of growth hormone and sex steroid can cause lipid accumulation. These hormonal changes probably produce more deposition of visceral than subcutaneous fat. Patients who are deficient in either testosterone or growth hormone show a reduction in visceral adiposity when their hormone levels are normalized. Stress has been shown to activate the HPA axis and may cause the hormonal changes associated with obesity. Individuals with elevated WHR have indications of high levels of stress and anxiety. Monkeys that were stressed by social disruption were found to have increased cortisol levels and low sex steroid levels. Many of these animals had insulin resistance and visceral adiposity. Stimulants, such as alcohol and smoking, also increase the activity of the HPA axis.

  3. Abnormal human sex chromosome constitutions

    SciTech Connect

    1993-12-31

    Chapter 22, discusses abnormal human sex chromosome constitution. Aneuploidy of X chromosomes with a female phenotype, sex chromosome aneuploidy with a male phenotype, and various abnormalities in X chromosome behavior are described. 31 refs., 2 figs.

  4. Exercises to Improve Gait Abnormalities

    MedlinePlus

    ... Home About iChip Articles Directories Videos Resources Contact Exercises to Improve Gait Abnormalities Home » Article Categories » Exercise and Fitness Font Size: A A A A Exercises to Improve Gait Abnormalities Next Page The manner ...

  5. Glucose and acute exercise influence factors secreted by circulating angiogenic cells in vitro.

    PubMed

    Witkowski, Sarah; Guhanarayan, Gayatri; Burgess, Rachel

    2016-02-01

    Circulating angiogenic cells (CAC) influence vascular repair through the secretion of proangiogenic factors and cytokines. While CAC are deficient in patients with diabetes and exercise has a beneficial effect on CACs, the impact of these factors on paracrine secretion from CAC is unknown. We aimed to determine whether the in vitro secretion of selected cytokines and nitric oxide (NO) from CAC is influenced by hyperglycemia and acute exercise. Colony-forming unit CAC (CFU-CAC) were cultured from young active men (n = 9, 24 ± 2 years) at rest and after exercise under normal (5 mmol/L) and elevated (15 mmol/L) glucose. Preliminary relative multiplex cytokine analysis revealed that CAC conditioned culture media contained three of six measured cytokines: transforming growth factor-beta-1 (TGFβ1), tumor necrosis factor alpha (TNFα), and monocyte chemotactic protein-1 (MCP-1). Single quantitative cytokine analysis was used to determine the concentration of each cytokine from the four conditions. NO was measured via Griess assay. There was a significant effect of CAC exposure to in vivo exercise on in vitro TGFβ1 secretion (P = 0.024) that was independent of glucose concentration. There was no effect of glucose or acute exercise on TNFα or MCP-1 concentration (both P > 0.05). The concentration of NO from CFU-CAC cultured in elevated glucose was lower following acute exercise (P = 0.002) suggesting that exercise did not maintain NO secretion under hyperglycemic conditions. Our results identify paracrine signaling factors that may be responsible for the proangiogenic function of CFU-CAC and an influence of acute exercise and elevated glucose on CFU-CAC soluble factor secretion. PMID:26847726

  6. Glucose and acute exercise influence factors secreted by circulating angiogenic cells in vitro.

    PubMed

    Witkowski, Sarah; Guhanarayan, Gayatri; Burgess, Rachel

    2016-02-01

    Circulating angiogenic cells (CAC) influence vascular repair through the secretion of proangiogenic factors and cytokines. While CAC are deficient in patients with diabetes and exercise has a beneficial effect on CACs, the impact of these factors on paracrine secretion from CAC is unknown. We aimed to determine whether the in vitro secretion of selected cytokines and nitric oxide (NO) from CAC is influenced by hyperglycemia and acute exercise. Colony-forming unit CAC (CFU-CAC) were cultured from young active men (n = 9, 24 ± 2 years) at rest and after exercise under normal (5 mmol/L) and elevated (15 mmol/L) glucose. Preliminary relative multiplex cytokine analysis revealed that CAC conditioned culture media contained three of six measured cytokines: transforming growth factor-beta-1 (TGFβ1), tumor necrosis factor alpha (TNFα), and monocyte chemotactic protein-1 (MCP-1). Single quantitative cytokine analysis was used to determine the concentration of each cytokine from the four conditions. NO was measured via Griess assay. There was a significant effect of CAC exposure to in vivo exercise on in vitro TGFβ1 secretion (P = 0.024) that was independent of glucose concentration. There was no effect of glucose or acute exercise on TNFα or MCP-1 concentration (both P > 0.05). The concentration of NO from CFU-CAC cultured in elevated glucose was lower following acute exercise (P = 0.002) suggesting that exercise did not maintain NO secretion under hyperglycemic conditions. Our results identify paracrine signaling factors that may be responsible for the proangiogenic function of CFU-CAC and an influence of acute exercise and elevated glucose on CFU-CAC soluble factor secretion.

  7. Intracellular staining and detection of cytokines by fluorescence-activated flow cytometry.

    PubMed

    Freer, Giulia

    2014-01-01

    The detection of cytokines inside cells producing them has made a tremendous impact on the way immune reactivity is measured. Intracellular cytokine staining is the only immunological technique allowing determination of antigen-specific T cell function and phenotype at the same time; for this reason, it is one of the most popular methods to measure antigenicity in the evaluation of vaccine efficacy and in the study of infectious diseases. It is a flow cytometric technique based on staining of intracellular cytokines and cell markers (surface or cytoplasmic) with fluorescent antibodies after short term culture of stimulated immune cells in the presence of a protein secretion inhibitor, followed by fixation and permeabilization. Most experiments involve detection of five to ten different colors but many more can be detected by modern flow cytometers. Here, we discuss our experience using a standard protocol for intracellular cytokine staining. PMID:24908309

  8. Abnormal ionization in sonoluminescence

    NASA Astrophysics Data System (ADS)

    Zhang, Wen-Juan; An, Yu

    2015-04-01

    Sonoluminescence is a complex phenomenon, the mechanism of which remains unclear. The present study reveals that an abnormal ionization process is likely to be present in the sonoluminescing bubble. To fit the experimental data of previous studies, we assume that the ionization energies of the molecules and atoms in the bubble decrease as the gas density increases and that the decrease of the ionization energy reaches about 60%-70% as the bubble flashes, which is difficult to explain by using previous models. Project supported by the Research Fund for the Doctoral Program of Higher Education of China (Grant No. 20120002110031) and the National Natural Science Foundation of China (Grant No. 11334005).

  9. Abnormal hematological indices in cirrhosis

    PubMed Central

    Qamar, Amir A; Grace, Norman D

    2009-01-01

    Abnormalities in hematological indices are frequently encountered in cirrhosis. Multiple causes contribute to the occurrence of hematological abnormalities. Recent studies suggest that the presence of hematological cytopenias is associated with a poor prognosis in cirrhosis. The present article reviews the pathogenesis, incidence, prevalence, clinical significance and treatment of abnormal hematological indices in cirrhosis. PMID:19543577

  10. Combinatorial signals by inflammatory cytokines and chemokines mediate leukocyte interactions with extracellular matrix.

    PubMed

    Vaday, G G; Franitza, S; Schor, H; Hecht, I; Brill, A; Cahalon, L; Hershkoviz, R; Lider, O

    2001-06-01

    On their extravasation from the vascular system into inflamed tissues, leukocytes must maneuver through a complex insoluble network of molecules termed the extracellular matrix (ECM). Leukocytes navigate toward their target sites by adhering to ECM glycoproteins and secreting degradative enzymes, while constantly orienting themselves in response to specific signals in their surroundings. Cytokines and chemokines are key biological mediators that provide such signals for cell navigation. Although the individual effects of various cytokines have been well characterized, it is becoming increasingly evident that the mixture of cytokines encountered in the ECM provides important combinatorial signals that influence cell behavior. Herein, we present an overview of previous and ongoing studies that have examined how leukocytes integrate signals from different combinations of cytokines that they encounter either simultaneously or sequentially within the ECM, to dynamically alter their navigational activities. For example, we describe our findings that tumor necrosis factor (TNF)-alpha acts as an adhesion-strengthening and stop signal for T cells migrating toward stromal cell-derived factor-1alpha, while transforming growth factor-beta down-regulates TNF-alpha-induced matrix metalloproteinase-9 secretion by monocytes. These findings indicate the importance of how one cytokine, such as TNF-alpha, can transmit diverse signals to different subsets of leukocytes, depending on its combination with other cytokines, its concentration, and its time and sequence of exposure. The combinatorial effects of multiple cytokines thus affect leukocytes in a step-by-step manner, whereby cells react to cytokine signals in their immediate vicinity by altering their adhesiveness, directional movement, and remodeling of the ECM. PMID:11404372

  11. Spirometric abnormalities among welders

    SciTech Connect

    Rastogi, S.K.; Gupta, B.N.; Husain, T.; Mathur, N.; Srivastava, S. )

    1991-10-01

    A group of manual welders age group 13-60 years having a mean exposure period of 12.4 {plus minus} 1.12 years were subjected to spirometry to evaluate the prevalence of spirometric abnormalities. The welders showed a significantly higher prevalence of respiratory impairment than that observed among the unexposed controls as a result of exposure to welding gases which comprised fine particles of lead, zinc, chromium, and manganese. This occurred despite the lower concentration of the pollutants at the work place. In the expose group, the smoking welders showed a prevalence of respiratory impairment significantly higher than that observed in the nonsmoking welders. The results of the pulmonary function tests showed a predominantly restrictive type of pulmonary impairment followed by a mixed ventilatory defect among the welders. The effect of age on pulmonary impairment was not discernible. Welders exposed for over 10 years showed a prevalence of respiratory abnormalities significantly higher than those exposed for less than 10 years. Smoking also had a contributory role.

  12. Pathogenesis and management of abnormal puberty.

    PubMed

    Hopwood, N J

    1985-01-01

    In the prepubertal child, the hypothalamic-pituitary-gonadal (H-P-G) axis is functional and extremely sensitive to negative feedback inhibition by low circulating levels of sex steroids. This feedback system may be under the control of unknown CNS inhibitory mechanisms. Clinical signs of puberty are preceded by increased pulsatile secretion of hypothalamic gonadotropin-releasing hormone (GnRH) followed by increased pituitary responsiveness to GnRH. Gonadotropin secretion, particularly LH, increases in both sexes, especially during sleep, resulting in gonadal stimulation, secretion of sex steroids, and progressive physical maturation. When any phase of the H-P-G axis malfunctions, abnormal puberty can result. Abnormal puberty may be precocious or delayed. When puberty is precocious it may be isosexual or heterosexual, complete or partial, intermittent (unsustained), or progressive. True (central) precocious puberty is usually progressive, and hormonally reflective of normal puberty, although occurring at an earlier age, whereas intermittent or unsustained precocious puberty usually is associated with immature patterns of gonadotropin secretion, or with complete gonadotropin suppression as in precocious pseudopuberty (ovarian or adrenal tumors). Cranial axial tomography, gonadotropin response to GnRH, and pelvic ultrasound in girls are useful tools to aid in the differential diagnosis of these conditions. Intermittent, or unsustained, puberty in girls is usually self-limited, requiring no medical or surgical intervention. True progressive central precocity may now be managed with GnRH analogues, which effectively arrest pubertal changes as well as slow rapid linear growth and skeletal maturation. Although a maturation lag usually explains most patterns of delayed puberty, it is often challenging to exclude other conditions that may contribute to slow pubertal progression, such as chronic illness, excessive exercise, emotional stress, anorexia, or drug use. Elevated

  13. The importance of liver microcirculation in promoting autoimmune hepatitis via maintaining an inflammatory cytokine milieu--a mathematical model study.

    PubMed

    Lettmann, Karsten Alexander; Hardtke-Wolenski, Matthias

    2014-05-01

    In autoimmune diseases, inflammatory cytokine concentrations are important for initiating and maintaining the status of autoimmunity. Autoimmune hepatitis (AIH) is an inflammatory liver disease characterized by a loss of immune tolerance against specific antigens located in hepatocytes. During the progression of the disease, antigen-presenting cells and different classes of T-helper cells secrete specific cytokines important for maintaining the disease. As these cytokines are secreted into the local liver environment, the blood flow in liver sinusoids might influence the local cytokine concentration. Considering the liver tissue as a porous medium, based on Darcy׳s law, the microcirculation within a liver lobule was modelled. Using realistic physiological pressure differences and tissue permeabilities, the blood velocity inside the sinusoids could be calculated and validated with blood velocity data obtained via Orthogonal Polarization Spectral Imaging (OPSI). Furthermore, oxygen consumption is modelled to obtain Rappaport׳s acinus model. Finally, steady state spatial distributions of secreted cytokines within the liver lobule could be estimated for specified realistic production rates of T-helper cells. It could be demonstrated that the characteristics of the liver microcirculation have an important impact on establishing inflammatory cytokine levels within the portal fields and the vascular septa promoting the occurrence of interface hepatitis.

  14. Gallium arsenide selectively up-regulates inflammatory cytokine expression at exposure site.

    PubMed

    Becker, Stephen M; McCoy, Kathleen L

    2003-12-01

    Gallium arsenide (GaAs), a technologically and economically important semiconductor, is widely utilized in both military and commercial applications. This chemical is a potential health hazard as a carcinogen and immunotoxicant. We previously reported that macrophages at the exposure site exhibit characteristics of activation. In vitro culture of macrophages with GaAs fails to recapitulate the in vivo phenotype, suggesting that complete GaAs-mediated activation in vivo may require other cells or components found in the body's microenvironment. Our present study examined the role of cytokines upon GaAs-mediated macrophage activation. Intraperitoneal administration of GaAs elicited rapid specific recruitment of blood monocytes to the exposure site. This recruitment occurred concomitant with up-regulation of 17 chemokine and inflammatory cytokine mRNAs, while transcripts of three inhibitory cytokines diminished. Administration of latex beads caused less cytokine induction than GaAs, indicating that changes in mRNA levels could not be attributed to phagocytosis. Four representative chemokines and cytokines were selected for further analysis. Increased cytokine mRNA expression was paralleled by similar increases in cytokine protein levels, and secreted protein products were detected in peritoneal fluid. Cytokine protein expression was constrained to myeloid cells, and to a lesser extent to B cells. Alterations in patterns of cytokine gene expression elucidate mechanisms for increased cellular activation and antigen processing, and modulation of the inflammatory response. Our findings indicate that in vivo GaAs exposure alters cytokine gene expression, which may lead to an inflammatory reaction and contribute to pathological tissue damage.

  15. IL-12 Family Cytokines: Immunological Playmakers

    PubMed Central

    Vignali, Dario A.A.; Kuchroo, Vijay K.

    2014-01-01

    The interleukin-12 (IL-12) family is unique in comprising the only heterodimeric cytokines, which includes IL-12, IL-23, IL-27 and IL-35. This endows these cytokines with a unique set of connections and functional interactions not shared within other cytokine families. Despite sharing many structural features and molecular partners, they mediate surprisingly diverse functional effects. Here we discuss the unique and unusual structural and functional characteristics of this cytokine family. We outline how cells might interpret seemingly similar cytokine signals to give rise to the diverse functional outcomes which characterize this cytokine family. We will also discuss the therapeutic implications of this complexity. PMID:22814351

  16. [Cytokines. Transmittor substances of the immune system].

    PubMed

    Pisa, P; Söder, O

    1995-07-12

    Cytokines are hormone-like proteins and peptides whose principal function is that of signalling substances within the immunoinflammatory and haematopoietic systems. Since the first cytokines were characterised 15 years ago, over 50 cytokines have been strictly defined and characterised. Cytokines are classified mainly on the basis of functional criteria into families--e.g, interleukins, interferons, colony stimulating factors, and chemokines. The article provides a broad review of cytokine physiology and pathophysiology with an emphasis on recent findings of their involvement in various diseases such as infections, autoimmune and haematological disorders, and cancer. Different treatment modalities that affect cytokine activity are discussed.

  17. Genome-Wide Analysis of Polymorphisms Associated with Cytokine Responses in Smallpox Vaccine Recipients

    PubMed Central

    Kennedy, Richard B.; Ovsyannikova, Inna G.; Pankratz, V. Shane; Haralambieva, Iana H.; Vierkant, Robert A.; Poland, Gregory A.

    2014-01-01

    The role that genetics plays in response to infection or disease is becoming increasingly clear as we learn more about immunogenetics and host-pathogen interactions. Here we report a genome-wide analysis of the effects of host genetic variation on cytokine responses to vaccinia virus stimulation in smallpox vaccine recipients. Our data show that vaccinia stimulation of immune individuals results in secretion of inflammatory and Th1 cytokines. We identified multiple SNPs significantly associated with variations in cytokine secretion. These SNPs are found in genes with known immune function, as well as in genes encoding for proteins involved in signal transduction, cytoskeleton, membrane channels and ion transport, as well as others with no previously identified connection to immune responses. The large number of significant SNP associations implies that cytokine secretion in response to vaccinia virus is a complex process controlled by multiple genes and gene families. Follow-up studies to replicate these findings and then pursue mechanistic studies will provide a greater understanding of how genetic variation influences vaccine responses. PMID:22610502

  18. Exercise and sleep deprivation do not change cytokine expression levels in patients with chronic fatigue syndrome.

    PubMed

    Nakamura, Toru; Schwander, Stephan; Donnelly, Robert; Cook, Dane B; Ortega, Felix; Togo, Fumiharu; Yamamoto, Yoshiharu; Cherniack, Neil S; Klapholz, Marc; Rapoport, David; Natelson, Benjamin H

    2013-11-01

    A major hypothesis regarding the cause of chronic fatigue syndrome (CFS) is immune dysregulation, thought to be reflected in upregulated proinflammatory cytokines leading to the symptoms that are characteristic of this illness. Because the symptoms worsen with physical exertion or sleep loss, we hypothesized that we could use these stressors to magnify the underlying potential pathogenic abnormalities in the cytokine systems of people with CFS. We conducted repeat blood sampling for cytokine levels from healthy subjects and CFS patients during both postexercise and total sleep deprivation nights and assayed for protein levels in the blood samples, mRNA activity in peripheral blood lymphocytes (PBLs), and function in resting and stimulated PBLs. We found that these environmental manipulations did not produce clinically significant upregulation of proinflammatory cytokines. These data do not support an important role of immune dysregulation in the genesis of stress-induced worsening of CFS.

  19. A Rare Stapes Abnormality

    PubMed Central

    Kanona, Hala; Virk, Jagdeep Singh; Kumar, Gaurav; Chawda, Sanjiv; Khalil, Sherif

    2015-01-01

    The aim of this study is to increase awareness of rare presentations, diagnostic difficulties alongside management of conductive hearing loss and ossicular abnormalities. We report the case of a 13-year-old female reporting progressive left-sided hearing loss and high resolution computed tomography was initially reported as normal. Exploratory tympanotomy revealed an absent stapedius tendon and lack of connection between the stapes superstructure and footplate. The footplate was fixed. Stapedotomy and stapes prosthesis insertion resulted in closure of the air-bone gap by 50 dB. A review of world literature was performed using MedLine. Middle ear ossicular discontinuity can result in significant conductive hearing loss. This can be managed effectively with surgery to help restore hearing. However, some patients may not be suitable or decline surgical intervention and can be managed safely conservatively. PMID:25628909

  20. Pathophysiology of insulin secretion.

    PubMed

    Scheen, A J

    2004-02-01

    Defects in pancreatic islet beta-cell function play a major role in the development of diabetes mellitus. Type 1 diabetes is caused by a more or less rapid destruction of pancreatic beta cells, and the autoimmune process begins years before the beta-cell destruction becomes complete, thereby providing a window of opportunity for intervention. During the preclinical period and early after diagnosis, much of the insulin deficiency may be the result of functional inhibition of insulin secretion that may be at least partially and transiently reversible. Type 2 diabetes is characterized by a progressive loss of beta-cell function throughout the course of the disease. The pattern of loss is an initial (probably of genetic origin) defect in acute or first-phase insulin secretion, followed by a decreasing maximal capacity of insulin secretion. Last, a defective steady-state and basal insulin secretion develops, leading to almost complete beta-cell failure requiring insulin treatment. Because of the reciprocal relation between insulin secretion and insulin sensitivity, valid representation of beta-cell function requires interpretation of insulin responses in the context of the prevailing degree of insulin sensitivity. This appropriate approach highlights defects in insulin secretion at the various stages of the natural history of type 2 diabetes and already present in individuals at risk to develop the disease. To date none of the available therapies can stop the progressive beta-cell defect and the progression of the metabolic disorder. The better understanding of the pathophysiology of the disease should lead to the development of new strategies to preserve beta-cell function in both type 1 and type 2 diabetes mellitus.

  1. TLR-mediated secretion of endoplasmic reticulum aminopeptidase 1 from macrophages.

    PubMed

    Goto, Yoshikuni; Ogawa, Kenji; Nakamura, Takahiro J; Hattori, Akira; Tsujimoto, Masafumi

    2014-05-01

    Macrophages play an important role in host defense under several immunological, inflammatory, and/or infectious conditions. In our previous work, we demonstrated that endoplasmic reticulum aminopeptidase 1 (ERAP1) was secreted from macrophages in response to LPS and IFN-γ, and it enhanced their phagocytic activity. In this study, we analyzed the mechanism of LPS/IFN-γ-induced ERAP1 secretion. LPS/IFN-γ-induced secretion of the enzyme from the murine macrophage cell line RAW264.7 was suppressed by polymyxin B. Several agonists of TLRs, such as Pam3CSK4, FSL-1, and ODN1826, induced its secretion. In contrast, neutralizing Abs to IFN-β and TNF-α receptor type 1 suppressed its secretion. Using murine peritoneal macrophages derived from TNF-α and type 1 IFNR knockout mice, we confirmed the involvement of these two cytokines in ERAP1 secretion. In addition, secretion of ERAP1 from both RAW264.7 cells and murine peritoneal macrophages was induced by A23187 and thapsigargin and inhibited by BAPTA-AM and the calmodulin inhibitor W7. These results suggest that LPS/IFN-γ-induced secretion of ERAP1 is mediated by TLRs via induction of intermediate cytokines such as IFN-β and TNF-α, which in turn lead to enhanced cytosolic Ca(2+) levels and calmodulin activation.

  2. Plasma Cytokine Profiles in Long-Term Strenuous Exercise

    PubMed Central

    Nielsen, Hilde G.; Øktedalen, Olav; Opstad, Per-Kristian; Lyberg, Torstein

    2016-01-01

    The open window theory indicates altered immunity 3 to 72 hours after exercise. The J-curve describes the risk of illness in response to exercise. The aim of this study was to examine the secretion of proinflammatory and anti-inflammatory cytokines before and after long-term strenuous exercise. Fourteen marathon and 16 half-marathon runners and 10 military cadets participating in a military ranger-training course were recruited to this study. Within-subject design was used measuring levels of plasma cytokines before, during, and after exercise. Plasma cytokines were measured using Luminex multiplex technology and ELISA. Comparing pre/post plasma levels both the marathon- and the half-marathon runners showed heavily increased levels of IL-6, IL-10, and IL-8 (P < 0.001). LPS stimulation among the half-marathon runners decreased the postrace levels of IL-6, IL-1b, and TNFα by 45%, 24%, and 43%, respectively (P < 0.01). During the ranger training course the spontaneous and LPS-stimulated levels of IL-6, IL-8, IL-10, IL-1b, and TNFα changed in a similar fashion as in the half-marathon runners although the fluctuations were smaller. Our study supports the open window and the J-curve theory; the immune system is more activated and the subjects are more threatened to infectious pathogens after intensive physical activity and in the period after exercise. PMID:27239554

  3. Overview of cytokines and nitric oxide involvement in immuno-pathogenesis of inflammatory bowel diseases

    PubMed Central

    Soufli, Imene; Toumi, Ryma; Rafa, Hayet; Touil-Boukoffa, Chafia

    2016-01-01

    Inflammatory bowel diseases (IBDs), including Crohn’s disease and ulcerative colitis are complex disorders with undetermined etiology. Several hypotheses suggest that IBDs result from an abnormal immune response against endogenous flora and luminal antigens in genetically susceptible individuals. The dysfunction of the mucosal immune response is implicated in the pathogenesis of IBD. The balance between pro-inflammatory cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-8, and IL-17A], anti-inflammatory cytokines (IL-4 and IL-13), and immunoregulatory cytokines (IL-10 and transforming growth factors β) is disturbed. Moreover, evidence from animal and clinical studies demonstrate a positive correlation between an increased concentration of nitric oxide (NO) and the severity of the disease. Interestingly, proinflammatory cytokines are involved in the up-regulation of inducible oxide synthase (iNOS) expression in IBD. However, anti-inflammatory and immunoregulatory cytokines are responsible for the negative regulation of iNOS. A positive correlation between NO production and increased pro-inflammatory cytokine levels (TNF-α, IL-6, IL-17, IL-12, and interferon-γ) were reported in patients with IBD. This review focuses on the role of cytokines in intestinal inflammation and their relationship with NO in IBD. PMID:27602236

  4. Overview of cytokines and nitric oxide involvement in immuno-pathogenesis of inflammatory bowel diseases.

    PubMed

    Soufli, Imene; Toumi, Ryma; Rafa, Hayet; Touil-Boukoffa, Chafia

    2016-08-01

    Inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis are complex disorders with undetermined etiology. Several hypotheses suggest that IBDs result from an abnormal immune response against endogenous flora and luminal antigens in genetically susceptible individuals. The dysfunction of the mucosal immune response is implicated in the pathogenesis of IBD. The balance between pro-inflammatory cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-8, and IL-17A], anti-inflammatory cytokines (IL-4 and IL-13), and immunoregulatory cytokines (IL-10 and transforming growth factors β) is disturbed. Moreover, evidence from animal and clinical studies demonstrate a positive correlation between an increased concentration of nitric oxide (NO) and the severity of the disease. Interestingly, proinflammatory cytokines are involved in the up-regulation of inducible oxide synthase (iNOS) expression in IBD. However, anti-inflammatory and immunoregulatory cytokines are responsible for the negative regulation of iNOS. A positive correlation between NO production and increased pro-inflammatory cytokine levels (TNF-α, IL-6, IL-17, IL-12, and interferon-γ) were reported in patients with IBD. This review focuses on the role of cytokines in intestinal inflammation and their relationship with NO in IBD. PMID:27602236

  5. Xuebijing injection alleviates cytokine-induced inflammatory liver injury in CLP-induced septic rats through induction of suppressor of cytokine signaling 1

    PubMed Central

    Li, Ailin; Li, Jing; Bao, Yuhua; Yuan, Dingshan; Huang, Zhongwei

    2016-01-01

    Dysregulation of inflammatory cytokines and liver injury are associated with the pathogenesis of sepsis. Xuebijing injection, a Chinese herbal medicine, has been used in the treatment of sepsis and can contribute to the improvement of patients' health. However, the underlying molecular mechanisms are not yet clearly illuminated. In the present study, a septic rat model with liver injury was established by the cecal ligation and puncture (CLP) method. Histological alterations to the liver, activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), levels of inflammatory cytokine secretion and the expression of suppressors of cytokine signaling 1 (SOCS-1) in the CLP model rats with and without Xuebijing treatment were determined. The results showed that Xuebijing injection ameliorated the pathological changes in liver tissues caused by sepsis, and reduced the sepsis-induced elevation in serum ALT and AST levels. Furthermore, Xuebijing injection markedly downregulated the expression of tumor necrosis factor α and interleukin (IL)-6, and upregulated the expression of IL-10. More importantly, SOCS1 expression levels at the protein and mRNA levels were further increased by Xuebijing. These findings demonstrate that Xuebijing injection can significantly alleviate liver injury in CLP-induced septic rats via the regulation of inflammatory cytokine secretion and the promotion of SOCS1 expression. The protective effects of Xuebijing injection suggest its therapeutic potential in the treatment of CLP-induced liver injury. PMID:27602076

  6. Xuebijing injection alleviates cytokine-induced inflammatory liver injury in CLP-induced septic rats through induction of suppressor of cytokine signaling 1

    PubMed Central

    Li, Ailin; Li, Jing; Bao, Yuhua; Yuan, Dingshan; Huang, Zhongwei

    2016-01-01

    Dysregulation of inflammatory cytokines and liver injury are associated with the pathogenesis of sepsis. Xuebijing injection, a Chinese herbal medicine, has been used in the treatment of sepsis and can contribute to the improvement of patients' health. However, the underlying molecular mechanisms are not yet clearly illuminated. In the present study, a septic rat model with liver injury was established by the cecal ligation and puncture (CLP) method. Histological alterations to the liver, activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), levels of inflammatory cytokine secretion and the expression of suppressors of cytokine signaling 1 (SOCS-1) in the CLP model rats with and without Xuebijing treatment were determined. The results showed that Xuebijing injection ameliorated the pathological changes in liver tissues caused by sepsis, and reduced the sepsis-induced elevation in serum ALT and AST levels. Furthermore, Xuebijing injection markedly downregulated the expression of tumor necrosis factor α and interleukin (IL)-6, and upregulated the expression of IL-10. More importantly, SOCS1 expression levels at the protein and mRNA levels were further increased by Xuebijing. These findings demonstrate that Xuebijing injection can significantly alleviate liver injury in CLP-induced septic rats via the regulation of inflammatory cytokine secretion and the promotion of SOCS1 expression. The protective effects of Xuebijing injection suggest its therapeutic potential in the treatment of CLP-induced liver injury.

  7. Cytokine Control of Inflammation and Repair in the Pathology of Multiple Sclerosis

    PubMed Central

    Rodgers, Jane M.; Miller, Stephen D.

    2012-01-01

    Cytokines are secreted signaling proteins that play an essential role in propagating and regulating immune responses during experimental autoimmune encephalomyelitis (EAE), the mouse model of the neurodegenerative, autoimmune disease multiple sclerosis (MS). EAE pathology is driven by a myelin-specific T cell response that is activated in the periphery and mediates the destruction of myelin upon T cell infiltration into the central nervous system (CNS). Cytokines provide cell signals both in the immune and CNS compartment, but interestingly, some have detrimental effects in the immune compartment while having beneficial effects in the CNS compartment. The complex nature of these signals will be reviewed. PMID:23239947

  8. Salivary Gland Secretion.

    ERIC Educational Resources Information Center

    Dorman, H. L.; And Others

    1981-01-01

    Describes materials and procedures for an experiment utilizing a live dog to demonstrate: (1) physiology of the salivary gland; (2) parasympathetic control of the salivary gland; (3) influence of varying salivary flow rates on sodium and potassium ions, osmolarity and pH; and (4) salivary secretion as an active process. (DS)

  9. Biliary lipid secretion.

    PubMed

    Hişmioğullari, Adnan Adil; Bozdayi, A Mithat; Rahman, Khalid

    2007-06-01

    The liver has many biochemical functions, of which one of the most important is bile formation. Bile is both a secretory and an excretory fluid and two of its most important functions are the delivery to the intestinal tract of: (i) bile acids to assist in fat digestion and absorption; and (ii) liver-derived metabolites of potentially toxic materials prior to their elimination from the body in the feces. Bile contains numerous solutes, including bile acids, phospholipids and cholesterol. Biliary lipids mainly consist of cholesterol and phospholipids and their secretion into bile is affected by the secretion of bile acids. Phospholipids and cholesterol are synthesized in the hepatocytes and are thought to be transferred via vesicle- and non-vesicle-mediated mechanisms into the bile canaliculus. Hepatocytes acquire biliary lipid by three pathways, which are biosynthesis, lipoproteins and existing molecules drawn from intracellular membranes, with the newly synthesized biliary lipid accounting for less than 20% of the total lipids. The hepatic determinants of biliary cholesterol elimination are not limited to total cholesterol homeostasis, but also concern biliary disease conditions, since excess biliary cholesterol secretion is involved in cholesterol gallstone formation, as well as being a major risk factor for gallbladder cancer. The purpose of this review was to highlight some of the major mechanisms involved in biliary lipid secretion.

  10. Cytokine Signature in Infective Endocarditis

    PubMed Central

    Araújo, Izabella Rodrigues; Ferrari, Teresa Cristina Abreu; Teixeira-Carvalho, Andréa; Campi-Azevedo, Ana Carolina; Rodrigues, Luan Vieira; Guimarães Júnior, Milton Henriques; Barros, Thais Lins Souza; Gelape, Cláudio Léo; Sousa, Giovane Rodrigo; Nunes, Maria Carmo Pereira

    2015-01-01

    Infective endocarditis (IE) is a severe disease with high mortality rate. Cytokines participate in its pathogenesis and may contribute to early diagnosis improving the outcome. This study aimed to evaluate the cytokine profile in IE. Serum concentrations of interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12 and tumor necrosis factor (TNF)-α were measured by cytometric bead array (CBA) at diagnosis in 81 IE patients, and compared with 34 healthy subjects and 30 patients with non-IE infections, matched to the IE patients by age and gender. Mean age of the IE patients was 47±17 years (range, 15–80 years), and 40 (50%) were male. The IE patients had significantly higher serum concentrations of IL-1β, IL-6, IL-8, IL-10 and TNF-α as compared to the healthy individuals. The median levels of IL-1β, TNF-α and IL-12 were higher in the IE than in the non-IE infections group. TNF-α and IL-12 levels were higher in staphylococcal IE than in the non-staphylococcal IE subgroup. There was a higher proportion of both low IL-10 producers and high producers of IL-1β, TNF-α and IL-12 in the staphylococcal IE than in the non-staphylococcal IE subgroup. This study reinforces a relationship between the expression of proinflammatory cytokines, especially IL-1β, IL-12 and TNF-α, and the pathogenesis of IE. A lower production of IL-10 and impairment in cytokine network may reflect the severity of IE and may be useful for risk stratification. PMID:26225421

  11. Pro- and anti-inflammatory cytokines in human immunodeficiency virus infection and acquired immunodeficiency syndrome.

    PubMed

    Breen, Elizabeth Crabb

    2002-09-01

    In persons with human immunodeficiency virus (HIV) infection and/or acquired immunodeficiency syndrome (AIDS), the immune system becomes dysfunctional in many ways. There is both immunodeficiency due to the loss of CD4-positive T helper cells and hyperactivity as a result of B-cell activation. Likewise, both decreases and increases are seen in the production and/or activity of cytokines. Cytokine changes in HIV infection have been assessed by a variety of techniques, ranging from determination of cytokine gene expression at the mRNA level to secretion of cytokine proteins in vivo and in vitro. Changes in cytokine levels in HIV-infected persons can affect the function of the immune system, and have the potential to directly impact the course of HIV disease by enhancing or suppressing HIV replication. In particular, the balance between the pro-inflammatory cytokines interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha, which up-regulate HIV expression, and IL-10, which can act both as an anti-inflammatory cytokine and a B-cell stimulatory factor, may play an important role in the progression to AIDS. In light of its ability to suppress the production of pro-inflammatory cytokines and, under some conditions, suppress HIV replication, increased IL-10 may be viewed as beneficial in slowing HIV disease progression. However, an association between increased IL-10 and the development of AIDS-associated B-cell lymphoma highlights the bifunctional nature of IL-10 as both an anti-inflammatory and B-cell-stimulatory cytokine that could have beneficial and detrimental effects on the course of HIV infection and AIDS.

  12. Ictal Cardiac Ryhthym Abnormalities

    PubMed Central

    Ali, Rushna

    2016-01-01

    Cardiac rhythm abnormalities in the context of epilepsy are a well-known phenomenon. However, they are under-recognized and often missed. The pathophysiology of these events is unclear. Bradycardia and asystole are preceded by seizure onset suggesting ictal propagation into the cortex impacting cardiac autonomic function, and the insula and amygdala being possible culprits. Sudden unexpected death in epilepsy (SUDEP) refers to the unanticipated death of a patient with epilepsy not related to status epilepticus, trauma, drowning, or suicide. Frequent refractory generalized tonic-clonic seizures, anti-epileptic polytherapy, and prolonged duration of epilepsy are some of the commonly identified risk factors for SUDEP. However, the most consistent risk factor out of these is an increased frequency of generalized tonic–clonic seizures (GTC). Prevention of SUDEP is extremely important in patients with chronic, generalized epilepsy. Since increased frequency of GTCS is the most consistently reported risk factor for SUDEP, effective seizure control is the most important preventive strategy. PMID:27347227

  13. Ictal Cardiac Ryhthym Abnormalities.

    PubMed

    Ali, Rushna

    2016-01-01

    Cardiac rhythm abnormalities in the context of epilepsy are a well-known phenomenon. However, they are under-recognized and often missed. The pathophysiology of these events is unclear. Bradycardia and asystole are preceded by seizure onset suggesting ictal propagation into the cortex impacting cardiac autonomic function, and the insula and amygdala being possible culprits. Sudden unexpected death in epilepsy (SUDEP) refers to the unanticipated death of a patient with epilepsy not related to status epilepticus, trauma, drowning, or suicide. Frequent refractory generalized tonic-clonic seizures, anti-epileptic polytherapy, and prolonged duration of epilepsy are some of the commonly identified risk factors for SUDEP. However, the most consistent risk factor out of these is an increased frequency of generalized tonic-clonic seizures (GTC). Prevention of SUDEP is extremely important in patients with chronic, generalized epilepsy. Since increased frequency of GTCS is the most consistently reported risk factor for SUDEP, effective seizure control is the most important preventive strategy. PMID:27347227

  14. Communication and abnormal behaviour.

    PubMed

    Crown, S

    1979-01-01

    In this paper the similarities between normal and abnormal behaviour are emphasized and selected aspects of communication, normal and aberrant, between persons are explored. Communication in a social system may be verbal or non-verbal: one person's actions cause a response in another person. This response may be cognitive, behavioural or physiological. Communication may be approached through the individual, the social situation or social interaction. Psychoanalysis approaches the individual in terms of the coded communications of psychoneurotic symptoms or psychotic behaviour; the humanist-existential approach is concerned more with emotional expression. Both approaches emphasize the development of individual identity. The interaction between persons and their social background is stressed. Relevant are sociological concepts such as illness behaviour, stigma, labelling, institutionalization and compliance. Two approaches to social interactions are considered: the gamesplaying metaphor, e.g. back pain as a psychosocial manipulation--the 'pain game'; and the 'spiral of reciprocal perspectives' which emphasizes the interactional complexities of social perceptions. Communicatory aspects of psychological treatments are noted: learning a particular metaphor such as 'resolution' of the problem (psychotherapy), learning more 'rewarding' behaviour (learning theory) or learning authenticity or self-actualization (humanist-existential).

  15. Communication and abnormal behaviour.

    PubMed

    Crown, S

    1979-01-01

    In this paper the similarities between normal and abnormal behaviour are emphasized and selected aspects of communication, normal and aberrant, between persons are explored. Communication in a social system may be verbal or non-verbal: one person's actions cause a response in another person. This response may be cognitive, behavioural or physiological. Communication may be approached through the individual, the social situation or social interaction. Psychoanalysis approaches the individual in terms of the coded communications of psychoneurotic symptoms or psychotic behaviour; the humanist-existential approach is concerned more with emotional expression. Both approaches emphasize the development of individual identity. The interaction between persons and their social background is stressed. Relevant are sociological concepts such as illness behaviour, stigma, labelling, institutionalization and compliance. Two approaches to social interactions are considered: the gamesplaying metaphor, e.g. back pain as a psychosocial manipulation--the 'pain game'; and the 'spiral of reciprocal perspectives' which emphasizes the interactional complexities of social perceptions. Communicatory aspects of psychological treatments are noted: learning a particular metaphor such as 'resolution' of the problem (psychotherapy), learning more 'rewarding' behaviour (learning theory) or learning authenticity or self-actualization (humanist-existential). PMID:261653

  16. Abnormal uterine bleeding.

    PubMed

    Whitaker, Lucy; Critchley, Hilary O D

    2016-07-01

    Abnormal uterine bleeding (AUB) is a common and debilitating condition with high direct and indirect costs. AUB frequently co-exists with fibroids, but the relationship between the two remains incompletely understood and in many women the identification of fibroids may be incidental to a menstrual bleeding complaint. A structured approach for establishing the cause using the Fédération International de Gynécologie et d'Obstétrique (FIGO) PALM-COEIN (Polyp, Adenomyosis, Leiomyoma, Malignancy (and hyperplasia), Coagulopathy, Ovulatory disorders, Endometrial, Iatrogenic and Not otherwise classified) classification system will facilitate accurate diagnosis and inform treatment options. Office hysteroscopy and increasing sophisticated imaging will assist provision of robust evidence for the underlying cause. Increased availability of medical options has expanded the choice for women and many will no longer need to recourse to potentially complicated surgery. Treatment must remain individualised and encompass the impact of pressure symptoms, desire for retention of fertility and contraceptive needs, as well as address the management of AUB in order to achieve improved quality of life. PMID:26803558

  17. Abortion for fetal abnormality.

    PubMed

    Maclean, N E

    1979-07-25

    I wish to thank Dr. Pauline Bennett for her reply (NZ Med J, 13 June). She has demonstrated well that in dealing with sensitive difficult issues such as abortion for fetal abnormality, the one thing the doctor is not recommended to do is to speak the truth] I am prompted to write this letter for 2 reasons. Firstly, the excellent letter written by Dr. A. M. Rutherford (NZ Med J, 13 June) on the subject of abortion stated, "The most disturbing feature about the whole controversy is the 'blunting of our conscience'." When the doctors are not encouraged to be honest with patients then indeed our conscience has been blunted. Secondly, I watched Holocaust last night, and cannot refrain from stating that I see frightening parallels between our liberal abortion policy and the activities of the Nazis. As I watched the "mental patients" being herded into the shed for gassing by the polite, tidy, white coated medical staff, and then heard the compassionate, sensitive, letter of the hospital authorities to the relatives of the deceased, the parallel became obvious. The mental patients were weak, defenseless, burdensome, and uneconomic; the unborn are weak, defenseless, burdensome, and uneconomic. The hospital authority's letter was acceptable in many ways, acceptable except that its words bore no relation to the truth. It is said that the "first casualty of war is the truth". Whether that war involves the Jews, or the insane, or the unborn, the statement would seem correct.

  18. Cytokine disturbances in systemic lupus erythematosus.

    PubMed

    Jacob, Noam; Stohl, William

    2011-07-06

    The pathogenesis of systemic lupus erythematosus (SLE) is complex, and the resulting disease manifestations are heterogeneous. Cytokine dysregulation is pervasive, and their protein and gene expression profiles may serve as markers of disease activity and severity. Importantly, biologic agents that target specific cytokines may represent novel therapies for SLE. Four cytokines (IL-6, TNFα, IFNα, and BLyS) are being evaluated as therapeutic targets in SLE. The present review will examine the roles of each of these cytokines in murine and human SLE, and will summarize results from clinical trials of agents that target these cytokines.

  19. Cytokine and Chemokine Profile in Amicrobial Pustulosis of the Folds

    PubMed Central

    Marzano, Angelo V.; Tavecchio, Simona; Berti, Emilio; Gelmetti, Carlo; Cugno, Massimo

    2015-01-01

    Abstract Autoinflammation has recently been suggested in the pathogenesis of neutrophilic dermatoses but systematic studies on their cytokine profile are lacking. Notably, amicrobial pustulosis of the folds (APF), classified among neutrophilic dermatoses, has been studied only in small case series. In our University Hospital, we conducted an observational study on 15 APF patients, analyzing their clinical and laboratory features with a follow-up of 9 months to 20 years. Skin cytokine pattern of 9 of them was compared to that of 6 normal controls. In all patients, primary lesions were pustules symmetrically involving the skin folds and anogenital region with a chronic-relapsing course and responding to corticosteroids. Dapsone, cyclosporine, and tumor necrosis factor blockers were effective in refractory cases. In skin samples, the expressions of interleukin (IL)-1β, pivotal cytokine in autoinflammation, and its receptors I and II were significantly higher in APF (P = 0.005, 0.018, and 0.034, respectively) than in controls. Chemokines responsible for neutrophil recruitment such as IL-8 (P = 0.003), CXCL 1/2/3 (C-X-C motif ligand 1/2/3) (P = 0.010), CXCL 16 (P = 0.045), and RANTES (regulated on activation, normal T cell expressed and secreted) (P = 0.034) were overexpressed. Molecules involved in tissue damage like matrix metalloproteinase-2 (MMP-2) (P = 0.010) and MMP-9 (P = 0.003) were increased. APF is a pustular neutrophilic dermatosis with a typical distribution in all patients. The disorder may coexist with an underlying autoimmune/dysimmune disease but is often associated only with a few autoantibodies without a clear autoimmunity. The overexpression of cytokines/chemokines and molecules amplifying the inflammatory network supports the view that APF has an important autoinflammatory component. PMID:26683967

  20. T cell activation status determines the cytokine pattern induced by zymosan and bacterial DNA both in thymocytes and splenocytes

    PubMed Central

    Zimmermann, C; Weber, A; Mausberg, A K; Kieseier, B C; Hartung, H P; Hofstetter, H H

    2013-01-01

    Proinflammatory cytokines are essential mediators of the immunopathology associated with microbial sepsis. The fungal cell wall component zymosan and bacterial DNA are well-studied experimental tools for investigating these processes, simulating the presence of fungal or bacterial infection. Cells of the immune periphery, but also immune cells in the thymus, are affected essentially by the presence of microbes or their immune stimuli in sepsis. For this reason, we investigated the cytokine pattern present in the spleen (containing mature immune cells) and the thymus (containing immature immune cells) upon exposure to zymosan and Escherichia coli DNA. To study the role of T cell activation status, we investigated ex-vivo cultures with and without αCD3 stimulation for changes in their cytokine secretion pattern as measured by cytokine enzyme-linked immunospot (ELISPOT) and flow cytometry analysis. We found that both substances strongly co-stimulate αCD3-induced interferon (IFN)-γ and interleukin (IL)-6 secretion in the thymus and in the spleen, but stimulate IL-17 production only moderately. Moreover, zymosan increases PLP peptide (PLPp)-specific IFN-γ and IL-6 production in experimental autoimmune encephalomyelitis (EAE) induced in Swiss Jim Lambert (SJL)/J mice, confirming that T cell activation status is crucial for the cytokines secreted by an immune cell population encountering a microbial pathogen or immunostimulating parts of it. PMID:23574321

  1. Optimal Method to Stimulate Cytokine Production and Its Use in Immunotoxicity Assessment

    PubMed Central

    Ai, Wenchao; Li, Haishan; Song, Naining; Li, Lei; Chen, Huiming

    2013-01-01

    Activation of lymphocytes can effectively produce a large amount of cytokines. The types of cytokines produced may depend on stimulating reagents and treatments. To find an optimal method to stimulate cytokine production and evaluate its effect on immunotoxicity assessments, the authors analyzed production of IL-2, IL-4, IL-6, IL-10, IL-13, IFN-γ, TNF-α, GM-CSF, RANTES and TGF-β in undiluted rat whole blood culture (incubation for 0, 2, 4, 6, 8 or 10 h) with different concentrations of PMA/ionomycin, PHA, Con A, LPS and PWM. We also evaluated the effects of cyclosporin A and azathioprine on cytokine production. The results revealed a rapid increase of IL-2, IFN-γ, TNF-α, RANTES and TGF-β secretion within 6 h after stimulation with 25 ng/mL PMA and 1 μg/mL ionomycin. The inhibition of these cytokine profiles reflected the effects of immunosuppressants on the immune system. Therefore, the results of this is study recommend the detection of cytokine profiles in undiluted whole blood stimulated 6 h with 25 ng/mL PMA and 1 μg/mL ionomycin as a powerful immunotoxicity assessment method. PMID:23985769

  2. Modulation of MUC1 and blood group antigen expression in gastric adenocarcinoma cells by cytokines.

    PubMed

    Grohmann, Georg P M; Schirmacher, Peter; Manzke, Oliver; Hanisch, Franz Georg; Dienes, Hans P; Baldus, Stephan E

    2003-08-01

    Immunohistological studies demonstrated that MUC1 expression in gastric cancer is associated with a poor prognosis. As a mediator of cell-cell interactions, MUC1 may also be involved in metastasis. However, these aspects are of relevance since cytokine levels are locally increased as a consequence of peritumorous inflammatory response and coexisting chronic gastritis. Therefore we analyzed the potential influence of several cytokines on the expression of tumor-associated MUC1 and Lewis blood group antigens in gastric carcinoma cells. Gastric cancer cell lines AGS and KATOIII were incubated with the cytokines interleukin-1beta, interferon-gamma, tumor necrosis factor-alpha (TNF-alpha), and hepatocyte growth factor over a period of 72 h. Expressions of mucin antigens and cytokine secretion were measured by immunocytochemistry and/or enzyme-linked immunosorbent assay (ELISA). Analysis by fluorescence-activated cell sorter (FACS) demonstrated that MUC1 and sialyl Lewis A reactivities of AGS cells were increased significantly following TNF-alpha stimulation but not by other cytokines. Expression of mucin-associated antigens by cell line KATOIII was not affected by any of the employed cytokines. These data provide evidence that TNF-alpha can raise the expression of important mucin peptide as well as mucin-associated carbohydrate antigens and thereby potentially influence the progression of gastric carcinomas. PMID:12906871

  3. Human cytokine responses induced by Gram-positive cell walls of normal intestinal microbiota

    PubMed Central

    Chen, T; Isomäki, P; Rimpiläinen, M; Toivanen, P

    1999-01-01

    The normal microbiota plays an important role in the health of the host, but little is known of how the human immune system recognizes and responds to Gram-positive indigenous bacteria. We have investigated cytokine responses of peripheral blood mononuclear cells (PBMC) to Gram-positive cell walls (CW) derived from four common intestinal indigenous bacteria, Eubacterium aerofaciens (Eu.a.), Eubacterium limosum(Eu.l.), Lactobacillus casei(L.c.), and Lactobacillus fermentum (L.f.). Our results indicate that Gram-positive CW of the normal intestinal microbiota can induce cytokine responses of the human PBMC. The profile, level and kinetics of these responses are similar to those induced by lipopolysaccharide (LPS) or CW derived from a pathogen, Streptococcus pyogenes (S.p.). Bacterial CW are capable of inducing production of a proinflammatory cytokine, tumour necrosis factor-alpha (TNF-α), and an anti-inflammatory cytokine, IL-10, but not that of IL-4 or interferon-gamma (IFN-γ). Monocytes are the main cell population in PBMC to produce TNF-α and IL-10. Induction of cytokine secretion is serum-dependent; both CD14-dependent and -independent pathways are involved. These findings suggest that the human cytokine responses induced by Gram-positive CW of the normal intestinal microbiota are similar to those induced by LPS or Gram-positive CW of the pathogens. PMID:10540188

  4. Extracellular secretion of recombinant proteins

    SciTech Connect

    Linger, Jeffrey G.; Darzins, Aldis

    2014-07-22

    Nucleic acids encoding secretion signals, expression vectors containing the nucleic acids, and host cells containing the expression vectors are disclosed. Also disclosed are polypeptides that contain the secretion signals and methods of producing polypeptides, including methods of directing the extracellular secretion of the polypeptides. Exemplary embodiments include cellulase proteins fused to secretion signals, methods to produce and isolate these polypeptides, and methods to degrade lignocellulosic biomass.

  5. Haem degradation in abnormal haemoglobins.

    PubMed Central

    Brown, S B; Docherty, J C

    1978-01-01

    The coupled oxidation of certain abnormal haemoglobins leads to different bile-pigment isomer distributions from that of normal haemoglobin. The isomer pattern may be correlated with the structure of the abnormal haemoglobin in the neighbourhood of the haem pocket. This is support for haem degradation by an intramolecular reaction. PMID:708385

  6. Systemic abnormalities in liver disease

    PubMed Central

    Minemura, Masami; Tajiri, Kazuto; Shimizu, Yukihiro

    2009-01-01

    Systemic abnormalities often occur in patients with liver disease. In particular, cardiopulmonary or renal diseases accompanied by advanced liver disease can be serious and may determine the quality of life and prognosis of patients. Therefore, both hepatologists and non-hepatologists should pay attention to such abnormalities in the management of patients with liver diseases. PMID:19554648

  7. Abnormal pressure in hydrocarbon environments

    USGS Publications Warehouse

    Law, B.E.; Spencer, C.W.

    1998-01-01

    Abnormal pressures, pressures above or below hydrostatic pressures, occur on all continents in a wide range of geological conditions. According to a survey of published literature on abnormal pressures, compaction disequilibrium and hydrocarbon generation are the two most commonly cited causes of abnormally high pressure in petroleum provinces. In young (Tertiary) deltaic sequences, compaction disequilibrium is the dominant cause of abnormal pressure. In older (pre-Tertiary) lithified rocks, hydrocarbon generation, aquathermal expansion, and tectonics are most often cited as the causes of abnormal pressure. The association of abnormal pressures with hydrocarbon accumulations is statistically significant. Within abnormally pressured reservoirs, empirical evidence indicates that the bulk of economically recoverable oil and gas occurs in reservoirs with pressure gradients less than 0.75 psi/ft (17.4 kPa/m) and there is very little production potential from reservoirs that exceed 0.85 psi/ft (19.6 kPa/m). Abnormally pressured rocks are also commonly associated with unconventional gas accumulations where the pressuring phase is gas of either a thermal or microbial origin. In underpressured, thermally mature rocks, the affected reservoirs have most often experienced a significant cooling history and probably evolved from an originally overpressured system.

  8. Electrocardiograph abnormalities revealed during laparoscopy.

    PubMed

    Nijjer, Sukhjinder; Dubrey, Simon William

    2010-01-01

    This brief case presents a well patient in whom an electrocardiograph abnormality consistent with an accessory pathway was found during a routine procedure. We present the electrocardiographs, explain the underlying condition, and consider why the abnormality was revealed in this manner.

  9. Cytokine Production in the Serum and Spleen of Mice from Day 6 to 14 of Gestation: Cytokines/Placenta/ Spleen/Serum

    PubMed Central

    Iconomidou, Bessy

    1995-01-01

    Pregnancy, like most biologic phenomena, involves the action of cytokines. These proteins have a short half-life and are believed to exert their effect close to their site of production, where diagnostic tests cannot be easily performed. Here we show that the cytokine content in the maternal serum reflects cytokine production and secretion from maternal spleen cells, which also correlates with production from decidual cells. We show that GM-CSF, IL- 3, and IL-10 are present in the serum at specific time intervals during the first half of murine pregnancy, which correlates with their production from maternal spleen cells. Purified GM-CSF and IL-3 from spleen-cell-culture supernatants are biologically active molecules, able to stimulate placental-cell proliferation. Furthermore, TNF-0, which has been identified in many cases of fetal rejection as well as in labor, is shown to be naturally produced during the second half of pregnancy. Additionally, within the limits of the sensitivity of the technique we have used, the detection of IL-4 and the absence of detectable levels of IL- 2 in the maternal serum strongly comforts the hypothesis that pregnancy is a Th2-dependent phenomenon. The results presented in this paper show that the cytokine profile during pregnancy can be monitored by simple blood tests, which may be of relevance both in the followup of a physiological human pregnancy and to the diagnosis of recurrent abortions due to cytokine imbalance. PMID:8924760

  10. Perilla frutescens extract ameliorates DSS-induced colitis by suppressing proinflammatory cytokines and inducing anti-inflammatory cytokines.

    PubMed

    Urushima, Hayato; Nishimura, Junichi; Mizushima, Tsunekazu; Hayashi, Noriyuki; Maeda, Kazuhisa; Ito, Toshinori

    2015-01-01

    Anti-inflammatory effects have been reported in Perilla frutescens leaf extract (PE), which is a plant of the genus belonging to the Lamiaceae family. We examined the effect of PE on dextran sulfate sodium (DSS)-induced colitis. Preliminarily, PE was safely administered for 7 wk without any adverse effects. In the preventive protocol, mice were fed 1.5% DSS solution dissolved in distilled water (control group) or 0.54% PE solution (PE group) ad libitum for 7 days. In the therapeutic protocol, distilled water or 0.54% PE solution was given for 10 days just after administration of 1.5% DSS for 5 days. PE intake significantly improved body weight loss. The serum cytokine profile demonstrated that TNF-α, IL-17A, and IL-10 were significantly lower in the PE group than in the control group. In the therapeutic protocol, mice in the PE group showed significantly higher body weight and lower histological colitis scores compared with mice in the control group on day 15. The serum cytokine profile demonstrated that TGF-β was significantly higher in the PE group than in the control group. In distal colon mRNA expression, TNF-α, and IL-17A were significantly downregulated. In vitro analyses of biologically active ingredients, such as luteolin, apigenin, and rosmarinic acid, in PE were performed. Luteolin suppressed production of proinflammatory cytokines, such as TNF-α, IL-1β, IL-6, and IL-17A. Apigenin also suppressed secretion of IL-17A and increased the anti-inflammatory cytokine IL-10. Rosmarinic acid increased the regulatory T cell population. We conclude that PE might be useful in treatment and prevention of DSS-induced colitis.

  11. Sequential cytokine dynamics in chronic rejection of rat renal allografts: roles for cytokines RANTES and MCP-1.

    PubMed Central

    Nadeau, K C; Azuma, H; Tilney, N L

    1995-01-01

    Chronic rejection, the most important cause of long-term graft failure, is thought to result from both alloantigen-dependent and -independent factors. To examine these influences, cytokine dynamics were assessed by semiquantitative competitive reverse transcriptase-PCR and by immunohistology in an established rat model of chronic rejection lf renal allografts. Isograft controls develop morphologic and immunohistologic changes that are similar to renal allograft changes, although quantitatively less intense and at a delayed speed; these are thought to occur secondary to antigen-independent events. Sequential cytokine expression was determined throughout the process. During an early reversible allograft rejection episode, both T-cell associated [interleukin (IL) 2, IL-2 receptor, IL-4, and interferon gamma] and macrophage (IL-1 alpha, tumor necrosis factor alpha, and IL-6) products were up-regulated despite transient immunosuppression. RANTES (regulated upon activation, normal T-cell expressed and secreted) peaked at 2 weeks; intercellular adhesion molecule (ICAM-1) was maximally expressed at 6 weeks. Macrophage products such as monocyte chemoattractant protein (MCP-1) increased dramatically (to 10 times), presaging intense peak macrophage infiltration at 16 weeks. In contrast, in isografts, ICAM-1 peaked at 24 weeks. MCP-1 was maximally expressed at 52 weeks, commensurate with a progressive increase in infiltrating macrophages. Cytokine expression in the spleen of allograft and isograft recipients was insignificant. We conclude that chronic rejection of kidney allografts in rats is predominantly a local macrophage-dependent event with intense up-regulation of macrophage products such as MCP-1, IL-6, and inducible nitric oxide synthase. The cytokine expression in isografts emphasizes the contribution of antigen-independent events. The dynamics of RANTES expression between early and late phases of chronic rejection suggest a key role in mediating the events of the

  12. TAM receptor-dependent regulation of SOCS3 and MAPKs contributes to pro-inflammatory cytokine downregulation following chronic NOD2 stimulation of human macrophages1

    PubMed Central

    Zheng, Shasha; Hedl, Matija; Abraham, Clara

    2014-01-01

    Microbial-induced cytokine regulation is critical to intestinal immune homeostasis. Acute stimulation of NOD2, the Crohn’s disease-associated sensor of bacterial peptidoglycan, induces cytokines. However, cytokines are attenuated after chronic NOD2 and pattern recognition receptor (PRR) stimulation of macrophages; similar attenuation is observed in intestinal macrophages. The role of Tyro3, Axl and Mer (TAM) receptors in regulating chronic PRR stimulation and NOD2-induced outcomes has not been examined. Moreover, TAM receptors have been relatively less investigated in human macrophages. Whereas TAM receptors did not downregulate acute NOD2-induced cytokines in primary human macrophages, they were essential for downregulating signaling and pro-inflammatory cytokine secretion after chronic NOD2 and TLR4 stimulation. Axl and Mer were similarly required in mice for cytokine downregulation after chronic NOD2 stimulation in vivo and in intestinal tissues. Consistently, TAM expression was increased in human intestinal myeloid-derived cells. Chronic NOD2 stimulation led to IL-10- and TGFβ-dependent TAM upregulation in human macrophages, which in turn, upregulated SOCS3 expression. Restoring SOCS3 expression under TAM knockdown conditions restored chronic NOD2-mediated pro-inflammatory cytokine downregulation. In contrast to the upregulated pro-inflammatory cytokines, attenuated IL-10 secretion was maintained in TAM-deficient macrophages upon chronic NOD2 stimulation. The level of MAPK activation in TAM-deficient macrophages after chronic NOD2 stimulation was insufficient to upregulate IL-10 secretion; however, full restoration of MAPK activation under these conditions restored c-Fos, c-Jun, MAFK and PU.1 binding to the IL-10 promoter and IL-10 secretion. Therefore, TAM receptors are critical for downregulating pro-inflammatory cytokines under the chronic NOD2 stimulation conditions observed in the intestinal environment. PMID:25567680

  13. Telling stories: keeping secrets.

    PubMed

    Jensen, Joan M

    2009-01-01

    This article addresses the reticence of some farm women to share their experiences with historians and how that desire to keep secrets collides with the desire by scholars to tell the stories of these women. It argues that scholars must continue to struggle with the issue of which stories to tell publicly and which to keep private. The author discusses her own experience telling stories about rural women in the 1970s and the need to give voice to the heritage of rural women, especially of groups that have feared revealing their experiences. She offers examples of historians of rural women who have successfully worked with formerly silenced populations and urges historians to continue to tell stories about these lives, to reevaluate what has been already learned, to ask new questions, and to discuss which secrets need to be shared.

  14. Cell secretion: an update.

    PubMed

    Jeremic, A

    2008-08-01

    This past decade has witnessed the publication of a flurry of scientific papers and reports on the subject of cell secretion, following discovery of a permanent plasma membrane structure termed 'porosome' and its determination as the universal secretory machinery in cells. This discovery has led to a paradigm shift in our understanding of the secretory process, demonstrating that membrane-bound secretory vesicles transiently dock and fuse at the porosome base to release their contents to the cell exterior. The regulated release of intravesicular contents during cell secretion is governed by dilation of the porosome opening to the outside, and the extent of vesicle swelling. In agreement, a great number of articles have been written and studies performed, which are briefly discussed in this article.

  15. Cell secretion: an update

    PubMed Central

    Jeremic, A

    2008-01-01

    This past decade has witnessed the publication of a flurry of scientific papers and reports on the subject of cell secretion, following discovery of a permanent plasma membrane structure termed ‘porosome’ and its determination as the universal secretory machinery in cells. This discovery has led to a paradigm shift in our understanding of the secretory process, demonstrating that membrane-bound secretory vesicles transiently dock and fuse at the porosome base to release their contents to the cell exterior. The regulated release of intravesicular contents during cell secretion is governed by dilation of the porosome opening to the outside, and the extent of vesicle swelling. In agreement, a great number of articles have been written and studies performed, which are briefly discussed in this article. PMID:18363838

  16. Bile Formation and Secretion

    PubMed Central

    Boyer, James L.

    2014-01-01

    Bile is a unique and vital aqueous secretion of the liver that is formed by the hepatocyte and modified down stream by absorptive and secretory properties of the bile duct epithelium. Approximately 5% of bile consists of organic and inorganic solutes of considerable complexity. The bile-secretory unit consists of a canalicular network which is formed by the apical membrane of adjacent hepatocytes and sealed by tight junctions. The bile canaliculi (~1 μm in diameter) conduct the flow of bile countercurrent to the direction of portal blood flow and connect with the canal of Hering and bile ducts which progressively increase in diameter and complexity prior to the entry of bile into the gallbladder, common bile duct, and intestine. Canalicular bile secretion is determined by both bile salt-dependent and independent transport systems which are localized at the apical membrane of the hepatocyte and largely consist of a series of adenosine triphosphate-binding cassette transport proteins that function as export pumps for bile salts and other organic solutes. These transporters create osmotic gradients within the bile canalicular lumen that provide the driving force for movement of fluid into the lumen via aquaporins. Species vary with respect to the relative amounts of bile salt-dependent and independent canalicular flow and cholangiocyte secretion which is highly regulated by hormones, second messengers, and signal transduction pathways. Most determinants of bile secretion are now characterized at the molecular level in animal models and in man. Genetic mutations serve to illuminate many of their functions. PMID:23897680

  17. Catechin secretion and phytotoxicity

    PubMed Central

    Kaushik, Shail

    2010-01-01

    Research indicates that the invasiveness of Centaurea stoebe is attributed to the stronger allelopathic effects on the native North American species than on the related European species, which is one of the unquestionable aspects of the “novel weapons hypothesis (NWH).” Studies originating from controlled to field conditions have shown that C. stoebe utilizes its biochemical potential to exert its invasiveness. The roots of C. stoebe secrete a potent phytotoxin, catechin, which has a detrimental effect on the surrounding plant species. Although, studies on catechin secretion and phytotoxicity represent one of the most well studied systems describing negative plant-plant interactions, it has also sparked controversies lately due to its phytotoxicity dosages and secretion effluxes. Previous reports negate the phytotoxic and pro-oxidant nature of catechin.1–3 In our recent study we have shown that catechin is highly phytotoxic against Arabidopsis thaliana and Festuca idahoensis. We also show that (±) catechin applied to roots of A. thaliana induces reactive oxygen species (ROS) confirming the pro-oxidant nature of catechin. In addition, activation of signature cell death genes such as acd2 and cad1 post catechin treatment in A. thaliana ascertains the phytotoxic nature of catechin. PMID:21057643

  18. Granzymes regulate proinflammatory cytokine responses.

    PubMed

    Wensink, Annette C; Hack, C Erik; Bovenschen, Niels

    2015-01-15

    Granzymes (Grs) are serine proteases mainly produced by cytotoxic lymphocytes and are traditionally considered to cause apoptosis in tumor cells and virally infected cells. However, the cytotoxicity of several Grs is currently being debated, and additional, predominantly extracellular, functions of Grs in inflammation are emerging. Extracellular soluble Grs are elevated in the circulation of patients with autoimmune diseases and infections. Additionally, Grs are expressed by several types of immune cells other than cytotoxic lymphocytes. Recent research has revealed novel immunomodulatory functions of Grs. In this review, we provide a comprehensive overview on the role of Grs in inflammation, highlighting their role in cytokine induction and processing.

  19. Cytokine profiles in axial spondyloarthritis

    PubMed Central

    Madej, Marta; Nowak, Beata; Sokolik, Renata; Chlebicki, Arkadiusz; Korman, Lucyna; Woytala, Patryk; Lubiński, Łukasz; Wiland, Piotr

    2015-01-01

    Objectives Current studies concentrate on the cytokine network and its role in the pathogenesis of spondyloarthritis (SpA). In this study, we analyzed whether the serum cytokine profile (interleukins: IL-10, IL-11, IL-12, IL-15, IL-17, IL-23 and IL-33) correlates with demographic data, clinical manifestations, disease activity and treatment outcome in a group of patients with axial spondyloarthritis. Material and methods Forty-nine patients with an established diagnosis of axial spondyloarthritis (aSpA) and 19 healthy volunteers as controls were enrolled in the study. Clinical evaluation included patient's medical history, 44 joint count, back pain intensity and global disease activity in the preceding week (VAS), the duration of morning stiffness and blood tests. Disease activity was assessed using BASDAI and ASDAS-CRP. Serum concentration of IL-10, IL-11, IL-12, IL-15, IL-17, IL-23 and IL-33 was determined. Results In patients with aSpA, elevated serum concentration of IL-10, IL-15, IL-17 and IL-23 was detected. In the aSpA group we detected higher values of serum concentration of IL-23 and IL-33 in the subgroup with anterior uveitis (83.1 ±184.0 pg/ml vs. 14.0 ±17.1 pg/ml, p < 0.0001 and 45.5 ±71.9 pg/ml vs. 18.4 ±14.3 pg/ml, p < 0.0001, respectively). Additionally, in the subgroup with peripheral arthritis, elevation of serum concentration of IL-12 (249.3 ±246.9 pg/ml vs. 99.9 ±105.9 pg/ml, p = 0.0001) was detected. Patients with preradiological SpA had higher serum concentration of IL-17 than patients with established diagnosis of AS (6.37 ±8.50 pg/ml vs. 2.04 ±2.98 pg/ml, p = 0.0295). No differences in serum concentration of analyzed cytokines were found between the subgroup with low to moderate disease activity and the subgroup with high to very high disease activity. Conclusions We report that in aSpA patients, compared to controls, elevated serum concentrations of IL-10, IL-15, IL-17 and IL-23 were observed. Some cytokines may predispose to a more

  20. Investigating IL-1β Secretion Using Real-Time Single-Cell Imaging.

    PubMed

    Diamond, Catherine; Bagnall, James; Spiller, David G; White, Michael R; Mortellaro, Alessandra; Paszek, Pawel; Brough, David

    2016-01-01

    The pro-inflammatory cytokine interleukin (IL)-1β is an important mediator of the inflammatory response. In order to perform its role in the inflammatory cascade, IL-1β must be secreted from the cell, yet it lacks a signal peptide that is required for conventional secretion, and the exact mechanism of release remains undefined. Conventional biochemical methods have limited the investigation into the processes involved in IL-1β secretion to population dynamics, yet heterogeneity between cells has been observed at a single-cell level. Here, greater sensitivity is achieved with the use of a newly developed vector that codes for a fluorescently labelled version of IL-1β. Combining this with real-time single-cell confocal microscopy using the methods described here, we have developed an effective protocol for investigating the mechanisms of IL-1β secretion and the testing of the hypothesis that IL-1β secretion requires membrane permeabilisation. PMID:27221482

  1. Short Chain Fatty Acids Induce Pro-Inflammatory Cytokine Production Alone And In Combination With Toll-like Receptor Ligands

    PubMed Central

    Mirmonsef, Paria; Zariffard, M Reza; Gilbert, Douglas; Makinde, Hadijat; Landay, Alan L.; Spear, Greg T.

    2011-01-01

    Problem Short chain fatty acids (SCFAs), produced at relatively high levels by anaerobic bacteria in bacterial vaginosis (BV), are believed to be anti-inflammatory. BV, a common alteration of the genital microbiota associated with increased susceptibility to HIV infection, is characterized by increased levels of both pro-inflammatory cytokines and SCFAs. We investigated how SCFAs alone or together with TLR-ligands affected pro-inflammatory cytokine secretion. Method of study Cytokines were measured by ELISA. Flow was used for phenotyping and reactive oxygen species (ROS) measurement. Results SCFAs, at 20mM, induced IL-8, IL-6, and IL-1β release while lower levels (0.02–2mM) did not induce cytokine secretion. Levels >20mM were toxic to cells. Interestingly, lower levels of SCFAs significantly enhanced TLR2 ligand- and TLR7 ligand-induced production of IL-8 and TNFα in a time- and dose-dependent manner, but had little effect on LPS-induced cytokine release. SCFAs mediated their effects on pro-inflammatory cytokine production at least in part by inducing generation of reactive oxygen species. Conclusions Our data suggest that SCFAs, especially when combined with specific TLR ligands, contribute to a pro-inflammatory milieu in the lower genital tract and help further our understanding of how BV affects susceptibility to microbial infections. PMID:22059850

  2. Suppressors of Cytokine Signaling in Sickness and in Health of Pancreatic β-Cells

    PubMed Central

    Ye, Cheng; Driver, John P.

    2016-01-01

    Suppressors of cytokine signaling (SOCS) are a family of eight proteins that negatively regulate Janus kinase and signal transducers and activators of transcription signaling in cells that utilize this pathway to respond to extracellular stimuli. SOCS are best known for attenuating cytokine signaling in the immune system. However, they are also expressed in many other cell types, including pancreatic β-cells, where there is considerable interest in harnessing SOCS molecules to prevent cytokine-mediated apoptosis during diabetes and allogeneic transplantation. Apart from their potential as therapeutic targets, SOCS molecules play a central role for regulating important functions in β-cells, including growth, glucose sensing, and insulin secretion. This review will discuss SOCS proteins as central regulators for diverse cellular processes important for normal β-cell function as well as their protective anti-apoptotic effects during β-cell stress. PMID:27242781

  3. Progesterone and threatened abortion: a randomized clinical trial on endocervical cytokine concentrations.

    PubMed

    Alimohamadi, Shohreh; Javadian, Pouya; Gharedaghi, Mohammad Hadi; Javadian, Nima; Alinia, Hossein; Khazardoust, Soghra; Borna, Sedigheh; Hantoushzadeh, Sedigheh

    2013-06-01

    The purpose of this study was to investigate the effect of vaginal progesterone on endocervical cytokine concentration in women at risk of threatened abortion. One hundred and sixty pregnant women with clinical symptoms of threatened abortion before the 20th week of pregnancy were randomly assigned to receive vaginal progesterone or placebo. Cervical fluids were collected and endocervical concentrations of different cytokines (IFNγ, TNFα, IL-8, IL-10 and IL-12) were analyzed before and one week after progesterone or placebo treatment. A significant decrease in IFNγ and increase in IL-10 in endocervical fluid was seen when the values were compared before and after progesterone treatment. However, there were no significant differences in pregnancy outcomes between the placebo and progesterone groups. We conclude that despite the failure of vaginal progesterone treatment to improve pregnancy outcomes, progesterone can induce a shift in the concentration of cytokines in endocervical secretions. PMID:23489467

  4. Fibrillin abnormalities and prognosis in Marfan syndrome and related disorders

    SciTech Connect

    Aoyama, T.; Furthmayr, H.; Francke, U.; Gasner, C.

    1995-08-28

    Marfan syndrome (MFS), a multisystem autosomal-dominant disorder, is characterized by mutations of the fibrillin-1 (FBN1) gene and by abnormal patterns of synthesis, secretion, and matrix deposition of the fibrillin protein. To determine the sensitivity and specificity of fibrillin protein abnormalities in the diagnosis of MFS, we studied dermal fibroblasts from 57 patients with classical MFS, 15 with equivocal MFS, 8 with single-organ manifestations, and 16 with other connective tissue disorders including homocystinuria and Ehlers-Danlos syndrome. Abnormal fibrillin metabolism was identified in 70 samples that were classified into four different groups based on quantitation of fibrillin synthesis and matrix deposition. Significant correlations were found for phenotypic features including arachnodactyly, striae distensae, cardiovascular manifestations, and fibrillin groups II and IV, which included 70% of the MFS patients. In addition, these two groups were associated with shortened {open_quotes}event-free{close_quotes} survival and more severe cardiovascular complications than groups I and III. The latter included most of the equivocal MFS/single manifestation patients with fibrillin abnormalities. Our results indicate that fibrillin defects at the protein level per se are not specific for MFS, but that the drastically reduced fibrillin deposition, caused by a dominant-negative effect of abnormal fibrillin molecules in individuals defined as groups II and IV, is of prognostic and possibly diagnostic significance. 25 refs., 3 figs., 6 tabs.

  5. Rapid flow cytometric measurement of cytokine-induced phosphorylation pathways [CIPP] in human peripheral blood leukocytes.

    PubMed

    Montag, David T; Lotze, Michael T

    2006-11-01

    Current strategies designed to assess cells in the peripheral blood are limited to evaluation of phenotype or delayed measurement [>6 h] of function, usually quantifying cytokine production, cytolytic activity, or response to antigens. We reasoned that measurable abnormalities in signaling pathways could reflect pathological environs that cells experience in the setting of inflammatory states/cancer and could be represented in the peripheral blood. Two major pathways regulating the immune response are the JAK/STAT and MAPK/ERK pathways. These pathways are initiated by ligand-receptor binding and are rapidly propagated by subsequent protein phosphorylation cascades. We evaluated the brief application of cytokines in vitro to interrogate the early phosphorylation events of these signaling pathways in normal peripheral blood mononuclear cells (PBMC). Individual cytokine doses and time intervals of treatment were assessed to identify conditions useful in a clinical laboratory and as an initial goal to induce maximal phosphorylation. Surprisingly, all of the STAT proteins assessed and ERK1/2 are maximally phosphorylated within 15 min in human PBMC simply following addition of cytokines without preactivation of the cells. At 2 h, cells typically return to their basal phosphorylation states. For most of the cytokines tested, increased phosphorylation directly correlated with increased concentrations of the individual cytokines. These strategies will enable robust development of simple blood analyses to identify normal levels as well as impairments in STAT and MAPK/ERK signaling pathways associated with various human disease states including acute and chronic inflammatory conditions throughout clinical immunology.

  6. Chromosomal abnormalities in human sperm

    SciTech Connect

    Martin, R.H.

    1985-01-01

    The ability to analyze human sperm chromosome complements after penetration of zona pellucida-free hamster eggs provides the first opportunity to study the frequency and type of chromosomal abnormalities in human gametes. Two large-scale studies have provided information on normal men. We have studied 1,426 sperm complements from 45 normal men and found an abnormality rate of 8.9%. Brandriff et al. (5) found 8.1% abnormal complements in 909 sperm from 4 men. The distribution of numerical and structural abnormalities was markedly dissimilar in the 2 studies. The frequency of aneuploidy was 5% in our sample and only 1.6% in Brandriff's, perhaps reflecting individual variability among donors. The frequency of 24,YY sperm was low: 0/1,426 and 1/909. This suggests that the estimates of nondisjunction based on fluorescent Y body data (1% to 5%) are not accurate. We have also studied men at increased risk of sperm chromosomal abnormalities. The frequency of chromosomally unbalanced sperm in 6 men heterozygous for structural abnormalities varied dramatically: 77% for t11;22, 32% for t6;14, 19% for t5;18, 13% for t14;21, and 0% for inv 3 and 7. We have also studied 13 cancer patients before and after radiotherapy and demonstrated a significant dose-dependent increase of sperm chromosome abnormalities (numerical and structural) 36 months after radiation treatment.

  7. Erythropoietin stimulation of human adipose tissue for therapeutic refilling releases protective cytokines

    PubMed Central

    Sabbatini, Maurizio; Bosetti, Michela; Borrone, Alessia; Moalem, Liah; Taveggia, Antonio; Verna, Giovanni; Cannas, Mario

    2016-01-01

    Apoptosis and inflammatory processes may be at the basis of reducing graft survival. Erythropoietin is a tissue-protective hormone with pleiotropic potential, and it interferes with the activities of pro-inflammatory cytokines and stimulates healing following injury, preventing destruction of tissue surrounding the injury site. It may represent a useful tool to increase the autograft integration. Through the use of multipanel kit cytokine analysis we have detected the cytokines secreted by human tissue adipose mass seeded in culture following withdrawal by Coleman’s modified technique in three groups: control, after lipopolysaccharides stimulation and after erythropoietin stimulation. In the control group, we have observed expression of factors that may have a role in protecting the tissue homeostatic mechanism. But the same factors were secreted following stimulation with lipopolysaccharides combined with others factors that delineated the inflammatory state. Instead through erythropoietin stimulation, the factors known to exert tissue-protective action were secreted. Therefore, the use of a trophic factors such as erythropoietin may help to inhibit the potential inflammatory process development and stimulate the activation of reparative/regenerative process in the tissue graft. PMID:27738510

  8. Secretion of biologically active human interleukin 22 (IL-22) by Lactococcus lactis.

    PubMed

    Loera-Arias, María J; Villatoro-Hernández, Julio; Parga-Castillo, Miguel A; Salcido-Montenegro, Alejandro; Barboza-Quintana, Oralia; Muñoz-Maldonado, Gerardo E; Montes-de-Oca-Luna, Roberto; Saucedo-Cárdenas, Odila

    2014-12-01

    Interleukin-22 (IL-22) participates in the modulation of innate immunity and inflammation. This cytokine has important therapeutic potential, such as with ulcerative colitis, liver and lung injury, and infection, in different animal models. We generated a Lactococcus lactis strain that secretes human IL-22 under the regulation of the nisin-inducible promoter. Identification and secretion of this cytokine was demonstrated using western blots of culture supernatants from IL-22-expressing bacteria. The recombinant IL-22 protein produced by L. lactis was biologically active as determined by its ability to induce IL-10 secretion when co-cultured with a colon epithelial cell line in vitro. We consider this novel strain a promising live vaccine for various therapeutic applications.

  9. Secretion of biologically active human interleukin 22 (IL-22) by Lactococcus lactis.

    PubMed

    Loera-Arias, María J; Villatoro-Hernández, Julio; Parga-Castillo, Miguel A; Salcido-Montenegro, Alejandro; Barboza-Quintana, Oralia; Muñoz-Maldonado, Gerardo E; Montes-de-Oca-Luna, Roberto; Saucedo-Cárdenas, Odila

    2014-12-01

    Interleukin-22 (IL-22) participates in the modulation of innate immunity and inflammation. This cytokine has important therapeutic potential, such as with ulcerative colitis, liver and lung injury, and infection, in different animal models. We generated a Lactococcus lactis strain that secretes human IL-22 under the regulation of the nisin-inducible promoter. Identification and secretion of this cytokine was demonstrated using western blots of culture supernatants from IL-22-expressing bacteria. The recombinant IL-22 protein produced by L. lactis was biologically active as determined by its ability to induce IL-10 secretion when co-cultured with a colon epithelial cell line in vitro. We consider this novel strain a promising live vaccine for various therapeutic applications. PMID:25214209

  10. Cytokine production in BALB/c mice immunized with radiation attenuated third stage larvae of the filarial nematode, Brugia pahangi

    SciTech Connect

    Bancroft, A.J.; Devaney, E. ); Grencis, R.K.; Else, K.J. )

    1993-02-15

    BALB/c mice immunized with radiation-attenuated third stage larvae of the filarial nematode Brugia pahangi are strongly immune to challenge infection. Investigation of the profile of cytokines secreted by spleen cells from immune mice stimulated in vitro with either parasite Ag or with Con A revealed high levels of IL-5 and IL-9 and moderate levels of IL-4. In contrast, secretion of IFN-[gamma] by spleen cells from immune animals was negligible. Spleen cells from control mice secreted low levels of all cytokines assayed. Levels of parasite-specific IgE were significantly elevated in immune animals and a peripheral blood eosinophilia was observed, which exhibited a biphasic distribution. Our results are consistent with the preferential expansion of Th2 cells in immune animals and provide the basis for dissecting the means by which radiation-attenuated larvae of filarial nematodes stimulate immunity. 5l refs., 3 figs., 3 tabs.

  11. Revealing cytokine-induced changes in the extracellular matrix with secondary ion mass spectrometry

    PubMed Central

    Taylor, Adam J; Ratner, Buddy D; Buttery, Lee DK; Alexander, Morgan R

    2015-01-01

    Cell-secreted matrices (CSMs), where extracellular matrix (ECM) deposited by monolayer cell cultures are decellularized, have been increasingly used to produce surfaces that may be reseeded with cells. Such surfaces are useful to help us understand cell-ECM interactions in a microenvironment closer to the in vivo situation than synthetic substrates with adsorbed proteins. We describe the production of CSMs from mouse primary osteoblasts (mPObs) exposed to cytokine challenge during matrix secretion, mimicking in vivo inflammatory environments. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) data revealed that CSMs with cytokine challenge at day 7 or day 12 of culture can be chemically distinguished from one another and from untreated CSM using multivariate analysis. Comparison of the differences with reference spectra from adsorbed protein mixtures points towards cytokine challenge resulting in a decrease in collagen content. This is supported by immunocytochemical and histological staining, demonstrating a 44% loss of collagen mass and a 32% loss in collagen I coverage. CSM surfaces demonstrate greater cell adhesion than adsorbed ECM proteins. When mPObs were reseeded onto cytokine-challenged CSMs they exhibited reduced adhesion and elongated morphology compared to untreated CSMs. Such changes may direct subsequent cell fate and function and provide insights into pathological responses at sites of inflammation. PMID:25523877

  12. Aberrant cytokine pattern of the nasal mucosa in granulomatosis with polyangiitis

    PubMed Central

    2012-01-01

    Introduction In granulomatosis with polyangiitis (GPA), a complex autoimmune small-vessel vasculitis frequently associated with chronic necrotizing inflammation of the nasal mucosa, elevated nasal Staphylococcus (S.) aureus carrier rates are a risk factor for relapse. As cytokines are primarily involved in the regulation of defense against potentially pathogenic microorganisms, the aim of this study was to compare healthy individuals and GPA patients with respect to their baseline cytokine expression of nasal epithelial cells (NEC), which form the first barrier against such triggers. The ability of S. aureus to influence the nasal microenvironment's cytokine secretion was assessed by exemplary stimulation experiments. Methods Baseline expression of 19 cytokines of primary NEC of GPA patients and normal controls (NC) was quantified by a multiplex cytokine assay. Stimulation experiments were performed with supernatants of S. aureus and expression of interleukin-8 was determined by ELISA. Results In GPA, an altered pattern of baseline cytokine expression with significantly up-regulated G-CSF and reduced interleukin (IL)-8 concentrations was observed. Both NEC of GPA patients and NC responded to stimulation with S. aureus, but GPA patients displayed a significantly lower IL-8 secretion and a diminished dynamic range of response towards the stimulus. Conclusions The data presented underline the hypothesis of a disturbed epithelial nasal barrier function in GPA. The dysregulated baseline expression of G-CSF and IL-8 and the reduced response to microbial stimulation may facilitate changes in the composition of the nasal flora and favour an imbalanced inflammatory response, which might be relevant for the disease course. PMID:23031229

  13. Analysis of intracellular cytokines using flowcytometry.

    PubMed

    Arora, Sunil K

    2002-01-01

    Characterization of T-cell clones and identification of functional subsets of the helper T-cells with polarized cytokine production is based on testing of cytokine expression. Several methods have been developed that allow cytokine expression to be measured like ELISA, RT-PCR, ELISPOT, ISH and flowcytometry. Among all these methods, monitoring of cytokine production using flowcytometric analysis has its own advantages and disadvantages. Multi-parametric characterization of cytokine production on single cell basis, without long-term culture and cloning along with high throughput of samples is main feature attached to flowcytometric analysis. The interpretation may be difficult at times due to change in the phenotype of the cells. Cells with similar surface phenotype but synthesizing different cytokines and having different functional characteristics can be analyzed with this technique. PMID:12815288

  14. Bioanalytical Chemistry of Cytokines-A Review

    PubMed Central

    Stenken, Julie A.; Poschenrieder, Andreas J.

    2014-01-01

    Cytokines are bioactive proteins produced by many different cells of the immune system. Due to their role in different inflammatory disease states and maintaining homeostasis, there is enormous clinical interest in the quantitation of cytokines. The typical standard methods for quantitation of cytokines are immunoassay-based techniques including enzyme-linked immusorbent assays (ELISA) and bead-based immunoassays read by either standard or modified flow cytometers. A review of recent developments in analytical methods for measurements of cytokine proteins is provided. This review briefly covers cytokine biology and the analysis challenges associated with measurement of these biomarker proteins for understanding both health and disease. New techniques applied to immunoassay-based assays are presented along with the uses of aptamers, electrochemistry, mass spectrometry, optical resonator-based methods. Methods used for elucidating the release of cytokines from single cells as well as in vivo collection methods are described. PMID:25467452

  15. Meibomian gland dysfunction and tear film abnormalities in rosacea.

    PubMed

    Zengin, N; Tol, H; Gündüz, K; Okudan, S; Balevi, S; Endoğru, H

    1995-03-01

    In order to determine the relationship between meibomian gland dysfunction and tear film abnormalities in rosacea, tear film flow and stability and meibomian gland function were assessed in 43 consecutive patients. Schirmer, tear film break-up time, and meibomian gland function values in patients with ocular rosacea (n = 28) were found to be significantly decreased as compared with those of the patients with only cutaneous involvement and control patients (p > 0.05). In patients with dermatologic rosacea (n = 15) these values were not different from those of the age- and sex-matched controls (p > 0.05). The effects of tetracycline and meibomian gland expression therapy also were investigated in patients with ocular rosacea. Neither meibomian gland expression therapy nor tetracycline administration had beneficial effects on decreased tear secretion, but tetracycline improved the break-up time values. Our findings showed a positive relationship between tear film abnormalities and meibomian gland dysfunction in patients with rosacea. Decreased tear secretion in patients with ocular rosacea would seem to be a result of structural changes secondary to meibomian gland dysfunction, and short break-up time might be due to an abnormal meibum composition.

  16. Cytokine-Modulating Strategies and Newer Cytokine Targets for Arthritis Therapy

    PubMed Central

    Venkatesha, Shivaprasad H.; Dudics, Steven; Acharya, Bodhraj; Moudgil, Kamal D.

    2014-01-01

    Cytokines are the key mediators of inflammation in the course of autoimmune arthritis and other immune-mediated diseases. Uncontrolled production of the pro-inflammatory cytokines such as interferon-γ (IFN-γ), tumor necrosis factor α (TNFα), interleukin-6 (IL-6), and IL-17 can promote autoimmune pathology, whereas anti-inflammatory cytokines including IL-4, IL-10, and IL-27 can help control inflammation and tissue damage. The pro-inflammatory cytokines are the prime targets of the strategies to control rheumatoid arthritis (RA). For example, the neutralization of TNFα, either by engineered anti-cytokine antibodies or by soluble cytokine receptors as decoys, has proven successful in the treatment of RA. The activity of pro-inflammatory cytokines can also be downregulated either by using specific siRNA to inhibit the expression of a particular cytokine or by using small molecule inhibitors of cytokine signaling. Furthermore, the use of anti-inflammatory cytokines or cytokine antagonists delivered via gene therapy has proven to be an effective approach to regulate autoimmunity. Unexpectedly, under certain conditions, TNFα, IFN-γ, and few other cytokines can display anti-inflammatory activities. Increasing awareness of this phenomenon might help develop appropriate regimens to harness or avoid this effect. Furthermore, the relatively newer cytokines such as IL-32, IL-34 and IL-35 are being investigated for their potential role in the pathogenesis and treatment of arthritis. PMID:25561237

  17. Altered waveform of plasma nocturnal melatonin secretion in premenstrual depression.

    PubMed

    Parry, B L; Berga, S L; Kripke, D F; Klauber, M R; Laughlin, G A; Yen, S S; Gillin, J C

    1990-12-01

    The nocturnal secretion of plasma melatonin was determined under dim to dark conditions in eight patients with prospectively confirmed premenstrual syndrome and in eight age- and menstrual cycle phase-matched normal control subjects. Plasma samples for melatonin were collected every 30 minutes from 6 PM to 9 AM during the early follicular, late follicular, midluteal and late luteal phases of the menstrual cycle. Compared with normal controls, patients with premenstrual syndrome had an earlier (phase-advanced) offset of melatonin secretion, which contributed to a shorter secretion duration and a decreased area under the curve. No statistically significant differences were found between women with premenstrual syndrome and normal controls for melatonin onset or peak concentration, or for estradiol or progesterone levels. The data demonstrate that women with premenstrual syndrome have chronobiological abnormalities of melatonin secretion. The fact that these patients respond to treatments that affect circadian physiology, such as sleep deprivation and phototherapy, suggests that circadian abnormalities may contribute to the pathogenesis of premenstrual syndrome.

  18. Cytokines and immune surveillance in humans

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, Gerald

    1993-01-01

    Evidence from both human and rodent studies has indicated that alterations in immunological parameters occur after space flight. Among the parameters shown, by us and others, to be affected is the production of interferons. Interferons are a family of cytokines that are antiviral and play a major role in regulating immune responses that control resistance to infection. Alterations in interferon and other cytokine production and activity could result in changes in immunity and a possible compromise of host defenses against both opportunistic and external infections. The purpose of the present study is to further explore the effects of space flight on cytokines and cytokine-directed immunological function.

  19. Bone mineral density and circulating cytokines in patients with acromegaly.

    PubMed

    Longobardi, S; Di Somma, C; Di Rella, F; Angelillo, N; Ferone, D; Colao, A; Merola, B; Lombardi, G

    1998-11-01

    Acromegalic patients present an increase of osteoblastic and osteoclastic activity, showing a different effect on the axial and appendicular skeletal structures. At this regard controversial data about bone mineral density (BMD) have been published in literature. In fact an increase of BMD levels in femoral neck and Ward's triangle without any difference in lumbar spine has been described. On the other hand normal BMD levels at forearm and reduced BMD levels at lumbar spine were found. These patients seem to have a reduction of trabecular BMD similar to postmenopausal osteoporotic patients despite normal or slightly elevated cortical BMD. Recently, it has been described that cytokines, in particular tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1), are implicated in the pathogenetic mechanism of postmenopausal osteoporosis. Taking into account that growth hormone (GH) can increase TNF-alpha and IL-1 secretion by mononuclear blood cells, the evaluation of possible relationship between the reduced BMD at lumbar spine and circulating cytokines levels was carried out in acromegalic patients. In addition we evaluated the effect of acute octreotide administration on serum TNF-alpha and IL-I concentrations. Eleven patients with active acromegaly and eleven healthy age-, sex-, weight- and heightmatched subjects were enrolled in this study. BMD was significantly reduced at lumbar spine (0.80 +/- 0.29 g/cm2 vs 1.02 +/- 0.11 g/cm2; p < 0.01), but not at femoral neck level or at Ward's triangle level (0.92 + 0.15 g/cm2 vs 0.97 + 0.11 g/cm2, p = NS; and 0.74 +/- 0.16 g/cm2 vs 0.85 +/- 0.1 g/cm2, p = NS) when compared to controls. Baseline serum levels of TNF-alpha and IL-1 were in the normal range both in patients and controls. After acute octreotide administration, no differences in circulating TNF-alpha and IL-1 levels were found. In conclusion, acromegalic patients present a reduced BMD at lumbar spine but not at femoral neck level and Ward's triangle

  20. Differential cytokine expression in EBV positive peripheral T cell lymphomas.

    PubMed Central

    Ho, J W; Liang, R H; Srivastava, G

    1999-01-01

    AIM: To investigate whether specific cytokines are secreted locally at the tumour site in Epstein-Barr virus (EBV) positive peripheral T cell lymphoma (PTCL). METHODS: An RNase protection assay system was used to study the differential expression of 21 cytokines in parallel in eight cases of EBV positive non-nasal PTCL, and compared with 11 EBV negative non-nasal PTCLs and three EBV positive nasal natural killer (NK) cell lymphomas. RESULTS: Among the eight EBV positive cases, interferon gamma (IFN-gamma), lymphotoxin beta (LT beta), interleukin 10 (IL-10), tumour necrosis factor alpha (TNF-alpha), transforming growth factor beta 1 (TGF-beta 1), and IL-1 receptor a (IL-Ra) were frequently detectable. IL-15, IL-6, IL-4, IL-1 beta, TNF-beta, and IL-9 were sporadically detectable. Of the frequently detectable cytokines, IFN-gamma and LT beta were commonly detected in the EBV negative cases. For cases with > 50% EBV encoded small non-polyadenylated RNA (EBER) positive cells, IL-10, TNF-alpha, and TGF-beta 1 were detected in three of three cases, and IL-1Ra in two of three cases. For cases with < 20% EBER positive cells, IL-10 was detected in three of five cases, TNF-alpha in two of four cases, but TGF-beta 1 and IL-1Ra were not detected. Interestingly, IL-6 was detected in two of three cases with > 50% EBER positive cells, but only in one of five cases with < 20% EBER positive cells. For comparison, in NK cell lymphomas, IL-10, TNF-alpha, IL-1Ra, and IL-6 were all detectable, but TGF-beta 1 was not detected at all. Immunohistochemical staining revealed IL-10 in many cells; in contrast, EBV latent membrane protein 1 (LMP1) was only found to be positive in isolated cells. CONCLUSIONS: Certain cytokines, such as IL-10 and TNF-alpha, might be expressed preferentially in EBV positive peripheral T cell lymphomas. It is likely that such a cytokine environment enhances EBV infection and contributes towards tumorigenesis. PMID:10748876

  1. Modeling the intra- and extracellular cytokine signaling pathway under heat stroke in the liver.

    PubMed

    Rodriguez-Fernandez, Maria; Grosman, Benyamin; Yuraszeck, Theresa M; Helwig, Bryan G; Leon, Lisa R; Doyle, Francis J

    2013-01-01

    Heat stroke (HS) is a life-threatening illness induced by prolonged exposure to a hot environment that causes central nervous system abnormalities and severe hyperthermia. Current data suggest that the pathophysiological responses to heat stroke may not only be due to the immediate effects of heat exposure per se but also the result of a systemic inflammatory response syndrome (SIRS). The observation that pro- (e.g., IL-1) and anti-inflammatory (e.g., IL-10) cytokines are elevated concomitantly during recovery suggests a complex network of interactions involved in the manifestation of heat-induced SIRS. In this study, we measured a set of circulating cytokine/soluble cytokine receptor proteins and liver cytokine and receptor mRNA accumulation in wild-type and tumor necrosis factor (TNF) receptor knockout mice to assess the effect of neutralization of TNF signaling on the SIRS following HS. Using a systems approach, we developed a computational model describing dynamic changes (intra- and extracellular events) in the cytokine signaling pathways in response to HS that was fitted to novel genomic (liver mRNA accumulation) and proteomic (circulating cytokines and receptors) data using global optimization. The model allows integration of relevant biological knowledge and formulation of new hypotheses regarding the molecular mechanisms behind the complex etiology of HS that may serve as future therapeutic targets. Moreover, using our unique modeling framework, we explored cytokine signaling pathways with three in silico experiments (e.g. by simulating different heat insult scenarios and responses in cytokine knockout strains in silico). PMID:24039931

  2. Modeling the Intra- and Extracellular Cytokine Signaling Pathway under Heat Stroke in the Liver

    PubMed Central

    Rodriguez-Fernandez, Maria; Grosman, Benyamin; Yuraszeck, Theresa M.; Helwig, Bryan G.; Leon, Lisa R.; Doyle III, Francis J.

    2013-01-01

    Heat stroke (HS) is a life-threatening illness induced by prolonged exposure to a hot environment that causes central nervous system abnormalities and severe hyperthermia. Current data suggest that the pathophysiological responses to heat stroke may not only be due to the immediate effects of heat exposure per se but also the result of a systemic inflammatory response syndrome (SIRS). The observation that pro- (e.g., IL-1) and anti-inflammatory (e.g., IL-10) cytokines are elevated concomitantly during recovery suggests a complex network of interactions involved in the manifestation of heat-induced SIRS. In this study, we measured a set of circulating cytokine/soluble cytokine receptor proteins and liver cytokine and receptor mRNA accumulation in wild-type and tumor necrosis factor (TNF) receptor knockout mice to assess the effect of neutralization of TNF signaling on the SIRS following HS. Using a systems approach, we developed a computational model describing dynamic changes (intra- and extracellular events) in the cytokine signaling pathways in response to HS that was fitted to novel genomic (liver mRNA accumulation) and proteomic (circulating cytokines and receptors) data using global optimization. The model allows integration of relevant biological knowledge and formulation of new hypotheses regarding the molecular mechanisms behind the complex etiology of HS that may serve as future therapeutic targets. Moreover, using our unique modeling framework, we explored cytokine signaling pathways with three in silico experiments (e.g. by simulating different heat insult scenarios and responses in cytokine knockout strains in silico). PMID:24039931

  3. A High-Dimensional Atlas of Human T Cell Diversity Reveals Tissue-Specific Trafficking and Cytokine Signatures.

    PubMed

    Wong, Michael Thomas; Ong, David Eng Hui; Lim, Frances Sheau Huei; Teng, Karen Wei Weng; McGovern, Naomi; Narayanan, Sriram; Ho, Wen Qi; Cerny, Daniela; Tan, Henry Kun Kiaang; Anicete, Rosslyn; Tan, Bien Keem; Lim, Tony Kiat Hon; Chan, Chung Yip; Cheow, Peng Chung; Lee, Ser Yee; Takano, Angela; Tan, Eng-Huat; Tam, John Kit Chung; Tan, Ern Yu; Chan, Jerry Kok Yen; Fink, Katja; Bertoletti, Antonio; Ginhoux, Florent; Curotto de Lafaille, Maria Alicia; Newell, Evan William

    2016-08-16

    Depending on the tissue microenvironment, T cells can differentiate into highly diverse subsets expressing unique trafficking receptors and cytokines. Studies of human lymphocytes have primarily focused on a limited number of parameters in blood, representing an incomplete view of the human immune system. Here, we have utilized mass cytometry to simultaneously analyze T cell trafficking and functional markers across eight different human tissues, including blood, lymphoid, and non-lymphoid tissues. These data have revealed that combinatorial expression of trafficking receptors and cytokines better defines tissue specificity. Notably, we identified numerous T helper cell subsets with overlapping cytokine expression, but only specific cytokine combinations are secreted regardless of tissue type. This indicates that T cell lineages defined in mouse models cannot be clearly distinguished in humans. Overall, our data uncover a plethora of tissue immune signatures and provide a systemic map of how T cell phenotypes are altered throughout the human body. PMID:27521270

  4. A High-Dimensional Atlas of Human T Cell Diversity Reveals Tissue-Specific Trafficking and Cytokine Signatures.

    PubMed

    Wong, Michael Thomas; Ong, David Eng Hui; Lim, Frances Sheau Huei; Teng, Karen Wei Weng; McGovern, Naomi; Narayanan, Sriram; Ho, Wen Qi; Cerny, Daniela; Tan, Henry Kun Kiaang; Anicete, Rosslyn; Tan, Bien Keem; Lim, Tony Kiat Hon; Chan, Chung Yip; Cheow, Peng Chung; Lee, Ser Yee; Takano, Angela; Tan, Eng-Huat; Tam, John Kit Chung; Tan, Ern Yu; Chan, Jerry Kok Yen; Fink, Katja; Bertoletti, Antonio; Ginhoux, Florent; Curotto de Lafaille, Maria Alicia; Newell, Evan William

    2016-08-16

    Depending on the tissue microenvironment, T cells can differentiate into highly diverse subsets expressing unique trafficking receptors and cytokines. Studies of human lymphocytes have primarily focused on a limited number of parameters in blood, representing an incomplete view of the human immune system. Here, we have utilized mass cytometry to simultaneously analyze T cell trafficking and functional markers across eight different human tissues, including blood, lymphoid, and non-lymphoid tissues. These data have revealed that combinatorial expression of trafficking receptors and cytokines better defines tissue specificity. Notably, we identified numerous T helper cell subsets with overlapping cytokine expression, but only specific cytokine combinations are secreted regardless of tissue type. This indicates that T cell lineages defined in mouse models cannot be clearly distinguished in humans. Overall, our data uncover a plethora of tissue immune signatures and provide a systemic map of how T cell phenotypes are altered throughout the human body.

  5. Leptin regulates gallbladder genes related to absorption and secretion.

    PubMed

    Swartz-Basile, Deborah A; Lu, Debao; Basile, David P; Graewin, Shannon J; Al-Azzawi, Hayder; Kiely, James M; Mathur, Abhishek; Yancey, Kyle; Pitt, Henry A

    2007-07-01

    Dysregulation of gallbladder ion and water absorption and/or secretion has been linked to cholesterol crystal and gallstone formation. We have recently demonstrated that obese, leptin-deficient (Lep(ob)) mice have enlarged gallbladder volumes and decreased gallbladder contractility and that leptin administration to these mice normalizes gallbladder function. However, the effect of leptin on gallbladder absorption/secretion is not known. Therefore, we sought to determine whether leptin would alter the expression of genes involved in water and ion transport across the gallbladder epithelium. Affymetrix oligonucleotide microarrays representing 39,000 transcripts were used to compare gallbladder gene-expression profiles from 12-wk-old control saline-treated Lep(ob) and from leptin-treated Lep(ob) female mice. Leptin administration to Lep(ob) mice decreased gallbladder volume, bile sodium concentration, and pH. Leptin repletion upregulated the expression of aquaporin 1 water channel by 1.3-fold and downregulated aquaporin 4 by 2.3-fold. A number of genes involved in sodium transport were also influenced by leptin replacement. Epithelial sodium channel-alpha and sodium hydrogen exchangers 1 and 3 were moderately downregulated by 2.0-, 1.6-, and 1.3-fold, respectively. Carbonic anhydrase-IV, which plays a role in the acidification of bile, was upregulated 3.7-fold. In addition, a number of inflammatory cytokines that are known to influence gallbladder epithelial cell absorption and secretion were upregulated. Thus leptin, an adipocyte-derived cytokine involved with satiety and energy balance, influences gallbladder bile volume, sodium, and pH as well as multiple inflammatory cytokine genes and genes related to water, sodium, chloride, and bicarbonate transport.

  6. Neuropeptides and nasal secretion.

    PubMed

    Baraniuk, J N; Kaliner, M

    1991-10-01

    The nasal mucosa is innervated by the sensory, parasympathetic, and sympathetic nervous systems. Nociceptive sensory nerves are stimulated by mucosal injury, inhalation of irritants, or mast cell degranulation and release of the calcitonin gene-related peptide, the tachykinins substance P and neurokinin A, and other peptides by the axon response mechanism. Sensory nerve stimulation initiates systemic reflexes, such as the sneeze, and central parasympathetic reflexes which release acetylcholine, vasoactive intestinal peptide, and other peptides and lead to glandular secretion. In concert, these proinflammatory neural responses lead to vasodilation, vascular permeability, and glandular secretion. Sympathetic nerves release neuropeptide Y and norepinephrine, potent vasoconstrictors which act to decompress the nasal mucosa and produce nasal patency. The balance between the effects of parasympathetic and sympathetic neurotransmitters may regulate nasal homeostasis, whereas the nociceptive sensory system may be held in reserve as a defense mechanism. Dysfunction of these systems may lead to pathological nasal syndromes. In the future, specific neuropeptide agonists and antagonists may be useful for the treatment of human rhinitic diseases. PMID:1928355

  7. Nasal visualization on radioiodine whole-body scintigraphy due to benign abnormality.

    PubMed

    Jiang, Xue; Wang, Qiao; Huang, Rui

    2015-04-01

    Nasal iodine activity can be observed on 123Iodine (123I) or 131I whole-body scintigraphy (WBS) commonly as a normal variant caused by nasal or salivary secretion of the tracer. We encountered 2 patients whose increased accumulation of 131I activity was associated with underlying abnormalities. One patient had a nasal polyp, whereas the other had an abscess.

  8. Phototherapy-treated apoptotic tumor cells induce pro-inflammatory cytokines production in macrophage

    NASA Astrophysics Data System (ADS)

    Lu, Cuixia; Wei, Yanchun; Xing, Da

    2014-09-01

    Our previous studies have demonstrated that as a mitochondria-targeting cancer phototherapy, high fluence low-power laser irradiation (HF-LPLI) induces mitochondrial superoxide anion burst, resulting in oxidative damage to tumor cells. In this study, we further explored the immunological effects of HF-LPLI-induced apoptotic tumor cells. When macrophages were co-incubated with apoptotic cells induced by HF-LPLI, we observed the increased levels of TNF-α secretion and NO production in macrophages. Further experiments showed that NF-κB was activated in macrophages after co-incubation with HF-LPLI-induced apoptotic cells, and inhibition of NF-κB activity by pyrrolidinedithiocarbamic acid (PDTC) reduced the elevated levels of TNF-α secretion and NO production. These data indicate that HF-LPLI-induced apoptotic tumor cells induce the secretion of pro-inflammatory cytokines in macrophages, which may be helpful for better understanding the biological effects of cancer phototherapy.

  9. Modeling mechanisms of cell secretion.

    PubMed

    Tsaneva-Atanasova, Krasimira; Osinga, Hinke M; Tabak, Joël; Pedersen, Morten Gram

    2010-12-01

    Secretion is a fundamental cellular process involving the regulated release of intracellular products from cells. Physiological functions such as neurotransmission, or the release of hormones and digestive enzymes, are all governed by cell secretion. Anomalies in the processes involved in secretion contribute to the development and progression of diseases such as diabetes and other hormonal disorders. To unravel the mechanisms that govern such diseases, it is essential to understand how hormones, growth factors and neurotransmitters are synthesized and processed, and how their signals are recognized, amplified and transmitted by intracellular signaling pathways in the target cells. Here, we discuss diverse aspects of the detailed mechanisms involved in secretion based on mathematical models. The models range from stochastic ones describing the trafficking of secretory vesicles to deterministic ones investigating the regulation of cellular processes that underlie hormonal secretion. In all cases, the models are closely related to experimental results and suggest theoretical predictions for the secretion mechanisms.

  10. Protecting Trade Secrets in Canada.

    PubMed

    Courage, Noel; Calzavara, Janice

    2015-01-01

    Patents in the life sciences industries are a key form of intellectual property (IP), particularly for products such as brand-name drugs and medical devices. However, trade secrets can also be a useful tool for many types of innovations. In appropriate cases, trade secrets can offer long-term protection of IP for a lower financial cost than patenting. This type of protection must be approached with caution as there is little room for error when protecting a trade secret. Strong agreements and scrupulous security can help to protect the secret. Once a trade secret is disclosed to the public, it cannot be restored as the owner's property; however, if the information is kept from the public domain, the owner can have a property right of unlimited duration in the information. In some situations patents and trade secrets may be used cooperatively to protect innovation, particularly for manufacturing processes. PMID:25986591

  11. Cytokine response to vitamin E supplementation is dependent on pre-supplementation cytokine levels.

    PubMed

    Belisle, Sarah E; Leka, Lynette S; Dallal, Gerard E; Jacques, Paul F; Delgado-Lista, Javier; Ordovas, Jose M; Meydani, Simin Nikbin

    2008-01-01

    Vitamin E supplementation has been suggested to improve immune response in the aged in part by altering cytokine production. However, there is not a consensus regarding the effect of supplemental vitamin E on cytokine production in humans. There is evidence that baseline immune health can affect immune response to supplemental vitamin E in the elderly. Thus, the effect of vitamin E on cytokines may depend on their pre-supplementation cytokine response. Using data from a vitamin E intervention in elderly nursing home residents, we examined if the effect of vitamin E on ex vivo cytokine production of IL-1 beta, IL-6, TNF-alpha, and IFN-gamma depended on baseline cytokine production. We observed that the effect of vitamin E supplementation on cytokine production depended on pre-supplementation production of the respective cytokines. The interactions between vitamin E and baseline cytokine production were not explained by covariates known to impact cytokine production. Our results offer evidence that baseline cytokine production should be considered in studies that examine the effect of supplemental vitamin E on immune and inflammatory responses. Our results could have implications in designing clinical trials to determine the impact of vitamin E on conditions in which cytokines are implicated such as infections and atherosclerotic disease.

  12. Cytokine response to vitamin E supplementation is dependent on pre-supplementation cytokine levels

    PubMed Central

    Belisle, Sarah E.; Leka, Lynette S.; Dallal, Gerard E.; Jacques, Paul F.; Delgado-Lista, Javier; Ordovas, Jose M.; Meydani, Simin Nikbin

    2009-01-01

    Vitamin E supplementation has been suggested to improve immune response in the aged in part by altering cytokine production. However, there is not a consensus regarding the effect of supplemental vitamin E on cytokine production in humans. There is evidence that baseline immune health can affect immune response to supplemental vitamin E in the elderly. Thus, the effect of vitamin E on cytokines may depend on their pre-supplementation cytokine response. Using data from a vitamin E intervention in elderly nursing home residents, we examined if the effect of vitamin E on ex vivo cytokine production of IL-1β, IL-6, TNF-α, and IFN-γ depended on baseline cytokine production. . We observed that the effect of vitamin E supplementation on cytokine production depended on pre-supplementation production of the respective cytokines. The interactions between vitamin E and baseline cytokine production were not explained covariates known to impact cytokine production. Our results offer evidence that baseline cytokine production should be considered in studies that examine the effect of supplemental vitamin E on immune and inflammatory responses. Our results could have implications in designing clinical trials to determine the impact of vitamin E on conditions in which cytokines are implicated such as infections and atherosclerotic disease. PMID:19478423

  13. Borrelia burgdorferi Spirochetes Induce Mast Cell Activation and Cytokine Release

    PubMed Central

    Talkington, Jeffrey; Nickell, Steven P.

    1999-01-01

    The Lyme disease spirochete, Borrelia burgdorferi, is introduced into human hosts via tick bites. Among the cell types present in the skin which may initially contact spirochetes are mast cells. Since spirochetes are known to activate a variety of cell types in vitro, we tested whether B. burgdorferi spirochetes could activate mast cells. We report here that freshly isolated rat peritoneal mast cells or mouse MC/9 mast cells cultured in vitro with live or freeze-thawed B. burgdorferi spirochetes undergo low but detectable degranulation, as measured by [5-3H] hydroxytryptamine release, and they synthesize and secrete the proinflammatory cytokine tumor necrosis factor alpha (TNF-α). In contrast to findings in previous studies, where B. burgdorferi-associated activity was shown to be dependent upon protein lipidation, mast cell TNF-α release was not induced by either lipidated or unlipidated recombinant OspA. This activity was additionally shown to be protease sensitive and surface expressed. Finally, comparisons of TNF-α-inducing activity in known low-, intermediate-, and high-passage B. burgdorferi B31 isolates demonstrated passage-dependent loss of activity, indicating that the activity is probably plasmid encoded. These findings document the presence in low-passage B. burgdorferi spirochetes of a novel lipidation-independent activity capable of inducing cytokine release from host cells. PMID:10024550

  14. Filaggrin genotype in ichthyosis vulgaris predicts abnormalities in epidermal structure and function.

    PubMed

    Gruber, Robert; Elias, Peter M; Crumrine, Debra; Lin, Tzu-Kai; Brandner, Johanna M; Hachem, Jean-Pierre; Presland, Richard B; Fleckman, Philip; Janecke, Andreas R; Sandilands, Aileen; McLean, W H Irwin; Fritsch, Peter O; Mildner, Michael; Tschachler, Erwin; Schmuth, Matthias

    2011-05-01

    Although it is widely accepted that filaggrin (FLG) deficiency contributes to an abnormal barrier function in ichthyosis vulgaris and atopic dermatitis, the pathomechanism of how FLG deficiency provokes a barrier abnormality in humans is unknown. We report here that the presence of FLG mutations in Caucasians predicts dose-dependent alterations in epidermal permeability barrier function. Although FLG is an intracellular protein, the barrier abnormality occurred solely via a paracellular route in affected stratum corneum. Abnormal barrier function correlated with alterations in keratin filament organization (perinuclear retraction), impaired loading of lamellar body contents, followed by nonuniform extracellular distribution of secreted organelle contents, and abnormalities in lamellar bilayer architecture. In addition, we observed reductions in corneodesmosome density and tight junction protein expression. Thus, FLG deficiency provokes alterations in keratinocyte architecture that influence epidermal functions localizing to the extracellular matrix. These results clarify how FLG mutations impair epidermal permeability barrier function.

  15. Understanding the mechanism of IL-1β secretion

    PubMed Central

    Lopez-Castejon, Gloria; Brough, David

    2011-01-01

    The cytokine interleukin-1β (IL-1β) is a key mediator of the inflammatory response. Essential for the host-response and resistance to pathogens, it also exacerbates damage during chronic disease and acute tissue injury. It is not surprising therefore that there is a huge level of interest in how this protein is produced and exported from cells. However, the mechanism of IL-1β release has proven to be elusive. It does not follow the conventional ER-Golgi route of secretion. A literature full of disparate observations arising from numerous experimental systems, has contributed to a complicated mix of diverse proposals. Here we summarise these observations and propose that secretion of IL-1β occurs on a continuum, dependent upon stimulus strength and the extracellular IL-1β requirement. PMID:22019906

  16. Circadian interleukin-6 secretion and quantity and depth of sleep.

    PubMed

    Vgontzas, A N; Papanicolaou, D A; Bixler, E O; Lotsikas, A; Zachman, K; Kales, A; Prolo, P; Wong, M L; Licinio, J; Gold, P W; Hermida, R C; Mastorakos, G; Chrousos, G P

    1999-08-01

    Patients with pathologically increased daytime sleepiness and fatigue have elevated levels of circulating interleukin-6 (IL-6). The latter is an inflammatory cytokine, which causes sickness manifestations, including somnolence and fatigue, and activation of the hypothalamic-pituitary-adrenal axis. In this study, we examined: 1) the relation between serial measurements of plasma IL-6 and quantity and depth of sleep, evaluated by polysomnography; and 2) the effects of sleep deprivation on the nyctohemeral pattern of IL-6 secretion. Eight healthy young male volunteers were sampled for 24 h twice, at the baseline state, after a normal night's sleep and after total overnight sleep deprivation. At the baseline state, IL-6 was secreted in a biphasic circadian pattern with two nadirs at 0800 and 2100 and two zeniths at 1900 and 0500 (P < 0.01). The baseline amount of sleep correlated negatively with the overall daytime secretion of the cytokine (P < 0.05). Also, depth of sleep at baseline correlated negatively with the postdeprivation increase of daytime secretion of IL-6 (P < 0.05). Sleep deprivation changed the temporal pattern of circadian IL-6 secretion but not the overall amount. Indeed, during the post-deprivation period, the mean daytime (0800-2200 h) levels of IL-6 were significantly higher (P < 0.05), whereas the nighttime (2200-0600 h) levels were lower than the predeprivation values. Thus, sleep-deprived subjects had daytime oversecretion and nighttime under-secretion of IL-6; the former might be responsible for their daylong somnolence and fatigue, the latter for the better quality (depth) of their sleep. These data suggest that a good night's sleep is associated with decreased daytime secretion of IL-6 and a good sense of well-being and that good sleep is associated with decreased exposure of tissues to the proinflammatory and potentially detrimental actions of IL-6. Sleep deprivation increases daytime IL-6 and causes somnolence and fatigue during the next day

  17. Inflammaging and Anti-Inflammaging: The Role of Cytokines in Extreme Longevity.

    PubMed

    Minciullo, Paola Lucia; Catalano, Antonino; Mandraffino, Giuseppe; Casciaro, Marco; Crucitti, Andrea; Maltese, Giuseppe; Morabito, Nunziata; Lasco, Antonino; Gangemi, Sebastiano; Basile, Giorgio

    2016-04-01

    Longevity and aging are two sides of the same coin, as they both derive from the interaction between genetic and environmental factors. Aging is a complex, dynamic biological process characterized by continuous remodeling. One of the most recent theories on aging focuses on immune response, and takes into consideration the activation of subclinical, chronic low-grade inflammation which occurs with aging, named "inflammaging". Long-lived people, especially centenarians, seem to cope with chronic subclinical inflammation through an anti-inflammatory response, called therefore "anti-inflammaging". In the present review, we have focused our attention on the contrast between inflammaging and anti-inflammaging systems, by evaluating the role of cytokines and their impact on extreme longevity. Cytokines are the expression of a network involving genes, polymorphisms and environment, and are involved both in inflammation and anti-inflammation. We have described the role of IL-1, IL-2, IL-6, IL-12, IL-15, IL-18, IL-22, IL-23, TNF-α, IFN-γ as pro-inflammatory cytokines, of IL-1Ra, IL-4, IL-10, TGF-β1 as anti-inflammatory cytokines, and of lipoxin A4 and heat shock proteins as mediators of cytokines. We believe that if inflammaging is a key to understand aging, anti-inflammaging may be one of the secrets of longevity.

  18. Impact of antidepressants on cytokine production of depressed patients in vitro.

    PubMed

    Munzer, Alexander; Sack, Ulrich; Mergl, Roland; Schönherr, Jeremias; Petersein, Charlotte; Bartsch, Stefanie; Kirkby, Kenneth C; Bauer, Katrin; Himmerich, Hubertus

    2013-11-01

    The interplay between immune and nervous systems plays a pivotal role in the pathophysiology of depression. In depressive episodes, patients show increased production of pro-inflammatory cytokines such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α. There is limited information on the effect of antidepressant drugs on cytokines, most studies report on a limited sample of cytokines and none have reported effects on IL-22. We systematically investigated the effect of three antidepressant drugs, citalopram, escitalopram and mirtazapine, on secretion of cytokines IL-1β, IL-2, IL-4, IL-6, IL-17, IL-22 and TNF-α in a whole blood assay in vitro, using murine anti-human CD3 monoclonal antibody OKT3, and 5C3 monoclonal antibody against CD40, to stimulate T and B cells respectively. Citalopram increased production of IL-1β, IL-6, TNF-α and IL-22. Mirtazapine increased IL-1β, TNF-α and IL-22. Escitalopram decreased IL-17 levels. The influence of antidepressants on IL-2 and IL-4 levels was not significant for all three drugs. Compared to escitalopram, citalopram led to higher levels of IL-1β, IL-6, IL-17 and IL-22; and mirtazapine to higher levels of IL-1β, IL-17, IL-22 and TNF-α. Mirtazapine and citalopram increased IL-22 production. The differing profile of cytokine production may relate to differences in therapeutic effects, risk of relapse and side effects. PMID:24257035

  19. EMD in periodontal regenerative surgery modulates cytokine profiles: A randomised controlled clinical trial

    PubMed Central

    Villa, Oscar; Wohlfahrt, Johan C.; Koldsland, Odd Carsten; Brookes, Steven J.; Lyngstadaas, Staale P.; Aass, Anne M.; Reseland, Janne E.

    2016-01-01

    The enamel matrix derivative (EMD) contains hundreds of peptides in different levels of proteolytic processing that may provide a range of biological effects of importance in wound healing. The aim of the present study was to compare the effect of EMD and its fractions on the cytokine profiles from human gingival fibroblasts in vitro and in gingival crevicular fluid (GCF) in a randomized controlled split-mouth clinical study (n = 12). Levels of cytokines in cell culture medium and in GCF were measured by Luminex over a 2-week period. In the clinical study, levels of pro-inflammatory cytokines and chemokines were increased, whereas the levels of transforming growth factor-α (TGF-α) and platelet-derived growth factor-BB (PDGF-BB) were reduced. The in vitro study showed that EMD and its high and low molecular weight fractions reduced the secretion of pro-inflammatory cytokines and chemokines compared to untreated cells. EMD had an effect on levels of cytokines related to fibroplasia, angiogenesis, inflammation and chemotaxis both in vitro and in vivo, however, the anti-inflammatory effect induced by EMD observed in the in vitro study could not be confirmed clinically. PMID:26976446

  20. Impact of Antidepressants on Cytokine Production of Depressed Patients in Vitro

    PubMed Central

    Munzer, Alexander; Sack, Ulrich; Mergl, Roland; Schönherr, Jeremias; Petersein, Charlotte; Bartsch, Stefanie; Kirkby, Kenneth C.; Bauer, Katrin; Himmerich, Hubertus

    2013-01-01

    The interplay between immune and nervous systems plays a pivotal role in the pathophysiology of depression. In depressive episodes, patients show increased production of pro-inflammatory cytokines such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α. There is limited information on the effect of antidepressant drugs on cytokines, most studies report on a limited sample of cytokines and none have reported effects on IL-22. We systematically investigated the effect of three antidepressant drugs, citalopram, escitalopram and mirtazapine, on secretion of cytokines IL-1β, IL-2, IL-4, IL-6, IL-17, IL-22 and TNF-α in a whole blood assay in vitro, using murine anti-human CD3 monoclonal antibody OKT3, and 5C3 monoclonal antibody against CD40, to stimulate T and B cells respectively. Citalopram increased production of IL-1β, IL-6, TNF-α and IL-22. Mirtazapine increased IL-1β, TNF-α and IL-22. Escitalopram decreased IL-17 levels. The influence of antidepressants on IL-2 and IL-4 levels was not significant for all three drugs. Compared to escitalopram, citalopram led to higher levels of IL-1β, IL-6, IL-17 and IL-22; and mirtazapine to higher levels of IL-1β, IL-17, IL-22 and TNF-α. Mirtazapine and citalopram increased IL-22 production. The differing profile of cytokine production may relate to differences in therapeutic effects, risk of relapse and side effects. PMID:24257035

  1. Salmonella-secreted Virulence Factors

    SciTech Connect

    Heffron, Fred; Niemann, George; Yoon, Hyunjin; Kidwai, Afshan S.; Brown, Roslyn N.; McDermott, Jason E.; Smith, Richard D.; Adkins, Joshua N.

    2011-05-01

    In this short review we discuss secreted virulence factors of Salmonella, which directly affect Salmonella interaction with its host. Salmonella secretes protein to subvert host defenses but also, as discussed, to reduce virulence thereby permitting the bacteria to persist longer and more successfully disperse. The type III secretion system (TTSS) is the best known and well studied of the mechanisms that enable secretion from the bacterial cytoplasm to the host cell cytoplasm. Other secretion systems include outer membrane vesicles, which are present in all Gram-negative bacteria examined to date, two-partner secretion, and type VI secretion will also be addressed. Excellent reviews of Salmonella secreted effectors have focused on themes such as actin rearrangements, vesicular trafficking, ubiquitination, and the activities of the virulence factors themselves. This short review is based on S. Typhimurium infection of mice because it is a model of typhoid like disease in humans. We have organized effectors in terms of events that happen during the infection cycle and how secreted effectors may be involved.

  2. Expansible quantum secret sharing network

    NASA Astrophysics Data System (ADS)

    Sun, Ying; Xu, Sheng-Wei; Chen, Xiu-Bo; Niu, Xin-Xin; Yang, Yi-Xian

    2013-08-01

    In the practical applications, member expansion is a usual demand during the development of a secret sharing network. However, there are few consideration and discussion on network expansibility in the existing quantum secret sharing schemes. We propose an expansible quantum secret sharing scheme with relatively simple and economical quantum resources and show how to split and reconstruct the quantum secret among an expansible user group in our scheme. Its trait, no requirement of any agent's assistant during the process of member expansion, can help to prevent potential menaces of insider cheating. We also give a discussion on the security of this scheme from three aspects.

  3. Prostaglandin E2 in tick saliva regulates macrophage cell migration and cytokine profile

    PubMed Central

    2013-01-01

    Background Ticks are obligate hematophagous ectoparasites that suppress the host’s immune and inflammatory responses by secreting immuno-modulatory and anti-inflammatory molecules in their saliva. In previous studies we have shown that tick salivary gland extract (SGE) and saliva from Dermacentor variabilis have distinct effects on platelet-derived growth factor (PDGF)-stimulated IC-21 macrophage and NIH3T3-L1 fibroblast migration. Since tick saliva contains a high concentration of prostaglandin E2 (PGE2), a potent modulator of inflammation, we used a PGE2 receptor antagonist to evaluate the role of PGE2 in the different migratory responses induced by saliva and its impact on macrophage cytokine profile. Methods Adult ticks were fed on female New Zealand white rabbits for 5-8 days. Female ticks were stimulated with dopamine/theophylline to induce salivation and saliva was pooled. Competitive enzyme immunoassays (EIA) were used to measure saliva PGE2 content and the changes in macrophage intracellular cyclic adenosine monophosphate (cAMP) levels. The effects of tick saliva on macrophage and fibroblast migration were assessed in the absence and presence of the PGE2 receptor antagonist, AH 6809, using blind well chamber assays. A cytokine antibody array was used to examine the effects of tick saliva on macrophage cytokine secretion. Statistical significance was determined by one-way ANOVA; Student Newman-Kuels post-test was used for multiple comparisons. Results The saliva-induced increase in PDGF-stimulated macrophage migration was reversed by AH 6809. The inhibition of PDGF-stimulated fibroblast migration by saliva was also antagonist-sensitive. Tick saliva induced macrophages to secrete copious amounts of PGE2, and conditioned medium from these cells caused an AH 6809-sensitive inhibition of stimulated fibroblast migration, showing that macrophages can regulate fibroblast activity. We show that tick saliva decreased the secretion of the pro

  4. Cytokine Regulation of Metastasis and Tumorigenicity.

    PubMed

    Yao, M; Brummer, G; Acevedo, D; Cheng, N

    2016-01-01

    The human body combats infection and promotes wound healing through the remarkable process of inflammation. Inflammation is characterized by the recruitment of stromal cell activity including recruitment of immune cells and induction of angiogenesis. These cellular processes are regulated by a class of soluble molecules called cytokines. Based on function, cell target, and structure, cytokines are subdivided into several classes including: interleukins, chemokines, and lymphokines. While cytokines regulate normal physiological processes, chronic deregulation of cytokine expression and activity contributes to cancer in many ways. Gene polymorphisms of all types of cytokines are associated with risk of disease development. Deregulation RNA and protein expression of interleukins, chemokines, and lymphokines have been detected in many solid tumors and hematopoetic malignancies, correlating with poor patient prognosis. The current body of literature suggests that in some tumor types, interleukins and chemokines work against the human body by signaling to cancer cells and remodeling the local microenvironment to support the growth, survival, and invasion of primary tumors and enhance metastatic colonization. Some lymphokines are downregulated to suppress tumor progression by enhancing cytotoxic T cell activity and inhibiting tumor cell survival. In this review, we will describe the structure/function of several cytokine families and review our current understanding on the roles and mechanisms of cytokines in tumor progression. In addition, we will also discuss strategies for exploiting the expression and activity of cytokines in therapeutic intervention. PMID:27613135

  5. Compartmentalized Cytokine Responses in Hidradenitis Suppurativa

    PubMed Central

    Savva, Athina; Kersten, Brigit; Pistiki, Aikaterini; van de Veerdonk, Frank L.; Netea, Mihai G.; van der Meer, Jos W.; Giamarellos-Bourboulis, Evangelos J.

    2015-01-01

    Background Favorable treatment outcomes with TNF blockade led us to explore cytokine responses in hidradenitis suppurativa (HS). Methods Blood monocytes of 120 patients and 24 healthy volunteers were subtyped by flow cytometry. Isolated blood mononuclear cells (PBMCs) were stimulated for cytokine production; this was repeated in 13 severe patients during treatment with etanercept. Cytokines in pus were measured. Results CD14brightCD16dim inflammatory monocytes and patrolling monocytes were increased in Hurley III patients. Cytokine production by stimulated PBMCs was low compared to controls but the cytokine gene copies did not differ, indicating post-translational inhibition. The low production of IL-17 was restored, when cells were incubated with adalimumab. In pus, high concentrations of pro-inflammatory cytokines were detected. Based on the patterns, six different cytokine profiles were discerned, which are potentially relevant for the choice of treatment. Clinical improvement with etanercept was predicted by increased production of IL-1β and IL-17 by PBMCs at week 8. Conclusions Findings indicate compartmentalized cytokine expression in HS; high in pus but suppressed in PBMCs. This is modulated through blockade of TNF. PMID:26091259

  6. Cytokine expression in CD4(+) cells exposed to the monocyte locomotion inhibitory factor produced by Entamoeba histolytica.

    PubMed

    Rojas-Dotor, Sara; Rico, Guadalupe; Pérez, Julia; Velázquez, Juan; Silva, Raúl; Morales, Esther; Kretschmer, Roberto

    2006-04-01

    Entamoeba histolytica produces monocyte locomotion inhibitory factor (MLIF), a pentapeptide with in vitro and in vivo anti-inflammatory properties. MLIF may interfere with leukocyte migration, disturbing the balance of pro- and anti-inflammatory cytokines secreted by CD4(+) T lymphocytes. We evaluated the effect of MLIF on expression of pro- and anti-inflammatory cytokines in human CD4(+) T lymphocytes. Regulatory cytokines [interleukin-1 beta (IL-1beta), IL-2, interferon gamma (IFN-gamma), IL-5, IL-6, and IL-10] were studied by enzyme-linked immunosorbent assay method in CD4(+)-cell supernatant fluids. Proinflammatory cytokines were produced per se by MLIF (IL-1beta, IL-2, and IFN-gamma) and also anti-inflammatory cytokines (IL-5, IL-6, and IL-10) with 1-phorbol-12 myristate-13 acetate + MLIF; the IL-1beta, IFN-gamma, IL-5 and IL-6 production was inhibited but not that of IL-10 which disclosed increase in its expression. MLIF disturbs the pro- and anti-inflammatory balance, and it induces inhibition of IL-1beta (principal proinflammatory cytokine) and increases IL-10 (prototype of an anti-inflammatory cytokine).

  7. On-chip immune cell activation and subsequent time-resolved magnetic bead-based cytokine detection.

    PubMed

    Kongsuphol, Patthara; Liu, Yunxiao; Ramadan, Qasem

    2016-10-01

    Cytokine profiling and immunophenotyping offer great potential for understanding many disease mechanisms, personalized diagnosis, and immunotherapy. Here, we demonstrate a time-resolved detection of cytokine from a single cell cluster using an in situ magnetic immune assay. An array of triple-layered microfluidic chambers was fabricated to enable simultaneous cell culture under perfusion flow and detection of the induced cytokines at multiple time-points. Each culture chamber comprises three fluidic compartments which are dedicated to, cell culture, perfusion and immunoassay. The three compartments are separated by porous membranes, which allow the diffusion of fresh nutrient from the perfusion compartment into the cell culture compartment and cytokines secretion from the cell culture compartment into the immune assay compartment. This structure hence enables capturing the released cytokines without disturbing the cell culture and without minimizing benefit gain from perfusion. Functionalized magnetic beads were used as a solid phase carrier for cytokine capturing and quantification. The cytokines released from differential stimuli were quantified in situ in non-differentiated U937 monocytes and differentiated macrophages.

  8. On-chip immune cell activation and subsequent time-resolved magnetic bead-based cytokine detection.

    PubMed

    Kongsuphol, Patthara; Liu, Yunxiao; Ramadan, Qasem

    2016-10-01

    Cytokine profiling and immunophenotyping offer great potential for understanding many disease mechanisms, personalized diagnosis, and immunotherapy. Here, we demonstrate a time-resolved detection of cytokine from a single cell cluster using an in situ magnetic immune assay. An array of triple-layered microfluidic chambers was fabricated to enable simultaneous cell culture under perfusion flow and detection of the induced cytokines at multiple time-points. Each culture chamber comprises three fluidic compartments which are dedicated to, cell culture, perfusion and immunoassay. The three compartments are separated by porous membranes, which allow the diffusion of fresh nutrient from the perfusion compartment into the cell culture compartment and cytokines secretion from the cell culture compartment into the immune assay compartment. This structure hence enables capturing the released cytokines without disturbing the cell culture and without minimizing benefit gain from perfusion. Functionalized magnetic beads were used as a solid phase carrier for cytokine capturing and quantification. The cytokines released from differential stimuli were quantified in situ in non-differentiated U937 monocytes and differentiated macrophages. PMID:27628061

  9. [Endocrine abnormalities in patients with chronic renal failure - part II].

    PubMed

    Krysiak, Robert; Kędzia, Agnieszka; Krupej-Kędzierska, Joanna; Kowalska, Beata; Okopień, Bogusław

    2015-05-01

    The kidneys play a crucial role in maintaining homeostasis of fluids and electrolytes, acid-base balance, and volume regulation. In subjects with chronic renal failure, particularly at its later stages, these adaptive responses are impaired and some of these alterations are of clinical relevance. The ways in which chronic renal failure affects function of endocrine organs include impaired secretion of kidney-derived hormones, altered peripheral hormone metabolism, disturbed binding to carrier proteins, accumulation of hormone inhibitors, as well as abnormal target organ responsiveness. Apart from secondary hyperparathyroidism, thyroid dysfunction and impaired growth, reviewed in our previous study, endocrine disturbances that most frequently affect this group of patients include: abnormal functioning of the hypothalamic-pituitary-adrenal and hypothalamicpituitary- gonadal axes, bone loss and gynecomastia. The clinical picture and laboratory findings of these endocrine disturbances depend on the treatment strategy.

  10. Time course of cytokine levels in sepsis.

    PubMed

    Thijs, L G; Hack, C E

    1995-11-01

    In severe sepsis, a network of proinflammatory cytokines (TNF, IL-1 beta, IL-6, IL-8) is activated and blood levels of these cytokines are elevated, albeit inconsistently and with large individual variations. In addition, elevated blood levels of anti-inflammatory cytokines (IL-10), as well as of soluble cytokine receptors (sTNF-RI and II, IL-1ra), have been found. They seem to have a regulatory function in the host response. Levels of TNF and IL-6 are usually highest at the time of admission, whereas the time course of IL-1 beta levels (when detectable) can vary considerably. Limited data on IL-8 levels suggest that they may remain elevated for longer periods. Elevated levels of sTNFR and IL-1ra may also persist for a prolonged period of time. The pathogenetic significance of these observations is still unclear, but persistingly high levels of proinflammatory cytokines may be associated with organ failure and mortality.

  11. Cytokines in juvenile rheumatoid arthritis (JRA).

    PubMed

    Mangge, H; Schauenstein, K

    1998-06-01

    Juvenile rheumatoid arthritis (JRA), unlike rheumatoid arthritis of adulthood (RA), is a heterogenous disease comprising at least five subtypes that differ in clinical course and prognosis, and require different therapeutical approaches. As compared to RA, the production of local and systemic cytokines in JRA have not yet been as extensively investigated. In this article we review the available literature on cytokine expression in serum and synovial fluid in all five different subtypes of JRA. Even though the data are still fragmentary, the evidence so far suggests that the determination of serum cytokines yields relevant information as to clinical subtype and inflammatory activity of the disease. Furthermore, the cytokine data suggest that the pathogenesis of JRA may even by more heterogenous than defined by the clinical subtypes. Finally, future directions of research in this area are proposed, and-based on the latest results-arguments for (anti)cytokine therapies in JRA are critically discussed.

  12. Interactions between Autophagy and Inhibitory Cytokines.

    PubMed

    Wu, Tian-Tian; Li, Wei-Min; Yao, Yong-Ming

    2016-01-01

    Autophagy is a degradative pathway that plays an essential role in maintaining cellular homeostasis. Most early studies of autophagy focused on its involvement in age-associated degeneration and nutrient deprivation. However, the immunological functions of autophagy have become more widely studied in recent years. Autophagy has been shown to be an intrinsic cellular defense mechanism in the innate and adaptive immune responses. Cytokines belong to a broad and loose category of proteins and are crucial for innate and adaptive immunity. Inhibitory cytokines have evolved to permit tolerance to self while also contributing to the eradication of invading pathogens. Interactions between inhibitory cytokines and autophagy have recently been reported, revealing a novel mechanism by which autophagy controls the immune response. In this review, we discuss interactions between autophagy and the regulatory cytokines IL-10, transforming growth factor-β, and IL-27. We also mention possible interactions between two newly discovered cytokines, IL-35 and IL-37, and autophagy.

  13. Interactions between Autophagy and Inhibitory Cytokines

    PubMed Central

    Wu, Tian-tian; Li, Wei-Min; Yao, Yong-Ming

    2016-01-01

    Autophagy is a degradative pathway that plays an essential role in maintaining cellular homeostasis. Most early studies of autophagy focused on its involvement in age-associated degeneration and nutrient deprivation. However, the immunological functions of autophagy have become more widely studied in recent years. Autophagy has been shown to be an intrinsic cellular defense mechanism in the innate and adaptive immune responses. Cytokines belong to a broad and loose category of proteins and are crucial for innate and adaptive immunity. Inhibitory cytokines have evolved to permit tolerance to self while also contributing to the eradication of invading pathogens. Interactions between inhibitory cytokines and autophagy have recently been reported, revealing a novel mechanism by which autophagy controls the immune response. In this review, we discuss interactions between autophagy and the regulatory cytokines IL-10, transforming growth factor-β, and IL-27. We also mention possible interactions between two newly discovered cytokines, IL-35 and IL-37, and autophagy. PMID:27313501

  14. Solubility and secretability.

    PubMed

    Schein, C H

    1993-08-01

    The solubility and secretability of proteins can often be affected by extremely small changes in their primary structure. Attempts to determine empirical rules for the alteration of protein structure to improve either of these characteristics have met with only partial success. Those (mostly serendipitous) improvements in solubility that have been obtained via mutagenesis cannot be considered to be 'protein engineering'. The most successful examples where directed mutagenesis has been used to alter protein solubility, hemoglobin and insulin, have relied on established crystal structures and a wealth of data about the relationship between sequence and structure of the targeted protein. Currently, optimizing culture growth conditions by trial and error remains the fastest way to improve expression.

  15. Kidney transplantation in abnormal bladder

    PubMed Central

    Mishra, Shashi K.; Muthu, V.; Rajapurkar, Mohan M.; Desai, Mahesh R.

    2007-01-01

    Structural urologic abnormalities resulting in dysfunctional lower urinary tract leading to end stage renal disease may constitute 15% patients in the adult population and up to 20-30% in the pediatric population. A patient with an abnormal bladder, who is approaching end stage renal disease, needs careful evaluation of the lower urinary tract to plan the most satisfactory technical approach to the transplant procedure. Past experience of different authors can give an insight into the management and outcome of these patients. This review revisits the current literature available on transplantation in abnormal bladder and summarizes the clinical approach towards handling this group of difficult transplant patients. We add on our experience as we discuss the various issues. The outcome of renal transplant in abnormal bladder is not adversely affected when done in a reconstructed bladder. Correct preoperative evaluation, certain technical modification during transplant and postoperative care is mandatory to avoid complications. Knowledge of the abnormal bladder should allow successful transplantation with good outcome. PMID:19718334

  16. Epigenetic regulation of high glucose-induced proinflammatory cytokine productionin monocytes by curcumin

    PubMed Central

    Yun, Jung-Mi; Jialal, Ishwarlal; Devaraj, Sridevi

    2010-01-01

    Diabetes is a pro-inflammatory state. We have previously shown increased monocyte pro-inflammatory cytokines in patients with Type 1 and Type 2 diabetes. High glucose induces pro-inflammatory cytokines via epigenetic changes. Curcumin, a polyphenol responsible for the yellow color of the spice turmeric, is known to exert potent anti-inflammatory activity in vitro. Recent studies indicate that it may regulate chromatin remodeling by inhibiting histone acetylation. In this study, we aimed to test the effect of curcumin on histone acetylation and pro-inflammatory cytokine secretion under high-glucose conditions in human monocytes. Human monocytic (THP-1) cells were cultured in presence of mannitol (osmolar control, mannitol) or normoglycemic (NG, 5.5 mmol/L glucose) or hyperglycemic (HG, 25 mmol/L glucose) conditions in absence or presence of curcumin (1.5-12.5μM) for 72 h. Cytokine level, nuclear factor κB (NF-κB) transactivation, histone deacetylases (HDACs) activity, histone acetylases (HATs) activity were measured by western blots, qRT-PCR, ELISA, Immunofluorescence (IF) staining. HG significantly induced histone acetylation, NF-κB activity and pro-inflammatory cytokine (IL-6, TNF-α and MCP-1) release from THP-1 cells. Curcumin suppressed NF-κB binding and cytokine release in THP-1 cells. Also, since p300 histone acetyltransferase is a coactivator of NF-κB, we examined its acetylation. Curcumin treatment also significantly reduced HAT activity, level of p300 and acetylated CBP/p300 gene expression, and induced histone deacetylase 2 (HDAC2) expression by curcumin. These results indicate that curcumin decreases HG-induced cytokine production in monocytes via epigenetic changes involving NF-κB. In conclusion, curcumin supplementation by reducing vascular inflammation may prevent diabetic complications. PMID:20655188

  17. Differential induction of innate defense antimicrobial peptides in primary nasal epithelial cells upon stimulation with inflammatory cytokines, Th17 cytokines or bacterial conditioned medium from Staphylococcus aureus isolates.

    PubMed

    Burgey, Christine; Kern, Winfried V; Römer, Winfried; Rieg, Siegbert

    2016-01-01

    To date it is incompletely understood why half of the human population is intrinsically resistant to Staphylococcus aureus colonization whereas the other half is intermittently or permanently colonized. Nasal colonization represents the primary niche for S. aureus. We therefore investigated whether primary nasal epithelial cells (HNEC) express antimicrobial peptides (AMPs) upon stimulation by inflammatory cytokines or bacterial conditioned medium (BCM) of different colonizing and invasive staphylococci. Stimulation with classical cytokines (IL-1β, TNF-α, IFN-γ) potently induced hBD-3 and RNase7 in HNEC. Th17 cytokines (IL-17A, IL-17F, IL-22) yielded comparably weak hBD-3 and RNase7 induction and no synergistic effects with classical cytokines. BCM of S. aureus and Staphylococcus epidermidis isolates moderately induced hBD3 and RNase7 mRNA expression without significant differences when comparing colonizing vs. invasive isolates. Our results indicate that HNEC contribute to the innate defense by secretion of an AMP-containing chemical defense shield along the nasal mucosa i.e. within the primary colonization niche of S. aureus. Further studies are needed to investigate whether a deficient AMP expression in the nasal mucosa may be related to different S. aureus carrier states. AMPs or AMP-inducing agents may be promising candidates for future topical decolonization regimens that aim to prevent invasive S. aureus infections.

  18. IL13 activates autophagy to regulate secretion in airway epithelial cells.

    PubMed

    Dickinson, John D; Alevy, Yael; Malvin, Nicole P; Patel, Khushbu K; Gunsten, Sean P; Holtzman, Michael J; Stappenbeck, Thaddeus S; Brody, Steven L

    2016-01-01

    Cytokine modulation of autophagy is increasingly recognized in disease pathogenesis, and current concepts suggest that type 1 cytokines activate autophagy, whereas type 2 cytokines are inhibitory. However, this paradigm derives primarily from studies of immune cells and is poorly characterized in tissue cells, including sentinel epithelial cells that regulate the immune response. In particular, the type 2 cytokine IL13 (interleukin 13) drives the formation of airway goblet cells that secrete excess mucus as a characteristic feature of airway disease, but whether this process is influenced by autophagy was undefined. Here we use a mouse model of airway disease in which IL33 (interleukin 33) stimulation leads to IL13-dependent formation of airway goblet cells as tracked by levels of mucin MUC5AC (mucin 5AC, oligomeric mucus/gel forming), and we show that these cells manifest a block in mucus secretion in autophagy gene Atg16l1-deficient mice compared to wild-type control mice. Similarly, primary-culture human tracheal epithelial cells treated with IL13 to stimulate mucus formation also exhibit a block in MUC5AC secretion in cells depleted of autophagy gene ATG5 (autophagy-related 5) or ATG14 (autophagy-related 14) compared to nondepleted control cells. Our findings indicate that autophagy is essential for airway mucus secretion in a type 2, IL13-dependent immune disease process and thereby provide a novel therapeutic strategy for attenuating airway obstruction in hypersecretory inflammatory diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis lung disease. Taken together, these observations suggest that the regulation of autophagy by Th2 cytokines is cell-context dependent.

  19. IL13 activates autophagy to regulate secretion in airway epithelial cells

    PubMed Central

    Dickinson, John D; Alevy, Yael; Malvin, Nicole P; Patel, Khushbu K; Gunsten, Sean P; Holtzman, Michael J; Stappenbeck, Thaddeus S; Brody, Steven L

    2016-01-01

    ABSTRACT Cytokine modulation of autophagy is increasingly recognized in disease pathogenesis, and current concepts suggest that type 1 cytokines activate autophagy, whereas type 2 cytokines are inhibitory. However, this paradigm derives primarily from studies of immune cells and is poorly characterized in tissue cells, including sentinel epithelial cells that regulate the immune response. In particular, the type 2 cytokine IL13 (interleukin 13) drives the formation of airway goblet cells that secrete excess mucus as a characteristic feature of airway disease, but whether this process is influenced by autophagy was undefined. Here we use a mouse model of airway disease in which IL33 (interleukin 33) stimulation leads to IL13-dependent formation of airway goblet cells as tracked by levels of mucin MUC5AC (mucin 5AC, oligomeric mucus/gel forming), and we show that these cells manifest a block in mucus secretion in autophagy gene Atg16l1-deficient mice compared to wild-type control mice. Similarly, primary-culture human tracheal epithelial cells treated with IL13 to stimulate mucus formation also exhibit a block in MUC5AC secretion in cells depleted of autophagy gene ATG5 (autophagy-related 5) or ATG14 (autophagy-related 14) compared to nondepleted control cells. Our findings indicate that autophagy is essential for airway mucus secretion in a type 2, IL13-dependent immune disease process and thereby provide a novel therapeutic strategy for attenuating airway obstruction in hypersecretory inflammatory diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis lung disease. Taken together, these observations suggest that the regulation of autophagy by Th2 cytokines is cell-context dependent. PMID:26062017

  20. Rat Mesenchymal Stromal Cells Inhibit T Cell Proliferation but Not Cytokine Production Through Inducible Nitric Oxide Synthase

    PubMed Central

    Vaage, John T.

    2012-01-01

    Mesenchymal stromal cells (MSC) have important immunomodulatory properties, they inhibit T lymphocyte allo-activation and have been used to treat graft-versus-host disease. How MSC exert their immunosuppressive functions is not completely understood but species specific mechanisms have been implicated. In this study we have investigated the mechanisms for rat MSC mediated inhibition of T lymphocyte proliferation and secretion of inflammatory cytokines in response to allogeneic and mitogenic stimuli in vitro. MSC inhibited the proliferation of T cells in allogeneic mixed lymphocyte reactions and in response to mitogen with similar efficacy. The anti-proliferative effect was mediated by the induced expression of nitric oxide (NO) synthase and production of NO by MSC. This pathway was required and sufficient to fully suppress lymphocyte proliferation and depended on proximity of MSC and target cells. Expression of inducible NO synthase by MSC was induced through synergistic stimulation with tumor necrosis factor α and interferon γ secreted by activated lymphocytes. Conversely, MSC had a pronounced inhibitory effect on the secretion of these cytokines by T cells which did not depend on NO synthase activity or cell contact, but was partially reversed by addition of the cyclooxygenase (COX) inhibitor indomethacin. In conclusion, rat MSC use different mechanisms to inhibit proliferative and inflammatory responses of activated T cells. While proliferation is suppressed by production of NO, cytokine secretion appears to be impaired at least in part by COX-dependent production of prostaglandin E2. PMID:22566943

  1. Complex patterns of abnormal heartbeats

    NASA Technical Reports Server (NTRS)

    Schulte-Frohlinde, Verena; Ashkenazy, Yosef; Goldberger, Ary L.; Ivanov, Plamen Ch; Costa, Madalena; Morley-Davies, Adrian; Stanley, H. Eugene; Glass, Leon

    2002-01-01

    Individuals having frequent abnormal heartbeats interspersed with normal heartbeats may be at an increased risk of sudden cardiac death. However, mechanistic understanding of such cardiac arrhythmias is limited. We present a visual and qualitative method to display statistical properties of abnormal heartbeats. We introduce dynamical "heartprints" which reveal characteristic patterns in long clinical records encompassing approximately 10(5) heartbeats and may provide information about underlying mechanisms. We test if these dynamics can be reproduced by model simulations in which abnormal heartbeats are generated (i) randomly, (ii) at a fixed time interval following a preceding normal heartbeat, or (iii) by an independent oscillator that may or may not interact with the normal heartbeat. We compare the results of these three models and test their limitations to comprehensively simulate the statistical features of selected clinical records. This work introduces methods that can be used to test mathematical models of arrhythmogenesis and to develop a new understanding of underlying electrophysiologic mechanisms of cardiac arrhythmia.

  2. Alginate microsphere compositions dictate different mechanisms of complement activation with consequences for cytokine release and leukocyte activation.

    PubMed

    Ørning, Pontus; Hoem, Kine Samset; Coron, Abba Elizabeth; Skjåk-Bræk, Gudmund; Mollnes, Tom Eirik; Brekke, Ole-Lars; Espevik, Terje; Rokstad, Anne Mari

    2016-05-10

    The inflammatory potential of 12 types of alginate-based microspheres was assessed in a human whole blood model. The inflammatory potential could be categorized from low to high based on the four main alginate microsphere types; alginate microbeads, liquefied core poly-l-ornithine (PLO)-containing microcapsules, liquefied core poly-l-lysine (PLL)-containing microcapsules, and solid core PLL-containing microcapsules. No complement or inflammatory cytokine activation was detected for the Ca/Ba alginate microbeads. Liquefied core PLO- and PLL-containing microcapsules induced significant fluid phase complement activation (TCC), but with low complement surface deposition (anti-C3c), and a low proinflammatory cytokine secretion, with exception of an elevated MCP-1(CCL2) secretion. The solid core PLL-containing microcapsules generated lower TCC but a marked complement surface deposition and significant induction of the proinflammatory cytokines interleukin (IL-1)β, TNF, IL-6, the chemokines IL-8 (CXCL8), and MIP-1α (CCL3) and MCP-1(CCL2). Inhibition with compstatin (C3 inhibitor) completely abolished complement surface deposition, leukocyte adhesion and the proinflammatory cytokines. The C5 inhibitions partly lead to a reduction of the proinflammatory cytokines. The leukocyte adhesion was abolished by inhibitory antibodies against CD18 and partly reduced by CD11b, but not by CD11c. Anti-CD18 significantly reduced the (IL-1)β, TNF, IL-6 and MIP-1α and anti-CD11b significantly reduced the IL-6 and VEGF secretion. MCP-1 was strongly activated by anti-CD18 and anti-CD11b. In conclusion the initial proinflammatory cytokine responses are driven by the microspheres potential to trigger complement C3 (C3b/iC3b) deposition, leukocyte activation and binding through complement receptor CR3 (CD11b/CD18). MCP-1 is one exception dependent on the fluid phase complement activation mediated through CR3. PMID:26993426

  3. The cytokine osteopontin modulates the severity of rotavirus diarrhea.

    PubMed

    Rollo, Ellen E; Hempson, Scott J; Bansal, Ajay; Tsao, Ernest; Habib, Iman; Rittling, Susan R; Denhardt, David T; Mackow, Erich R; Shaw, Robert D

    2005-03-01

    Osteopontin (OPN) is a sialated phosphoprotein found in tissues and secreted into body fluids. It is an integrin ligand with pleiotropic functions as an extracellular matrix protein in mineralized tissues and a cytokine that is active in cell signaling (A. B. Tuck, C. Hota, S. M. Wilson, and A. F. Chambers, Oncogene 22:1198-1205, 2003). To determine whether OPN may be important in mucosal defense against viral pathogens, we evaluated the OPN response to rotavirus infection and the extent of diarrhea manifested by infected opn null mutant (opn-/-) mice. Reverse transcription-PCR, Northern and Western blots, and immunohistochemical studies of the HT-29 intestinal epithelial cell line and murine intestine were used to evaluate OPN mRNA and product. Intestinal closed loops and diarrheal observations determined disease severity and duration. OPN mRNA levels increased after infection of HT-29 cells, peaking in 4 to 6 h. Infected cultures contained 925 microg of OPN/ml, while for controls the levels were below detection (50 microg/ml). Infection increased OPN mRNA levels in intestinal tissue between 2 and 24 h postinoculation and increased OPN protein in intestinal fluid. The cellular localization of OPN was supranuclear and apical, and responding cells were diffusely distributed on the villus surface. Three days after infection, closed intestinal loops from opn-/- mice contained more fluid than loops from controls, although secretion levels at the onset of illness were similar. Null mutant mice experienced more intense and prolonged diarrhea than controls. Rotavirus infection of intestinal epithelial cells and murine intestine caused marked increases in OPN mRNA levels and secreted OPN protein. OPN-deficient mice suffered prolonged disease.

  4. Role of Fc Gamma Receptors in Triggering Host Cell Activation and Cytokine Release by Borrelia burgdorferi

    PubMed Central

    Talkington, Jeffrey; Nickell, Steven P.

    2001-01-01

    Borrelia burgdorferi, the spirochetal bacterium that causes human Lyme disease, encodes numerous lipoproteins which have the capacity to trigger the release of proinflammatory cytokines from a variety of host cell types, and it is generally believed that these cytokines contribute to the disease process in vivo. We previously reported that low-passage-number infectious B. burgdorferi spirochetes express a novel lipidation-independent activity which induces secretion of the proinflammatory cytokine tumor necrosis factor alpha (TNF-α) by the mouse MC/9 mast cell line. Using RNase protection assays, we determined that mast cells exposed in vitro to low-passage-number, but not high-passage-number, B. burgdorferi spirochetes show increased expression of additional mRNAs representing several chemokines, including macrophage-inflammatory protein 1α (MIP-1α), MIP-1β, and TCA3, as well as the proinflammatory cytokine interleukin-6. Furthermore, mast cell TNF-α secretion can be inhibited by the phosphatidylinositol 3-kinase inhibitor wortmannin and also by preincubation with purified mouse immunoglobulin G1 (IgG1) and IgG2a, but not mouse IgG3, and by a mouse Fc gamma receptor II and III (FcγRII/III)-specific rat monoclonal antibody, suggesting the likely involvement of host FcγRIII in B. burgdorferi-mediated signaling. A role for passively adsorbed rabbit or bovine IgG or serum components in B. burgdorferi-mediated FcγR signaling was excluded in control experiments. These studies confirm that low-passage-number B. burgdorferi spirochetes express a novel activity which upregulates the expression of a variety of host cell chemokine and cytokine genes, and they also establish a novel antibody-independent role for FcγRs in transduction of activation signals by bacterial products. PMID:11119532

  5. T-cell immunity and cytokine production in cosmonauts after long-duration space flights

    NASA Astrophysics Data System (ADS)

    Morukov, B.; Rykova, M.; Antropova, E.; Berendeeva, T.; Ponomaryov, S.; Larina, I.

    2011-04-01

    Long-duration spaceflight effects on T-cell immunity and cytokine production were studied in 12 Russian cosmonauts flown onto the International Space Station. Specific assays were performed before launch and after landing and included analysis of peripheral leukocyte distribution, analysis of T-cell phenotype, expression of activation markers, apoptosis, proliferation of T cells in response to a mitogen, concentrations of cytokines in supernatants of cell cultures. Statistically significant increase was observed in leukocytes', lymphocytes', monocytes' and granulocytes' total number, increase in percentage and absolutely number of CD3 +CD4 +-cells, CD4 +CD45RA +-cells and CD4 +CD45RA +/CD4 +CD45RО + ratio, CD4 +CD25 +Bright regulatory cells ( p<0,05) in peripheral blood after landing. T-lymphocytes' capacity to present CD69 and CD25 on its own surfaces was increased for the majority of crewmembers. Analysis of T-cell response to PHA-stimulation in vitro revealed there were some trends toward reduced proliferation of stimulated T-lymphocytes. There was an apparent post flight decrease in secreted IFN-g for the majority of crewmembers and in most instances there was elevation in secreted IL-10. It revealed depression of IFN-g/IL-10 ratio after flight. Correlation analysis according to Spearman's rank correlation test established significant positive correlations ( p<0.05) between cytokine production and T-cell activation (CD25+, CD38+) and negative correlation ( p<0.05) between cytokine production and number of bulk memory CD4+T-cells (CD45RO+). Thus, these results suggest that T-cell dysfunction can be conditioned by cytokine dysbalance and could lead to development of disease after long-duration space flights.

  6. [Emotion Disorders and Abnormal Perspiration].

    PubMed

    Umeda, Satoshi

    2016-08-01

    This article reviewed the relationship between emotional disorders and abnormal perspiration. First, I focused on local brain areas related to emotional processing, and summarized the functions of the emotional network involving those local areas. Functional disorders followed by the damage in the amygdala, orbitofrontal cortex, and insular cortex were reviewed, including related abnormal perspiration. I then addressed the mechanisms of how autonomic disorders influence emotional processing. Finally, possible future directions for integrated understanding of the connection between neural activities and bodily reactions were discussed. PMID:27503817

  7. [Emotion Disorders and Abnormal Perspiration].

    PubMed

    Umeda, Satoshi

    2016-08-01

    This article reviewed the relationship between emotional disorders and abnormal perspiration. First, I focused on local brain areas related to emotional processing, and summarized the functions of the emotional network involving those local areas. Functional disorders followed by the damage in the amygdala, orbitofrontal cortex, and insular cortex were reviewed, including related abnormal perspiration. I then addressed the mechanisms of how autonomic disorders influence emotional processing. Finally, possible future directions for integrated understanding of the connection between neural activities and bodily reactions were discussed.

  8. [Cytokines and the nervous system: the relationship between seizures and epilepsy].

    PubMed

    Velasco-Ramirez, S F; Rosales-Rivera, L Y; Ramirez-Anguiano, A C; Bitzer-Quintero, O K

    2013-08-16

    INTRODUCTION. The immune system and the peripheral and central nervous system are in constant communication by means of messengers and signalling molecules released, such as cytokines, neuropeptides, neurohormones and neurotransmitters, among others. Seizures are defined as the transitory appearance of signs and symptoms that trigger an abnormally excessive neuronal activity in the brain. Following seizures the generation of a neuroinflammatory process has been observed to occur, with the consequent release of proinflammatory cytokines and inflammation-mediating molecules, which make the patient more prone to epilepsy. AIM. To offer evidence suggesting and supporting the role of cytokines in the appearance of seizures and in epilepsy, since these molecules have proven to have dual properties. DEVELOPMENT. The central nervous system, by means of the blood-brain barrier, restricts the flow of activated cells and inflammation mediators released from the peripheral system towards the brain parenchyma. Moreover, there is also another series of mechanisms that contributes to the 'selective and modified' immunity of the central nervous system. The purpose of all this series of events is to limit the responses of the immune system at central level, although it has been shown that in the central nervous system they are permanently under the control and regulation of the immune system. CONCLUSIONS. Cytokines in epilepsy play a dual role with pro- and anti-convulsive properties. Seizures do not induce the expression of cytokines only inside the brain, but also peripherally.

  9. Study Guide: Seven Simple Secrets

    ERIC Educational Resources Information Center

    Satterfield, Nancy; Breaux, Annette; Whitaker, Todd

    2007-01-01

    This study guide has been developed to accompany the "Seven Simple Secrets" book written by Dr. Todd Whitaker and Annette Breaux. "Seven Simple Secrets" focuses on those attributes that have been found to help teachers be their absolute best in their daily challenges of teaching and improving student learning. The study guide is divided into the…

  10. Bacterial Secretion Systems: An Overview.

    PubMed

    Green, Erin R; Mecsas, Joan

    2016-02-01

    Bacterial pathogens utilize a multitude of methods to invade mammalian hosts, damage tissue sites, and thwart the immune system from responding. One essential component of these strategies for many bacterial pathogens is the secretion of proteins across phospholipid membranes. Secreted proteins can play many roles in promoting bacterial virulence, from enhancing attachment to eukaryotic cells, to scavenging resources in an environmental niche, to directly intoxicating target cells and disrupting their functions. Many pathogens use dedicated protein secretion systems to secrete virulence factors from the cytosol of the bacteria into host cells or the host environment. In general, bacterial protein secretion apparatuses can be divided into classes, based on their structures, functions, and specificity. Some systems are conserved in all classes of bacteria and secrete a broad array of substrates, while others are only found in a small number of bacterial species and/or are specific to only one or a few proteins. In this chapter, we review the canonical features of several common bacterial protein secretion systems, as well as their roles in promoting the virulence of bacterial pathogens. Additionally, we address recent findings that indicate that the innate immune system of the host can detect and respond to the presence of protein secretion systems during mammalian infection.

  11. Targeted cytokine delivery to neuroblastoma.

    PubMed

    Dehal, P K; Embleton, M J; Kemshead, J T; Hawkins, R E

    2002-08-01

    The aim of this study was to construct a fusion protein from the cytokine granulocyte/macrophage colony-stimulating factor (GM-CSF) and a single-chain Fv fragment (scFv D29) and to investigate its potential to activate cells of the immune system against neuroblastoma cells expressing neural cell adhesion molecule (NCAM). Mammalian cell expression of the scFv D29-GM-CSF fusion protein was compared using a number of vectors, including retroviral and adenoviral vectors. The resultant fusion protein, expressed by HeLa cells, was found by ELISA to bind immobilized recombinant NCAM. Moreover, FACS analysis confirmed binding to the human neuroblastoma cell line SKNBE and a murine neuroblastoma cell line engineered to express the glycosylphosphatidylinositol form of human NCAM (N2A-rKNIE). The fusion protein was also found to stimulate the proliferation of the FDC-P1 haemopoietic cell line, which is dependent on GM-CSF (or interleukin 3) for continued growth. In vitro clonogenic assays indicated that scFv-GM-CSF could selectively induce growth inhibition of SKNBE cells by murine lymphoid cells.

  12. Inflammatory cytokines in newborn infants.

    PubMed Central

    Sarandakou, A; Giannaki, G; Malamitsi-Puchner, A; Rizos, D; Hourdaki, E; Protonotariou, E; Phocas, I

    1998-01-01

    Serum levels of IL-1beta, IL-6 and TNF-alpha were measured in 48 healthy, termed neonates on the 1st (N1), 5th (N5) and 40th (N40) day after birth, compared with those in maternal serum (MS), umbilical cord (UC) and adult controls. Cytokine values in N1 and N5 were significantly elevated, than those in UC and in controls (P<0.0001). IL-1beta and IL-6 declined significantly from N1 to N40 (P<0.0001), while TNF-alpha increased significantly from N1 to N5 and declined thereafter. MS infinity IL-1beta and IL-6, but not MS infinity TNF-alpha, were significantly higher than those of controls (P<0.0001). IL-1beta values depended on the mode of delivery. In conclusion, the increased concentrations of IL-1beta, IL-6 and TNF-alpha during the perinatal period might suggest their involvement in an inflammation-like process during normal parturition, and reflect also a newborn immune response to the stress of delivery and environmental changes. PMID:9883964

  13. Inflammatory cytokines in newborn infants.

    PubMed

    Sarandakou, A; Giannaki, G; Malamitsi-Puchner, A; Rizos, D; Hourdaki, E; Protonotariou, E; Phocas, I

    1998-01-01

    Serum levels of IL-1beta, IL-6 and TNF-alpha were measured in 48 healthy, termed neonates on the 1st (N1), 5th (N5) and 40th (N40) day after birth, compared with those in maternal serum (MS), umbilical cord (UC) and adult controls. Cytokine values in N1 and N5 were significantly elevated, than those in UC and in controls (P<0.0001). IL-1beta and IL-6 declined significantly from N1 to N40 (P<0.0001), while TNF-alpha increased significantly from N1 to N5 and declined thereafter. MS infinity IL-1beta and IL-6, but not MS infinity TNF-alpha, were significantly higher than those of controls (P<0.0001). IL-1beta values depended on the mode of delivery. In conclusion, the increased concentrations of IL-1beta, IL-6 and TNF-alpha during the perinatal period might suggest their involvement in an inflammation-like process during normal parturition, and reflect also a newborn immune response to the stress of delivery and environmental changes.

  14. Modulation of cytokine production by carnitine

    PubMed Central

    De Simone, Claudio

    1993-01-01

    The ability of carnitine congeners to modulate cytokine production by human peripheral blood mononuclear cells (PBMC) was investigated. Modulation of cytokine production by PBMC of young (30 years of age or younger) and old (70 years of age or older) normal donors was first compared. The PBMC were collected over Ficoll–Hypaque and incubated in the presence of various concentrations of acetyl L-carnitine for 24 h. Subsequently the supernatants were collected and examined for cytokine production. The presence of cytokines in tissue culture supernatants was examined by ELISA. The cytokines measured included IL-1α, IL-1β, IL-2, IL-4, IL-6, TNFα, GM–CSF, and IFNγ. The results showed that at 50 μg/ml of acetyl L-carnitine the most significant response was obtained for TNFα. In this regard four of five young donors responded, but only one of five old donors responded. More recently these studies were expanded to examine the ability of L-carnitine to modulate cytokine production at higher doses, 200 and 400 μg/ml, in young donors. The results of these studies showed that in addition to TNFα, significant production of IL-1β and IL-6 was observed. These preliminary studies provide evidence that carnitine may modulate immune functions through the production of selected cytokines. PMID:18475565

  15. Electrocardiograph abnormalities in intracerebral hemorrhage.

    PubMed

    Takeuchi, Satoru; Nagatani, Kimihiro; Otani, Naoki; Wada, Kojiro; Mori, Kentaro

    2015-12-01

    This study investigated the prevalence and type of electrocardiography (ECG) abnormalities, and their possible association with the clinical/radiological findings in 118 consecutive patients with non-traumatic, non-neoplastic intracerebral hemorrhage (ICH). ECG frequently demonstrates abnormalities in patients with ischemic stroke and subarachnoid hemorrhage, but little is known of ECG changes in ICH patients. Clinical and radiological information was retrospectively reviewed. ECG recordings that were obtained within 24 hours of the initial hemorrhage were analyzed. Sixty-six patients (56%) had one or more ECG abnormalities. The most frequent was ST depression (24%), followed by left ventricular hypertrophy (20%), corrected QT interval (QTc) prolongation (19%), and T wave inversion (19%). The logistic regression analysis demonstrated the following: insular involvement was an independent predictive factor of ST depression (p<0.001; odds ratio OR 10.18; 95% confidence interval [CI] 2.84-36.57); insular involvement (p<0.001; OR 23.98; 95% CI 4.91-117.11) and presence of intraventricular hemorrhage (p<0.001; OR 8.72; 95% CI 2.69-28.29) were independent predictive factors of QTc prolongation; deep hematoma location (p<0.001; OR 19.12; 95% CI 3.82-95.81) and hematoma volume >30 ml (p=0.001; OR 6.58; 95% CI 2.11-20.46) were independent predictive factors of T wave inversion. We demonstrate associations between ECG abnormalities and detailed characteristics of ICH.

  16. Cytokine medicines in clinical practice: current issues.

    PubMed

    Barnes, Theresa; Moots, Robert J; Goodacre, John

    2005-10-21

    Cytokine medicines have been licensed for the treatment of rheumatoid arthritis since 2000. The rheumatology community has accrued a large amount of experience in the use of these medications. This experience has led to the development of guidelines for their use that include ongoing vigilance for long term adverse events and efficacy using the Biologics Register. Delivery of these expensive therapies has prompted extensive system developments within rheumatology. The cytokine medicines have provided important tools to probe the pathogenesis of rheumatoid and other inflammatory diseases. Further cytokine medicines, in various stages of development, are on the horizon and continue to stimulate excitement within this fast expanding field.

  17. Spontaneous secretion of interferon γ and interleukin 4 by human intraepithelial and lamina propria gut lymphocytes

    PubMed Central

    Carol, M; Lambrechts, A; Van Gossum, A; Libin, M; Goldman, M; Mascart-Lemone, F

    1998-01-01

    Background—Cytokines secreted by intestinal T lymphocytes probably play a critical role in regulation of the gut associated immune responses. 
Aims—To quantify interferon γ (IFN-γ) and interleukin 4 (IL-4) secreting cells (SC) among human intraepithelial (IEL) and lamina propria (LPL) lymphocytes from the duodenum and right colon in non-pathological situations and in the absence of in vitro stimulation. 
Patients—Duodenal and right colonic biopsy specimens were obtained from patients with no inflammation of the intestinal mucosa. 
Methods—Intraepithelial and lamina propria cell suspensions were assayed for numbers of cells spontaneously secreting IFN-γ and IL-4 by a two site reverse enzyme linked immunospot technique (ELISPOT). 
Results—The relatively high proportion of duodenal lymphocytes spontaneously secreting IFN-γ (IEL 3.6%; LPL 1.9%) and IL-4 (IEL 1.3%; LPL 0.7%) contrasted with the very low numbers of spontaneously IFN-γ SC and the absence of spontaneously IL-4 SC among peripheral blood mononuclear cells. In the basal state, both IFN-γ and IL-4 were mainly produced by CD4+ cells. Within the colon, only 0.2% of IEL and LPL secreted IFN-γ in the basal state, and 0.1% secreted IL-4. 
Conclusions—Compared with peripheral lymphocytes substantial proportions of intestinal epithelial and lamina propria lymphocytes spontaneously secrete IFN-γ and/or IL-4. These cytokines are probably involved in the normal homoeostasis of the human intestinal mucosa. Disturbances in their secretion could play a role in the pathogenesis of gastrointestinal diseases. 

 Keywords: intestinal lymphocytes; ELISPOT; interferon γ; interleukin 4 PMID:9659157

  18. Cytokine-Defined B Cell Responses as Therapeutic Targets in Multiple Sclerosis

    PubMed Central

    Li, Rui; Rezk, Ayman; Healy, Luke M.; Muirhead, Gillian; Prat, Alexandre; Gommerman, Jennifer L.; Bar-Or, Amit

    2016-01-01

    Important antibody-independent pathogenic roles of B cells are emerging in autoimmune diseases, including multiple sclerosis (MS). The contrasting results of different treatments targeting B cells in patients (in spite of predictions of therapeutic benefits from animal models) call for a better understanding of the multiple roles that distinct human B cell responses likely play in MS. In recent years, both murine and human B cells have been identified with distinct functional properties related to their expression of particular cytokines. These have included regulatory (Breg) B cells (secreting interleukin (IL)-10 or IL-35) and pro-inflammatory B cells (secreting tumor necrosis factor α, LTα, IL-6, and granulocyte macrophage colony-stimulating factor). Better understanding of human cytokine-defined B cell responses is necessary in both health and diseases, such as MS. Investigation of their surface phenotype, distinct functions, and the mechanisms of regulation (both cell intrinsic and cell extrinsic) may help develop effective treatments that are more selective and safe. In this review, we focus on mechanisms by which cytokine-defined B cells contribute to the peripheral immune cascades that are thought to underlie MS relapses, and the impact of B cell-directed therapies on these mechanisms. PMID:26779181

  19. Hypothyroidism affects pulsatile LH secretion in pubertal orchiectomized rats.

    PubMed

    Maia, A L; Favaretto, A L; Carvaho, T L; Rodrigues, J A; Iazigi, N

    1995-08-01

    The present study evaluated the effect of hypothyroidism on the pituitary-testicular axis in rats rendered hypothyroid on the beginning of puberty. Rats were treated with propylthiouracil for 8 weeks and killed for determination of hormonal status and body parameters. For determination of pulsatile LH secretion other animals were orchiectomized two weeks before sampling. Analysis of the results led us to conclude that although the absolute weight of sex organs tended to decrease in hypothyroid animals, the relative weights were equal or higher than control, suggesting that the development of these organs were not affected by hypothyroidism; the androgenic activity of hypothyroid rat testes were preserved; basal plasma levels of pituitary hormones were similar in control and hypothyroid groups; the pulsatile LH secretion showed a decrease in the number of pulses, nadir mean and total LH secretion in hypothyroid animals. Our results demonstrate that although hypothalamic-pituitary axis of hypothyroid pubertal rats displays an abnormal pulsation LH release, no evidences of abnormalities in the reproductive system functions were found.

  20. Unconventional Protein Secretion in Plants.

    PubMed

    Davis, Destiny J; Kang, Byung-Ho; Heringer, Angelo S; Wilkop, Thomas E; Drakakaki, Georgia

    2016-01-01

    Unconventional protein secretion (UPS) describes secretion pathways that bypass one or several of the canonical secretion pit-stops on the way to the plasma membrane, and/or involve the secretion of leaderless proteins. So far, alternatives to conventional secretion were primarily observed and studied in yeast and animal cells. The sessile lifestyle of plants brings with it unique restraints on how they adapt to adverse conditions and environmental challenges. Recently, attention towards unconventional secretion pathways in plant cells has substantially increased, with the large number of leaderless proteins identified through proteomic studies. While UPS pathways in plants are certainly not yet exhaustively researched, an emerging notion is that induction of UPS pathways is correlated with pathogenesis and stress responses. Given the multitude UPS events observed, comprehensively organizing the routes proteins take to the apoplast in defined UPS categories is challenging. With the establishment of a larger collection of studied plant proteins taking these UPS pathways, a clearer picture of endomembrane trafficking as a whole will emerge. There are several novel enabling technologies, such as vesicle proteomics and chemical genomics, with great potential for dissecting secretion pathways, providing information about the cargo that travels along them and the conditions that induce them. PMID:27665550

  1. Cytokines profile and peripheral blood mononuclear cells morphology in Rett and autistic patients.

    PubMed

    Pecorelli, Alessandra; Cervellati, Franco; Belmonte, Giuseppe; Montagner, Giulia; Waldon, PhiAnh; Hayek, Joussef; Gambari, Roberto; Valacchi, Giuseppe

    2016-01-01

    A potential role for immune dysfunction in autism spectrum disorders (ASD) has been well established. However, immunological features of Rett syndrome (RTT), a genetic neurodevelopmental disorder closely related to autism, have not been well addressed yet. By using multiplex Luminex technology, a panel of 27 cytokines and chemokines was evaluated in serum from 10 RTT patients with confirmed diagnosis of MECP2 mutation (typical RTT), 12 children affected by classic autistic disorder and 8 control subjects. The cytokine/chemokine gene expression was assessed by real time PCR on mRNA of isolated peripheral blood mononuclear cells (PBMCs). Moreover, ultrastructural analysis of PBMCs was performed using transmission electron microscopy (TEM). Significantly higher serum levels of interleukin-8 (IL-8), IL-9, IL-13 were detected in RTT compared to control subjects, and IL-15 shows a trend toward the upregulation in RTT. In addition, IL-1β and VEGF were the only down-regulated cytokines in autistic patients with respect to RTT. No difference in cytokine/chemokine profile between autistic and control groups was detected. These data were also confirmed by ELISA real time PCR. At the ultrastructural level, the most severe morphological abnormalities were observed in mitochondria of both RTT and autistic PBMCs. In conclusion, our study shows a deregulated cytokine/chemokine profile together with morphologically altered immune cells in RTT. Such abnormalities were not quite as evident in autistic subjects. These findings indicate a possible role of immune dysfunction in RTT making the clinical features of this pathology related also to the immunology aspects, suggesting, therefore, novel possible therapeutic interventions for this disorder.

  2. Secret key generation via a modified quantum secret sharing protocol

    NASA Astrophysics Data System (ADS)

    Smith, A. M.; Evans, P. G.; Lawrie, B.; Legré, M.; Lougovski, P.; Ray, W.; Williams, B. P.; Qi, B.; Grice, W. P.

    2015-05-01

    We present and experimentally show a novel protocol for distributing secret information between two and only two parties in a N-party single-qubit Quantum Secret Sharing (QSS) system. We demonstrate this new algorithm with N = 3 active parties over ~6km of telecom. fiber. Our experimental device is based on the Clavis2 Quantum Key Distribution (QKD) system built by ID Quantique but is generalizable to any implementation. We show that any two out of the N parties can build secret keys based on partial information from each other and with collaboration from the remaining N - 2 parties. This algorithm allows for the creation of two-party secret keys were standard QSS does not and significantly reduces the number of resources needed to implement QKD on a highly connected network such as the electrical grid.

  3. Secret Key Generation via a Modified Quantum Secret Sharing Protocol

    SciTech Connect

    Smith IV, Amos M; Evans, Philip G; Lawrie, Benjamin J; Legre, Matthieu; Lougovski, Pavel; Ray, William R; Williams, Brian P; Qi, Bing; Grice, Warren P

    2015-01-01

    We present and experimentally show a novel protocol for distributing secret information between two and only two parties in a N-party single-qubit Quantum Secret Sharing (QSS) system. We demonstrate this new algorithm with N = 3 active parties over 6km of telecom. ber. Our experimental device is based on the Clavis2 Quantum Key Distribution (QKD) system built by ID Quantique but is generalizable to any implementation. We show that any two out of the N parties can build secret keys based on partial information from each other and with collaboration from the remaining N > 2 parties. This algorithm allows for the creation of two-party secret keys were standard QSS does not and signicantly reduces the number of resources needed to implement QKD on a highly connected network such as the electrical grid.

  4. [Targeted therapy in inflammatory disease: cytokines].

    PubMed

    von Frenckell, C; Malaise, M G

    2012-01-01

    Summarizing 15 years of therapeutic development of a discipline into a few lines is not an easy thing to do. There are many potential targets involved in the inflammatory of auto-immune diseases. Due to the development of biotherapies the choice has become larger, and it is now possible to target practically any molecule (cytokine, chemokine or surface receptor for example). Cytokines represent the first example of therapeutic target that played a major role in the revolution of our discipline. The first part of presentation will focus on the pro-inflammatory cytokines (TNFalpha, and interleukines 1 and 6). We shall then, detail the development of a new cytokinic target: BLyS (B lymphocyte stimulator) whose role in the autoimmune diseases appeared recently.

  5. Dynamical Systems, Cytokine Storms, and Blood Filtration

    NASA Astrophysics Data System (ADS)

    Foster, Glenn; Hubler, Alfred

    2008-03-01

    Various infections and non-infectious diseases can trigger immune cells and the proteins (cytokines) the cells use to communicate with each other to be caught in a positive feedback loop; this ``cytokine storm'' is frequently fatal. By examining the network of cytokine-immune cell interactions we will illustrate why anti-mediator drugs have been generally ineffective in stopping this feedback. A more effective approach may be to try and reduce interactions by dampening many signals at once by filtering the cytokines out of the blood directly (think dialysis). We will argue that feedback on an out of control nonlinear dynamical system is easier to understand than its normal healthy state and apply filtration to a toy model of immune response.

  6. Cytokines in neuroblastoma: from pathogenesis to treatment.

    PubMed

    Pistoia, Vito; Bianchi, Giovanna; Borgonovo, Giacomo; Raffaghello, Lizzia

    2011-07-01

    Cytokines released by cancer cells or by cells of the tumor microenvironment stimulate angiogenesis, act as autocrine or paracrine growth factors for malignant cells, promote tumor cell migration and metastasis or create an immunosuppressive microenvironment. These tumor-promoting effects of cytokines also apply to neuroblastoma (NB), a pediatric neuroectodermal malignancy with frequent metastatic presentation at diagnosis and poor prognosis. IL-6 and VEGF are the best characterized cytokines that stimulated tumor growth and metastasis, while others such as IFN-γ can exert anti-NB activity by inducing tumor cell apoptosis and inhibiting angiogenesis. On the other hand, cytokines are part of the anti-NB therapeutic armamentarium, as exemplified by IL-2 and granulocyte-macrophage colony stimulating factor that potentiate the activity of anti-NB antibodies. These recent results raise hope for more efficacious treatment of this ominous pediatric malignancy.

  7. Regulation of autoimmune arthritis by the pro-inflammatory cytokine interferon-γ

    PubMed Central

    Kim, Eugene Y.; Chi, Howard H.; Bouziane, Mohammed; Gaur, Amitabh; Moudgil, Kamal D.

    2008-01-01

    The pathogenesis of T cell-mediated diseases like rheumatoid arthritis (RA) has typically been explained in the context of the Th1-Th2 paradigm: the initiation/propagation by pro-inflammatory cytokines, and downregulation by Th2 cytokines. However, in our study based on the adjuvant-induced arthritis (AA) model of RA, we observed that Lewis (LEW) (RT.1l) rats at the recovery phase of AA showed the highest level of IFN-γ in recall response to mycobacterial heat-shock protein 65 (Bhsp65), whereas AA-resistant Wistar-Kyoto (WKY) (RT.1l) rats secreted high levels of IFN-γ much earlier following disease induction. However, no significant secretion of IL-10 or TGF-β was observed in either strain. Furthermore, pre-treatment of LEW rats with a peptide of self (rat) hsp65 (R465), which induced T cells secreting predominantly IFN-γ, afforded protection against AA and decreased IL-17 expression by the arthritogenic epitope-restimulated T cells. These results provide a novel perspective on the pathogenesis of autoimmune arthritis. PMID:18276192

  8. Anti cytokine therapy in chronic inflammatory arthritis.

    PubMed

    Thompson, Charlotte; Davies, Ruth; Choy, Ernest

    2016-10-01

    This is a review looking at anti cytokine therapy in Rheumatoid Arthritis (RA), Psoriatic Arthritis (PSA) and Ankylosing Spondylitis (AS). The review explores the similarities and differences in the clinical features, as well as treatments and cytokines involved in the development and propagation of the disease. Particular attention is paid to TNFα inhibitors IL-1ra, IL-6 and JAK kinase Inhibitors, anti IL23 and IL-12 and the new developments with anti-IL-17. PMID:27497159

  9. The role of cytokines in cancer.

    PubMed

    Oppenheim, J; Fujiwara, H

    1996-10-01

    The role of cytokines was intensively discussed over the course of a two and a half day meeting sponsored by the US-JAPAN Cancer Cooperative Research Program of the Office of International Affairs, National Cancer Institute and held at The National Institutes of Health, Bethesda, Maryland on 15-17 January 1996. Most of the first day was devoted to a discussion of the role of cytokines in modulating angiogenesis and the consequent effect of this on tumor growth and metastases. This was followed by sessions on the effect of various cytokines in enhancing or suppressing immunological responses to tumors. Several presentations focused on the direct inhibitory or growth promoting effects of cytokines on tumor growth. The final session consisted of a comparison of the efficacy of different approaches to tumor vaccination including gene therapy, enhanced antigen presentation, use of polymeric carriers or of DNA vectors. For background information the reader is referred to appropriate chapters on the role of cytokines in neoplastic diseases (Oppenheim JJ, Rossio JL, Gearing AJH, eds. In Clinical Application of Cytokines: Role of Pathogenesis, Diagnosis and Therapy. Oxford University Press, New York, 1993 [1]).

  10. Cytokine expression in muscle following traumatic injury

    PubMed Central

    Jackson, Wesley M.; Aragon, Amber B.; Onodera, Jun; Koehler, Steven M.; Ji, Youngmi; Bulken-Hoover, Jamie D.; Vogler, Jared A.; Tuan, Rocky S.; Nesti, Leon J.

    2011-01-01

    Heterotopic ossification (HO) occurs at a high frequency in severe orthopaedic extremity injuries; however, the etiology of traumatic HO is virtually unknown. Osteogenic progenitor cells have previously been identified within traumatized muscle. Although the signaling mechanisms that lead to this dysregulated differentiation pathway have not been identified, it is assumed that inflammation and fibrosis, which contribute to an osteoinductive environment, are necessary for the development of HO. The hypothesis of this study was that cytokines related to chronic inflammation, fibrogenesis and osteogenesis become up-regulated following severe muscle trauma where HO forms. Classification of these cytokines by their differential expression relative to control muscle will provide guidance for further study of the mechanisms leading to HO. Real-time RT-PCR analysis revealed no significant up-regulation of cytokines typically associated with HO (e.g., BMP-4, as observed in the genetic form of heterotopic ossification, Fibrodysplasia Ossificans Progressiva). Instead, the cytokine gene expression profile associated with the traumatized muscle included up-regulation of cytokines associated with osteogenesis and fibrosis (i.e., BMP-1 and TGF-beta1). Using immunohistochemistry, these cytokines were localized to fibroproliferative lesions, which have previously been implicated in HO. This study identifies other cell and tissue-level interactions in traumatized muscle that should be investigated further to better define the etiology of HO. PMID:21452302

  11. Serum cytokine changes in systemic vasculitis.

    PubMed Central

    Grau, G E; Roux-Lombard, P; Gysler, C; Lambert, C; Lambert, P H; Dayer, J M; Guillevin, L

    1989-01-01

    Cytokines are known to alter a number of vascular tissue cell functions. The aim of this retrospective study was to determine serum cytokine levels in patients with vasculitis and to analyse the possible relation to the severity of the disease. Tumour necrosis factor alpha (TNF alpha), interleukin-1 (IL-1)beta, IL-2, interferon (IFN)- and IFN-gamma were assayed in 33 patients with polyarteritis nodosa (PAN) or Churg and Strauss angiitis (CSA), and three with Wegener granulomatosis (WG). Serum cytokine changes were observed in most patients with active disease, i.e. before treatment was started. In the majority of patients with PAN or CSA, there was a marked increase in serum IFN-alpha and IL-2 levels, while TNF-alpha and IL-beta levels were moderately elevated. Serum IFN-gamma remained undetectable in all but one of these patients. In patients with WG, serum IFN-alpha and IL-2 levels were also elevated, whereas IL-1 beta, IFN-gamma and TNF alpha levels remained within normal limits. In paired samples of patients with PAN, IFN-alpha and IL-2 levels were significantly higher before than after treatment. These preliminary data suggest that a particular pattern of cytokine changes is associated with vasculitis and that cytokines might be involved in the pathogenesis of PAN/CSA and WG. Prospective studies are warranted to determine whether cytokines could be considered for the monitoring of disease activity and therapy. PMID:2478451

  12. Calcitriol inhibits TNF-alpha-induced inflammatory cytokines in human trophoblasts.

    PubMed

    Díaz, Lorenza; Noyola-Martínez, Nancy; Barrera, David; Hernández, Guillermo; Avila, Euclides; Halhali, Ali; Larrea, Fernando

    2009-07-01

    Elevated placental proinflammatory cytokine release is associated with miscarriage, preterm labor and preeclampsia. Specifically, tumor necrosis factor-alpha (TNF-alpha)-induced cytokines may threaten pregnancy outcome. Since trophoblasts produce calcitriol, a hormone with strong immunosuppressive properties, we assessed the effects of this secosteroid on inflammatory cytokines induced in trophoblasts by challenge with TNF-alpha. The effects of calcitriol on synthesis of mRNAs encoding interleukin-6 (IL-6), interferon-gamma (IFN-gamma), and TNF-alpha were measured by real time RT-PCR. Secreted cytokines were quantified by ELISA. The effects of TNF-alpha on CYP24A1, chorionic gonadotropin (hCG), 3beta-hydroxysteroid dehydrogenase (HSD3B1) and P(450)-aromatase (CYP19) mRNA expression were also studied. TNF-alpha stimulated IL-6, IFN-gamma and its own expression more than 3-fold over controls (P<0.05). Calcitriol inhibited the expression profile of inflammatory cytokine genes in a dose-response manner (P<0.05). This effect was prevented by addition of the vitamin D receptor antagonist TEI-9647. TNF-alpha also significantly inhibited expression of hCG, HSD3B1 and CYP19 genes, and stimulated CYP24A1 gene expression. These data show that calcitriol prevents TNF-alpha induction of inflammatory cytokines through a process likely to be mediated by the vitamin D receptor. We conclude that TNF-alpha inhibits placental hormone synthesis and stimulates calcitriol catabolism by regulating enzymes involved in these processes.

  13. Multiplex Immunoassay of Plasma Cytokine Levels in Men with Alcoholism and the Relationship to Psychiatric Assessments.

    PubMed

    Manzardo, Ann M; Poje, Albert B; Penick, Elizabeth C; Butler, Merlin G

    2016-01-01

    Chronic alcohol use alters adaptive immunity and cytokine activity influencing immunological and hormone responses, inflammation, and wound healing. Brain cytokine disturbances may impact neurological function, mood, cognition and traits related to alcoholism including impulsiveness. We examined the relationship between plasma cytokine levels and self-rated psychiatric symptoms in 40 adult males (mean age 51 ± 6 years; range 33-58 years) with current alcohol dependence and 30 control males (mean age 48 ± 6 years; range 40-58 years) with no history of alcoholism using multiplex sandwich immunoassays with the Luminex magnetic-bead based platform. Log-transformed cytokine levels were analyzed for their relationship with the Symptom Checklist-90R (SCL-90R), Barratt Impulsivity Scales (BIS) and Alcoholism Severity Scale (ASS). Inflammatory cytokines (interferon γ-induced protein-10 (IP-10); monocyte chemoattractant protein-1 (MCP1); regulated on activation, normal T cell expressed and secreted (RANTES)) were significantly elevated in alcoholism compared to controls while bone marrow-derived hematopoietic cytokines and chemokines (granulocyte-colony stimulating factor (GCSF); soluble CD40 ligand (sCD40L); growth-related oncogene (GRO)) were significantly reduced. GRO and RANTES levels were positively correlated with BIS scales; and macrophage-derived chemokine (MDC) levels were positively correlated with SCL-90R scale scores (p < 0.05). Elevated inflammatory mediators in alcoholism may influence brain function leading to increased impulsiveness and/or phobia. The novel association between RANTES and GRO and impulsivity phenotype in alcoholism should be further investigated in alcoholism and psychiatric conditions with core impulsivity and anxiety phenotypes lending support for therapeutic intervention. PMID:27043532

  14. Multiplex Immunoassay of Plasma Cytokine Levels in Men with Alcoholism and the Relationship to Psychiatric Assessments

    PubMed Central

    Manzardo, Ann M.; Poje, Albert B.; Penick, Elizabeth C.; Butler, Merlin G.

    2016-01-01

    Chronic alcohol use alters adaptive immunity and cytokine activity influencing immunological and hormone responses, inflammation, and wound healing. Brain cytokine disturbances may impact neurological function, mood, cognition and traits related to alcoholism including impulsiveness. We examined the relationship between plasma cytokine levels and self-rated psychiatric symptoms in 40 adult males (mean age 51 ± 6 years; range 33–58 years) with current alcohol dependence and 30 control males (mean age 48 ± 6 years; range 40–58 years) with no history of alcoholism using multiplex sandwich immunoassays with the Luminex magnetic-bead based platform. Log-transformed cytokine levels were analyzed for their relationship with the Symptom Checklist-90R (SCL-90R), Barratt Impulsivity Scales (BIS) and Alcoholism Severity Scale (ASS). Inflammatory cytokines (interferon γ-induced protein-10 (IP-10); monocyte chemoattractant protein-1 (MCP1); regulated on activation, normal T cell expressed and secreted (RANTES)) were significantly elevated in alcoholism compared to controls while bone marrow-derived hematopoietic cytokines and chemokines (granulocyte-colony stimulating factor (GCSF); soluble CD40 ligand (sCD40L); growth-related oncogene (GRO)) were significantly reduced. GRO and RANTES levels were positively correlated with BIS scales; and macrophage-derived chemokine (MDC) levels were positively correlated with SCL-90R scale scores (p < 0.05). Elevated inflammatory mediators in alcoholism may influence brain function leading to increased impulsiveness and/or phobia. The novel association between RANTES and GRO and impulsivity phenotype in alcoholism should be further investigated in alcoholism and psychiatric conditions with core impulsivity and anxiety phenotypes lending support for therapeutic intervention. PMID:27043532

  15. Airway acidification initiates host defense abnormalities in cystic fibrosis mice

    PubMed Central

    Shah, Viral S.; Meyerholz, David K.; Tang, Xiao Xiao; Reznikov, Leah; Alaiwa, Mahmoud Abou; Ernst, Sarah E.; Karp, Philip H.; Wohlford-Lenane, Christine L.; Heilmann, Kristopher P.; Leidinger, Mariah R.; Allen, Patrick D.; Zabner, Joseph; McCray, Paul B.; Ostedgaard, Lynda S.; Stoltz, David A.; Randak, Christoph O.; Welsh, Michael J.

    2016-01-01

    Cystic fibrosis (CF) is caused by mutations in the gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. In humans and pigs, the loss of CFTR impairs respiratory host defenses, causing airway infection. But CF mice are spared. We found that in all three species, CFTR secreted bicarbonate into airway surface liquid. In humans and pigs lacking CFTR, unchecked H+ secretion by the nongastric H+/K+ adenosine triphosphatase (ATP12A) acidified airway surface liquid, which impaired airway host defenses. In contrast, mouse airways expressed little ATP12A and secreted minimal H+; consequently, airway surface liquid in CF and non-CF mice had similar pH. Inhibiting ATP12A reversed host defense abnormalities in human and pig airways. Conversely, expressing ATP12A in CF mouse airways acidified airway surface liquid, impaired defenses, and increased airway bacteria. These findings help explain why CF mice are protected from infection and nominate ATP12A as a potential therapeutic target for CF. PMID:26823428

  16. Elevated peripheral cytokines characterize a subgroup of people with schizophrenia displaying poor verbal fluency and reduced Broca's area volume.

    PubMed

    Fillman, S G; Weickert, T W; Lenroot, R K; Catts, S V; Bruggemann, J M; Catts, V S; Weickert, C S

    2016-08-01

    Previous studies on schizophrenia have detected elevated cytokines in both brain and blood, suggesting neuroinflammation may contribute to the pathophysiology in some cases. We aimed to determine the extent to which elevated peripheral cytokine messenger RNA (mRNA) expression: (1) characterizes a subgroup of people with schizophrenia and (2) shows a relationship to cognition, brain volume and/or symptoms. Forty-three outpatients with schizophrenia or schizoaffective disorder and matched healthy controls were assessed for peripheral cytokine mRNAs (interleukin (IL)-1β, IL-2, IL-6, IL-8 and IL-18), intelligence quotient, memory and verbal fluency, symptom severity and cortical brain volumes integral to language (that is, Broca's and Wernicke's areas). IL-1β mRNA levels were 28% increased in schizophrenia compared with controls (t(82)=2.64, P<0.01). Using a two-step clustering procedure, we identified a subgroup of people displaying relatively elevated cytokine mRNA levels (17/43 people with schizophrenia and 9/42 controls). Individuals with schizophrenia in the elevated cytokine subgroup performed significantly worse than the low-cytokine subgroup on verbal fluency (F(1,40)=15.7, P<0.001). There was a 17% volume reduction of the left pars opercularis (POp) (Broca's area) in patients with elevated cytokines compared with patients with lower cytokines (F(1,29)=9.41, P=0.005). Negative linear relationships between IL-1β mRNA levels and both verbal fluency and left POp volume were found in schizophrenia. This study is among the first to link blood biomarkers of inflammation with both cognitive deficits and brain volume reductions in people with schizophrenia, supporting that those with elevated cytokines represent a neurobiologically meaningful subgroup. These findings raise the possibility that targeted anti-inflammatory treatments may ameliorate cognitive and brain morphological abnormalities in some people with schizophrenia. PMID:26194183

  17. Elevated peripheral cytokines characterize a subgroup of people with schizophrenia displaying poor verbal fluency and reduced Broca's area volume

    PubMed Central

    Fillman, S G; Weickert, T W; Lenroot, R K; Catts, S V; Bruggemann, J M; Catts, V S; Weickert, C S

    2016-01-01

    Previous studies on schizophrenia have detected elevated cytokines in both brain and blood, suggesting neuroinflammation may contribute to the pathophysiology in some cases. We aimed to determine the extent to which elevated peripheral cytokine messenger RNA (mRNA) expression: (1) characterizes a subgroup of people with schizophrenia and (2) shows a relationship to cognition, brain volume and/or symptoms. Forty-three outpatients with schizophrenia or schizoaffective disorder and matched healthy controls were assessed for peripheral cytokine mRNAs (interleukin (IL)-1β, IL-2, IL-6, IL-8 and IL-18), intelligence quotient, memory and verbal fluency, symptom severity and cortical brain volumes integral to language (that is, Broca's and Wernicke's areas). IL-1β mRNA levels were 28% increased in schizophrenia compared with controls (t(82)=2.64, P<0.01). Using a two-step clustering procedure, we identified a subgroup of people displaying relatively elevated cytokine mRNA levels (17/43 people with schizophrenia and 9/42 controls). Individuals with schizophrenia in the elevated cytokine subgroup performed significantly worse than the low-cytokine subgroup on verbal fluency (F(1,40)=15.7, P<0.001). There was a 17% volume reduction of the left pars opercularis (POp) (Broca's area) in patients with elevated cytokines compared with patients with lower cytokines (F(1,29)=9.41, P=0.005). Negative linear relationships between IL-1β mRNA levels and both verbal fluency and left POp volume were found in schizophrenia. This study is among the first to link blood biomarkers of inflammation with both cognitive deficits and brain volume reductions in people with schizophrenia, supporting that those with elevated cytokines represent a neurobiologically meaningful subgroup. These findings raise the possibility that targeted anti-inflammatory treatments may ameliorate cognitive and brain morphological abnormalities in some people with schizophrenia. PMID:26194183

  18. Differential expression of cytokines in subcutaneous and marrow fat of aging C57BL/6J mice.

    PubMed

    Gasparrini, Marco; Rivas, Daniel; Elbaz, Alexandre; Duque, Gustavo

    2009-09-01

    Increasing marrow adipogenesis plays a causative role in the pathogenesis of age-related bone loss that could be associated with high cytokine production. In this study, we characterized the age-related changes in cytokine expression by bone marrow (BM) adipocytes as compared with subcutaneous (SC) fat. BM and SC adipocytes were isolated from young (4 months) and old (24 months) male C57BL/6J. Total proteins were extracted and proteomic analysis of 96 cytokines was performed using a cytokine antibody array. Proteins showing a significant change were grouped according with their known function in bone. We found a significant age-induced difference in the expression of 53 cytokines. As compared with SC adipocytes, aging BM adipocytes showed a more pro-adipogenic, anti-osteoblastogenic and pro-apoptotic phenotype. These data suggest that, with aging, BM adipocytes become significantly more toxic than SC adipocytes. These cytokines, if secreted, could play a role in the pathogenesis of age-related bone loss by affecting other cells within the marrow milieu.

  19. [Transient abnormal Q-waves].

    PubMed

    Godballe, C; Hoeck, H C; Sørensen, J A

    1990-01-01

    We present a case of transient abnormal Q-waves (TAQ) and a review of the literature. TAQ are defined as abnormal Q-waves, which disappear within ten days. They are most often seen in patients with ischemic heart disease (IHD) but are also seen in other conditions. Brief episodes of myocardial ischemia giving rise to reversible biochemical and ultrastructural myocardial changes, resulting in transient ECG changes, provide an accepted theory for the pathogenesis of TAO. Investigations have shown that the occurrence of exercise-induced TAQ may be a symptom of IHD. It is impossible to distinguish TAQ from Q-waves induced by myocardial infarction. Appearance of TAQ during exercise-testing frequently indicates IHD. PMID:2301045

  20. [Chromosome abnormalities in human cancer].

    PubMed

    Salamanca-Gómez, F

    1995-01-01

    Recent investigation on the presence of chromosome abnormalities in neoplasias has allowed outstanding advances in the knowledge of malignant transformation mechanisms and important applications in the clinical diagnosis and prognosis of leukaemias, lymphomas and solid tumors. The purpose of the present paper is to discuss the most relevant cytogenetic aberrations, some of them described at the Unidad de Investigación Médica en Genética Humana, Instituto Mexicano del Seguro Social, and to correlate these abnormalities with recent achievements in the knowledge of oncogenes, suppressor genes or antioncogenes, their chromosome localization, and their mutations in human neoplasia; as well as their perspectives in prevention and treatment of cancer that such findings permit to anticipate.

  1. Association of bactericidal activity of genital tract secretions with Escherichia coli colonization in pregnancy

    PubMed Central

    GHARTEY, Jeny P.; CARPENTER, Colleen; GIALANELLA, Philip; RISING, Charlotte; McANDREW, Thomas C.; MHATRE, Mohak; TUGETMAN, Jessica; EINSTEIN, Mark H.; CHAZOTTE, Cynthia; HEROLD, Betsy C.

    2012-01-01

    Objective Genital tract secretions exhibit bactericidal activity against Escherichia coli. We hypothesized that this defense may be modulated during pregnancy. Study Design Secretions were collected by vaginal swab from 70 pregnant women (35–37 weeks gestation) and 35 non-pregnant controls. Escherichia coli were mixed with swab eluants or control buffer and colonies enumerated to measure bactericidal activity. Cytokines, chemokines and antimicrobial peptides were quantified by Luminex or ELISA. Results Pregnant women had significantly greater bactericidal activity, higher concentrations of pro-inflammatory cytokines and lower levels of beta defensins compared to controls. Seven (10%) pregnant and 8 (23%) non-pregnant women were vaginally colonized with Escherichia coli; colonization was inversely associat ed with bactericidal activity. Conclusion The soluble mucosal immune environment is altered in pregnancy. We speculate that the observed changes may protect against colonization and ascending infection and could provide a biomarker to identify pregnant women at risk for infectious complications including preterm birth. PMID:22867687

  2. Glibenclamide reduces pro-inflammatory cytokine production by neutrophils of diabetes patients in response to bacterial infection

    NASA Astrophysics Data System (ADS)

    Kewcharoenwong, Chidchamai; Rinchai, Darawan; Utispan, Kusumawadee; Suwannasaen, Duangchan; Bancroft, Gregory J.; Ato, Manabu; Lertmemongkolchai, Ganjana

    2013-11-01

    Type 2 diabetes mellitus is a major risk factor for melioidosis, which is caused by Burkholderia pseudomallei. Our previous study has shown that polymorphonuclear neutrophils (PMNs) from diabetic subjects exhibited decreased functions in response to B. pseudomallei. Here we investigated the mechanisms regulating cytokine secretion of PMNs from diabetic patients which might contribute to patient susceptibility to bacterial infections. Purified PMNs from diabetic patients who had been treated with glibenclamide (an ATP-sensitive potassium channel blocker for anti-diabetes therapy), showed reduction of interleukin (IL)-1β and IL-8 secretion when exposed to B. pseudomallei. Additionally, reduction of these pro-inflammatory cytokines occurred when PMNs from diabetic patients were treated in vitro with glibenclamide. These findings suggest that glibenclamide might be responsible for the increased susceptibility of diabetic patients, with poor glycemic control, to bacterial infections as a result of its effect on reducing IL-1β production by PMNs.

  3. Ultrasound screening for fetal abnormalities.

    PubMed

    Chitty, L S

    1995-12-01

    Ultrasound screening for fetal abnormalities is increasingly becoming part of routine antenatal care in Europe and the UK. However, there has been very little formal evaluation of this practice. In this article reports of routine ultrasound screening are reviewed and the advantages and disadvantages discussed. The majority of routine anomaly scanning is done in the second trimester but there may be a case for screening at other times in pregnancy and alternative anomaly screening policies are discussed. PMID:8710765

  4. Progesterone inhibits mast cell secretion.

    PubMed

    Vasiadi, M; Kempuraj, D; Boucher, W; Kalogeromitros, D; Theoharides, T C

    2006-01-01

    Mast cells are involved in allergic reactions, where they secrete numerous vasoactive, inflammatory and nociceptive mediators in response to immunoglobulin E (IgE) and antigen. However, they have also been implicated in inflammatory conditions, such as painful bladder syndrome/interstitial cystitis (PBS/IC), irritable bowel syndrome (IBS) and migraines, all of which occur more often in women and are exacerbated during ovulation, but are suppressed during pregnancy. Mast cells express high affinity estrogen receptors and estradiol augments their secretion, while tamoxifen inhibits it. Here we report that progesterone (100 nM), but not the structurally related cholesterol, inhibits histamine secretion from purified rat peritoneal mast cells stimulated immunologically or by substance P (SP), an effect also documented by electron microscopy. These results suggest that mast cell secretion may be regulated by progesterone and may explain the reduced symptoms of certain inflammatory conditions during pregnancy.

  5. Plant secretome: unlocking secrets of the secreted proteins.

    PubMed

    Agrawal, Ganesh Kumar; Jwa, Nam-Soo; Lebrun, Marc-Henri; Job, Dominique; Rakwal, Randeep

    2010-02-01

    Plant secretomics is a newly emerging area of the plant proteomics field. It basically describes the global study of secreted proteins into the extracellular space of plant cell or tissue at any given time and under certain conditions through various secretory mechanisms. A combination of biochemical, proteomics and bioinformatics approaches has been developed to isolate, identify and profile secreted proteins using complementary in vitro suspension-cultured cells and in planta systems. Developed inventories of secreted proteins under normal, biotic and abiotic conditions revealed several different types of novel secreted proteins, including the leaderless secretory proteins (LSPs). On average, LSPs can account for more than 50% of the total identified secretome, supporting, as in other eukaryotes, the existence of novel secretory mechanisms independent of the classical endoplasmic reticulum-Golgi secretory pathway, and suggesting that this non-classical mechanism of protein expression is, for as yet unknown reasons, more massively used than in other eukaryotic systems. Plants LSPs, which seem to be potentially involved in the defense/stress responses, might have dual (extracellular and/or intracellular) roles as most of them have established intracellular functions, yet presently unknown extracellular functions. Evidence is emerging on the role of glycosylation in the apical sorting and trafficking of secretory proteins. These initial secretome studies in plants have considerably advanced our understanding on secretion of different types of proteins and their underlying mechanisms, and opened a door for comparative analyses of plant secretomes with those of other organisms. In this first review on plant secretomics, we summarize and discuss the secretome definition, the applied approaches for unlocking secrets of the secreted proteins in the extracellular fluid, the possible functional significance and secretory mechanisms of LSPs, as well as glycosylation of

  6. Pattern recognition receptor-mediated cytokine response in infants across 4 continents⋆☆

    PubMed Central

    Smolen, Kinga K.; Ruck, Candice E.; Fortuno, Edgardo S.; Ho, Kevin; Dimitriu, Pedro; Mohn, William W.; Speert, David P.; Cooper, Philip J.; Esser, Monika; Goetghebuer, Tessa; Marchant, Arnaud; Kollmann, Tobias R.

    2014-01-01

    Background Susceptibility to infection as well as response to vaccination varies among populations. To date, the underlying mechanisms responsible for these clinical observations have not been fully delineated. Because innate immunity instructs adaptive immunity, we hypothesized that differences between populations in innate immune responses may represent a mechanistic link to variation in susceptibility to infection or response to vaccination. Objective Determine whether differences in innate immune responses exist among infants from different continents of the world. Methods We determined the innate cytokine response following pattern recognition receptor (PRR) stimulation of whole blood from 2-year-old infants across 4 continents (Africa, North America, South America, and Europe). Results We found that despite the many possible genetic and environmental exposure differences in infants across 4 continents, innate cytokine responses were similar for infants from North America, South America, and Europe. However, cells from South African infants secreted significantly lower levels of cytokines than did cells from infants from the 3 other sites, and did so following stimulation of extracellular and endosomal but not cytosolic PRRs. Conclusions Substantial differences in innate cytokine responses to PRR stimulation exist among different populations of infants that could not have been predicted. Delineating the underlying mechanism(s) for these differences will not only aid in improving vaccine-mediated protection but possibly also provide clues for the susceptibility to infection in different regions of the world. PMID:24290283

  7. CRFR1 activation protects against cytokine-induced β-cell death.

    PubMed

    Blaabjerg, Lykke; Christensen, Gitte L; Matsumoto, Masahito; van der Meulen, Talitha; Huising, Mark O; Billestrup, Nils; Vale, Wylie W

    2014-12-01

    During the development of diabetes β-cells are exposed to elevated concentrations of proinflammatory cytokines, TNFα and IL1β, which in vitro induce β-cell death. The class B G-protein-coupled receptors (GPCRs): corticotropin-releasing factor receptor 1 (CRFR1) and CRFR2 are expressed in pancreatic islets. As downstream signaling by other class B GPCRs can protect against cytokine-induced β-cell apoptosis, we evaluated the protective potential of CRFR activation in β-cells in a pro-inflammatory setting. CRFR1/CRFR2 ligands activated AKT and CRFR1 signaling and reduced apoptosis in human islets. In rat and mouse insulin-secreting cell lines (INS-1 and MIN6), CRFR1 agonists upregulated insulin receptor substrate 2 (IRS2) expression, increased AKT activation, counteracted the cytokine-mediated decrease in BAD phosphorylation, and inhibited apoptosis. The anti-apoptotic signaling was dependent on prolonged exposure to corticotropin-releasing factor family peptides and followed PKA-mediated IRS2 upregulation. This indicates that CRFR signaling counteracts proinflammatory cytokine-mediated apoptotic pathways through upregulation of survival signaling in β-cells. Interestingly, CRFR signaling also counteracted basal apoptosis in both cultured INS-1 cells and intact human islets. PMID:25324488

  8. Changes in circulating immunosuppressive cytokine levels of cancer patients after high intensity focused ultrasound treatment.

    PubMed

    Zhou, Qiang; Zhu, Xue-Qiang; Zhang, Jun; Xu, Zhong-Lin; Lu, Pei; Wu, Feng

    2008-01-01

    Immunosuppression in a patient with malignant tumor is a major obstacle in cancer treatment. In this study, we investigated changes in the circulating level of all measured immunosuppressive cytokines in patients with malignancy before and after high intensity focused ultrasound (HIFU) treatment. Fifteen patients with solid malignancy were enrolled in this study and an enzyme-linked immunoabsorbent assay (ELISA) method was used to measure serum level of vascular endothelial growth factor (VEGF), transforming growth factor-beta1 (TGF-beta1), transforming growth factor-beta2 (TGF-beta2), interleukin 6 (IL-6) and interleukin 10 (IL-10), respectively before and 1 wk after HIFU treatment. Among them, seven patients had distant metastasis and the remaining eight had no metastasis. All patients received one-session HIFU treatment for primary cancer, including complete ablation in eight patients without metastasis, and partial ablation in seven patients with metastases. The results showed that serum immunosuppressive cytokine levels decreased after HIFU treatment, and there were significant decreases of VEGF, TGF-beta1, and TGF-beta2 before and after HIFU treatment. Compared with the values in the metastatic patients, serum levels of immunosuppressive cytokines were significantly lower in the nonmetastatic patients after HIFU treatment. It is concluded that HIFU can decrease tumor-secreted immunosuppressive cytokine production in addition to its direct tumor destruction. This change may lessen tumor-induced immunosuppression and renew antitumor immunity after HIFU in cancer patients.

  9. Direct Write Protein Patterns for Multiplexed Cytokine Detection from Live Cells Using Electron Beam Lithography.

    PubMed

    Lau, Uland Y; Saxer, Sina S; Lee, Juneyoung; Bat, Erhan; Maynard, Heather D

    2016-01-26

    Simultaneous detection of multiple biomarkers, such as extracellular signaling molecules, is a critical aspect in disease profiling and diagnostics. Precise positioning of antibodies on surfaces, especially at the micro- and nanoscale, is important for the improvement of assays, biosensors, and diagnostics on the molecular level, and therefore, the pursuit of device miniaturization for parallel, fast, low-volume assays is a continuing challenge. Here, we describe a multiplexed cytokine immunoassay utilizing electron beam lithography and a trehalose glycopolymer as a resist for the direct writing of antibodies on silicon substrates, allowing for micro- and nanoscale precision of protein immobilization. Specifically, anti-interleukin 6 (IL-6) and antitumor necrosis factor alpha (TNFα) antibodies were directly patterned. Retention of the specific binding properties of the patterned antibodies was shown by the capture of secreted cytokines from stimulated RAW 264.7 macrophages. A sandwich immunoassay was employed using gold nanoparticles and enhancement with silver for the detection and visualization of bound cytokines to the patterns by localized surface plasmon resonance detected with dark-field microscopy. Multiplexing with both IL-6 and TNFα on a single chip was also successfully demonstrated with high specificity and in relevant cell culture conditions and at different times after cell stimulation. The direct fabrication of capture antibody patterns for cytokine detection described here could be useful for biosensing applications.

  10. In vivo Cytokine Gene Transfer by Gene Gun Reduces Tumor Growth in Mice

    NASA Astrophysics Data System (ADS)

    Sun, Wenn H.; Burkholder, Joseph K.; Sun, Jian; Culp, Jerilyn; Turner, Joel; Lu, Xing G.; Pugh, Thomas D.; Ershler, William B.; Yang, Ning-Sun

    1995-03-01

    Implantation of tumor cells modified by in vitro cytokine gene transfer has been shown by many investigators to result in potent in vivo antitumor activities in mice. Here we describe an approach to tumor immunotherapy utilizing direct transfection of cytokine genes into tumorbearing animals by particle-mediated gene transfer. In vivo transfection of the human interleukin 6 gene into the tumor site reduced methylcholanthrene-induced fibrosarcoma growth, and a combination of murine tumor necrosis factor α and interferon γ genes inhibited growth of a renal carcinoma tumor model (Renca). In addition, treatment with murine interleukin 2 and interferon γ genes prolonged the survival of Renca tumor-bearing mice and resulted in tumor eradication in 25% of the test animals. Transgene expression was demonstrated in treated tissues by ELISA and immunohistochemical analysis. Significant serum levels of interleukin 6 and interferon γ were detected, demonstrating effective secretion of transgenic proteins from treated skin into the bloodstream. This in vivo cytokine gene therapy approach provides a system for evaluating the antitumor properties of various cytokines in different tumor models and has potential utility for human cancer gene therapy.

  11. Role of Cytokines in Intervertebral Disc Degeneration: Pain and Disc-content

    PubMed Central

    Risbud, Makarand V.; Shapiro, Irving. M

    2014-01-01

    Degeneration of the intervertebral disc is the major contributor to back/neck and radicular pain. It is characterized by an elevation in levels of the inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1 α/β, IL-6 and IL-17 secreted by the disc cells themselves; these cytokines promote matrix degradation, chemokine production and changes in cell phenotype. The resulting imbalance between catabolic and anabolic responses leads to degeneration, as well as herniation and radicular pain. Release of chemokines from degenerating discs promote infiltration and activation of T and B cells, macrophages, neutrophils, and mast cells further amplifying the inflammatory cascade. Immunocyte migration into the disc is accompanied by the appearance of microvasculature and nerve fibers arising from the dorsal root ganglion (DRG). In this inflammatory milieu, neurogenic factors in particular nerve growth factor (NGF) and brain-derive neurotrophic factor (BDNF) generated by disc and immune cells induce expression of pain associated cation channels in DRGs. Depolarization of these channels is likely to promote discogenic and radicular pain and reinforce the cytokine-mediated degenerative cascade. Taken together, the enhanced understanding of the contribution of cytokines and immune cells to catabolic and nociceptive processes provide new targets for treating symptomatic disc disease. PMID:24166242

  12. Nonlinear secret image sharing scheme.

    PubMed

    Shin, Sang-Ho; Lee, Gil-Je; Yoo, Kee-Young

    2014-01-01

    Over the past decade, most of secret image sharing schemes have been proposed by using Shamir's technique. It is based on a linear combination polynomial arithmetic. Although Shamir's technique based secret image sharing schemes are efficient and scalable for various environments, there exists a security threat such as Tompa-Woll attack. Renvall and Ding proposed a new secret sharing technique based on nonlinear combination polynomial arithmetic in order to solve this threat. It is hard to apply to the secret image sharing. In this paper, we propose a (t, n)-threshold nonlinear secret image sharing scheme with steganography concept. In order to achieve a suitable and secure secret image sharing scheme, we adapt a modified LSB embedding technique with XOR Boolean algebra operation, define a new variable m, and change a range of prime p in sharing procedure. In order to evaluate efficiency and security of proposed scheme, we use the embedding capacity and PSNR. As a result of it, average value of PSNR and embedding capacity are 44.78 (dB) and 1.74t⌈log2 m⌉ bit-per-pixel (bpp), respectively.

  13. Nonlinear secret image sharing scheme.

    PubMed

    Shin, Sang-Ho; Lee, Gil-Je; Yoo, Kee-Young

    2014-01-01

    Over the past decade, most of secret image sharing schemes have been proposed by using Shamir's technique. It is based on a linear combination polynomial arithmetic. Although Shamir's technique based secret image sharing schemes are efficient and scalable for various environments, there exists a security threat such as Tompa-Woll attack. Renvall and Ding proposed a new secret sharing technique based on nonlinear combination polynomial arithmetic in order to solve this threat. It is hard to apply to the secret image sharing. In this paper, we propose a (t, n)-threshold nonlinear secret image sharing scheme with steganography concept. In order to achieve a suitable and secure secret image sharing scheme, we adapt a modified LSB embedding technique with XOR Boolean algebra operation, define a new variable m, and change a range of prime p in sharing procedure. In order to evaluate efficiency and security of proposed scheme, we use the embedding capacity and PSNR. As a result of it, average value of PSNR and embedding capacity are 44.78 (dB) and 1.74t⌈log2 m⌉ bit-per-pixel (bpp), respectively. PMID:25140334

  14. Nonlinear Secret Image Sharing Scheme

    PubMed Central

    Shin, Sang-Ho; Yoo, Kee-Young

    2014-01-01

    Over the past decade, most of secret image sharing schemes have been proposed by using Shamir's technique. It is based on a linear combination polynomial arithmetic. Although Shamir's technique based secret image sharing schemes are efficient and scalable for various environments, there exists a security threat such as Tompa-Woll attack. Renvall and Ding proposed a new secret sharing technique based on nonlinear combination polynomial arithmetic in order to solve this threat. It is hard to apply to the secret image sharing. In this paper, we propose a (t, n)-threshold nonlinear secret image sharing scheme with steganography concept. In order to achieve a suitable and secure secret image sharing scheme, we adapt a modified LSB embedding technique with XOR Boolean algebra operation, define a new variable m, and change a range of prime p in sharing procedure. In order to evaluate efficiency and security of proposed scheme, we use the embedding capacity and PSNR. As a result of it, average value of PSNR and embedding capacity are 44.78 (dB) and 1.74t⌈log2⁡m⌉ bit-per-pixel (bpp), respectively. PMID:25140334

  15. METEORIN-LIKE is a cytokine associated with barrier tissues and alternatively activated macrophages

    PubMed Central

    Ushach, Irina; Burkhardt, Amanda M.; Martinez, Cynthia; Hevezi, Peter A.; Gerber, Peter Arne; Buhren, Bettina Alexandra; Schrumpf, Holger; Valle-Rios, Ricardo; Vazquez, Monica I.; Homey, Bernhard; Zlotnik, Albert

    2014-01-01

    Cytokines are involved in many functions of the immune system including initiating, amplifying and resolving immune responses. Through bioinformatics analyses of a comprehensive database of gene expression (BIGE: Body Index of Gene Expression) we observed that a small secreted protein encoded by a poorly characterized gene called meteorin-like (METRNL), is highly expressed in mucosal tissues, skin and activated macrophages. Further studies indicate that Metrnl is produced by Alternatively Activated Macrophages (AAM) and M-CSF cultured bone marrow macrophages (M2-like macrophages). In the skin, METRNL is expressed by resting fibroblasts and IFNγ-treated keratinocytes. A screen of human skin-associated diseases showed significant over-expression of METRNL in psoriasis, prurigo nodularis, actinic keratosis and atopic dermatitis. METRNL is also up-regulated in synovial membranes of human rheumatoid arthritis. Taken together, these results indicate that Metrnl represents a novel cytokine, which is likely involved in both innate and acquired immune responses. PMID:25486603

  16. [Neuropeptides, Cytokines and Thymus Peptides as Effectors of Interactions Between Thymus and Neuroendocrine System].

    PubMed

    Torkhovskaya, T I; Belova, O V; Zimina, I V; Kryuchkova, A V; Moskvina, S N; Bystrova, O V; Arion, V Ya; Sergienko, V I

    2015-01-01

    The review presents data on mutual influence of nervous system and thymus, realized through the neuroendocrine-immune interactions. The pres- ence of adrenergic and peptidergic nerves in thymus creates conditions for implementation of the effect of neuropeptides secreted by them. These neuropeptides induce activation of thymus cells receptors and influence on the main processes in thymus, including T-lymphocyte maturation, cytokine and hormones production. In turn, thymuspeptides and/or cytokines, controlled by them, enter the brain and exert influence on neuro- nalfunction, which creates the basis for changes of behavior and homeostasis maintenance in response to infection. Ageing and some infectious, autoimmune, neurodegenerative and cancer diseases are accompanied by distortion of interactions between thymus and central nervous system. Mechanisms of signaling pathways, which determine these interactions, are not revealed yet, and their understanding will promote the development of effective therapeutic strategies.

  17. Brain sites mediating corticosteroid feedback inhibition of stimulated ACTH secretion

    SciTech Connect

    Jacobson, L.

    1989-01-01

    There is substantial evidence that the brain mediates stress-induced and circadian increases in ACTH secretion and that corticosteroid concentrations which normalize basal plasma ACTH are insufficient to normalize ACTH responses to circadian or stressful stimuli in adrenalectomized rats. To identify brain sites mediating corticosteroid inhibition of stimulated ACTH secretion, two approaches were used. The first compared brain ({sup 14}C)-2-deoxyglucose uptake in rats with differential ACTH responses to stress. Relative to sham-adrenalectomized (SHAM) rats, adrenalectomized rats replaced with low, constant corticosterone levels via a subcutaneous corticosterone pellet (B-PELLET) exhibited elevated and prolonged ACTH responses to a variety of stimuli. Adrenalectomized rate given a circadian corticosterone rhythm via corticosterone in their drinking water exhibited elevated ACTH levels immediately after stress, but unlike B-PELLET rats, terminated stress induced ACTH secretion normally relative to SHAMS. Therefore, the abnormal ACTH responses to stress in B-PELLET rats were due to the lack of both circadian variations and stress-induced increases in corticosterone. Hypoxia was selected as a standardized stimulus for correlating brain ({sup 14}C)-2-deoxyglucose uptake with ACTH secretion. In intact rats, increases in plasma ACTH and decreases in arterial PO{sub 2} correlated with the severity of hypoxia at arterial PCO{sub 2} below 60 mm Hg. Hypoxia PELLET vs. SHAM rats. However, in preliminary experiments, although hypoxia increased brain 2-deoxyglucose uptake in most brain regions, plasma ACTH correlated poorly with 2-deoxyglucose uptake at 12% and 10% O{sub 2}.

  18. A genetic contribution to circulating cytokines and obesity in children

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cytokines are considered to be involved in obesity-related metabolic diseases. Study objectives are to determine the heritability of circulating cytokine levels, to investigate pleiotropy between cytokines and obesity traits, and to present genome scan results for cytokines in 1030 Hispanic children...

  19. IL-6 and its circadian secretion in humans.

    PubMed

    Vgontzas, A N; Bixler, E O; Lin, H-M; Prolo, P; Trakada, G; Chrousos, G P

    2005-01-01

    Interleukin-6 (IL-6) is a pleiotropic cytokine produced by numerous types of immune and nonimmune cells and is involved in many pathophysiologic mechanisms in humans. Many studies suggest that IL-6 is a putative 'sleep factor' and its circadian secretion correlates with sleep/sleepiness. IL-6 is elevated in disorders of excessive daytime sleepiness such as narcolepsy and obstructive sleep apnea. It correlates positively with body mass index and may be a mediator of sleepiness in obesity. Also the secretion of this cytokine is stimulated by total acute or partial short-term sleep loss reflecting the increased sleepiness experienced by sleep-deprived individuals. Studies that evaluated the 24-hour secretory pattern of IL-6 in healthy young adults suggest that IL-6 is secreted in a biphasic circadian pattern with two nadirs at about 08.00 and 21.00, and two zeniths at about 19.00 and 05.00 h. In contrast, following sleep deprivation or in disorders of sleep disturbance, e.g., insomnia, IL-6 peaks during the day and, based on the level of stress system activity, i.e., cortisol secretion, contributes to either sleepiness and deep sleep (low cortisol) or feelings of tiredness and fatigue and poor sleep (high cortisol). In order to address concerns about the potential impact of differences of IL-6 levels between the beginning and the end of the 24-hour blood-drawing experiment, we proceeded with a cosinor analysis of 'detrended' data in young and old healthy individuals. This new analysis did not affect the biphasic circadian pattern of IL-6 secretion in young adults, while it augmented the flattened circadian pattern in old individuals in whom the difference was greater. Finally, IL-6 appears to be somnogenic in rats and exhibits a diurnal rhythm that follows the sleep/wake cycle in these animals. We conclude that IL-6 is a mediator of sleepiness and its circadian pattern reflects the homeostatic drive for sleep. PMID:15905620

  20. Modulation of PBMC-decay accelerating factor (PBMC-DAF) and cytokines in rheumatoid arthritis.

    PubMed

    Pahwa, Roma; Kumar, Uma; Das, Nibhriti

    2016-03-01

    Studies have suggested that abnormal expression of complement regulatory proteins and cytokines contribute significantly to the path-physiology of rheumatoid arthritis. In this context, Decay accelerating factor (DAF) a complement regulatory protein is gaining increased attention. With the notion that immune effecter mechanisms are all interlinked and circulating peripheral blood mononuclear cells (PBMCs) should have a role in a systemic disease like rheumatoid arthritis, we studied the modulation and significance of PBMC-DAF and cytokines in RA. Seventy-five RA patients and 75 healthy controls were recruited. Expression of DAF and cytokines (IFN-γ, IL-17A and IL-10) in the PBMCs of patients and controls was determined. Correlations among DAF, cytokines, and disease activity were evaluated by standard statistical methods. The effect of IFN-γ, IL-17A, and IL-10 on the expression of DAF in patients and controls was studied in vitro. Expression of PBMC-DAF declined in patients both at mRNA and surface level and correlated negatively with the disease activity. Expression of IFN-γ also declined in patients but correlated positively with DAF and negatively with disease activity. Expression of IL-17A and IL-10 was higher in patients. The levels correlated positively with disease activity and negatively with DAF both in patients and controls. In vitro studies indicated that IFN-γ up-regulated DAF expression in PBMCs, whereas IL-17A and IL-10 had negative effect on the same. The decline in the PBMC-DAF is a contributing factor in manifestations of RA. Cytokine environment contributes to this decline. These findings brought novel insights into the complement-cytokine axis in the path-physiology of RA. PMID:26906204