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1

Macrophage immunomodulatory activity of polysaccharides isolated from Opuntia polyacantha.  

PubMed

Opuntia polyacantha (prickly pear cactus) has been used extensively for its nutritional properties; however, less is known regarding medicinal properties of Opuntia tissues. In the present study, we extracted polysaccharides from O. polyacantha and used size-exclusion chromatography to fractionate the crude polysaccharides into four polysaccharide fractions (designated as Opuntia polysaccharides C-I to C-IV). The average M(r) of fractions C-I through C-IV was estimated to be 733, 550, 310, and 168 kDa, respectively, and sugar composition analysis revealed that Opuntia polysaccharides consisted primarily of galactose, galacturonic acid, xylose, arabinose, and rhamnose. Analysis of the effects of Opuntia polysaccharides on human and murine macrophages demonstrated that all four fractions had potent immunomodulatory activity, inducing production of reactive oxygen species, nitric oxide, tumor necrosis factor alpha, and interleukin 6. Furthermore, modulation of macrophage function by Opuntia polysaccharides was mediated, at least in part, through activation of nuclear factor kappaB. Together, our results provide a molecular basis to explain a portion of the beneficial therapeutic properties of extracts from O. polyacantha and support the concept of using Opuntia polysaccharides as an immunotherapeutic adjuvant. PMID:18597716

Schepetkin, Igor A; Xie, Gang; Kirpotina, Liliya N; Klein, Robyn A; Jutila, Mark A; Quinn, Mark T

2008-10-01

2

Macrophage immunomodulatory activity of polysaccharides isolated from Opuntia polyacantha  

PubMed Central

Opuntia polyacantha (prickly pear cactus) has been used extensively for its nutritional properties; however, less is known regarding medicinal properties of Opuntia tissues. In the present study, we extracted polysaccharides from O. polyacantha and used size-exclusion chromatography to fractionate the crude polysaccharides into four polysaccharide fractions (designated as Opuntia polysaccharides C-I to C-IV). The average Mr of fractions C-I through C-IV was estimated to be 733, 550, 310, and 168 kDa, respectively, and sugar composition analysis revealed that Opuntia polysaccharides consisted primarily of galactose, galacturonic acid, xylose, arabinose, and rhamnose. Analysis of the effects of Opuntia polysaccharides on human and murine macrophages demonstrated that all four fractions had potent immunomodulatory activity, inducing production of reactive oxygen species, nitric oxide, tumor necrosis factor ?, and interleukin 6. Furthermore, modulation of macrophage function by Opuntia polysaccharides was mediated, at least in part, through activation of nuclear factor ?B. Together, our results provide a molecular basis to explain a portion of the beneficial therapeutic properties of extracts from O. polyacantha and support the concept of using Opuntia polysaccharides as an immunotherapeutic adjuvant. PMID:18597716

Schepetkin, Igor A.; Xie, Gang; Kirpotina, Liliya N.; Klein, Robyn A.; Jutila, Mark A.; Quinn, Mark T.

2008-01-01

3

Immunomodulatory Activity of a Novel, Synthetic Beta-glucan (?-glu6) in Murine Macrophages and Human Peripheral Blood Mononuclear Cells  

PubMed Central

Natural ?-glucans extracted from plants and fungi have been used in clinical therapies since the late 20th century. However, the heterogeneity of natural ?-glucans limits their clinical applicability. We have synthesized ?-glu6, which is an analog of the lentinan basic unit, ?-(1?6)-branched ?-(1?3) glucohexaose, that contains an ?-(1?3)-linked bond. We have demonstrated the stimulatory effect of this molecule on the immune response, but the mechanisms by which ?-glu6 activates innate immunity have not been elucidated. In this study, murine macrophages and human PBMCs were used to evaluate the immunomodulatory effects of ?-glu6. We showed that ?-glu6 activated ERK and c-Raf phosphorylation but suppressed the AKT signaling pathway in murine macrophages. Additionally, ?-glu6 enhanced the secretion of large levels of cytokines and chemokines, including CD54, IL-1?, IL-1?, IL-16, IL-17, IL-23, IFN-?, CCL1, CCL3, CCL4, CCL12, CXCL10, tissue inhibitor of metalloproteinase-1 (TIMP-1) and G-CSF in murine macrophages as well as IL-6, CCL2, CCL3, CCL5, CXCL1 and macrophage migration inhibitory factor (MIF) in human PBMCs. In summary, it demonstrates the immunomodulatory activity of ?-glu6 in innate immunity. PMID:24223225

Liu, Chunhong; Sun, Shuhui; Gu, Jianxin; Wang, Xun; Boraschi, Diana; Huang, Yuxian; Qu, Di

2013-01-01

4

Immunomodulatory activities on macrophage of a polysaccharide from Sipunculus nudus L.  

PubMed

A water-soluble polysaccharide, named as SNP, was extracted and fractioned from the body wall of Sipunculus nudus L. by DEAE-Sepharose anion exchange and Sepharose CL-6B column chromatography. The structural characteristics of SNP investigated by high performance size exclusion chromatography (HP-SEC), Fourier transform infrared spectroscopy (FT-IR) and gas chromatography-mass spectrometry (GC-MS) indicated that SNP was a homogeneous polysaccharide with a molecular mass of 350kD and the monosaccharide composition was determined to be rhamnose (28%), fucose (16%) and galactose (56%). SNP was able to upregulate the expression of cytokines (IL-6 and TNF-?), but did not affect IL-10 secretion by murine macrophages and human peripheral blood mononuclear cells. RT-PCR analysis demonstrated that the SNP also induced the expression of iNOS and COX-2, responsible for the induction of NO and PGE2 respectively, and SNP suppressed the arginase activity. These results suggest that the polysaccharide isolated from S. nudus activates macrophages and has potent immunostimulating activity. PMID:21802471

Zhang, Chen-Xiao; Dai, Zi-Ru

2011-11-01

5

C-type lectins on macrophages participate in the immunomodulatory response to Fasciola hepatica products  

PubMed Central

Fasciola hepatica releases excretory–secretory products (FhESP), and immunomodulatory properties have been described for the carbohydrates present in these parasite products. The interaction of FhESP with the innate immune cells, such as macrophages, is crucial in the early stage of infection. In this work we observed that peritoneal macrophages from naive BALB/c mice stimulated in vitro with FhESP presented: an increased arginase activity as well as Arginase I expression, and high levels of transforming growth factor-? and interleukin-10. A similar macrophage population was also observed in the peritoneum of infected mice. A partial inhibition of the immunomodulatory effects described above was observed when macrophages were pre-incubated with Mannan, anti-mannose receptor, Laminarin or anti-Dectin-1, and then stimulated with FhESP. In addition, we observed a partial inhibition of these effects in macrophages obtained from mice that were intraperitoneally injected with Mannan or Laminarin before being infected. Taken together, these results suggest the participation of at least two C-type lectin receptors, mannose receptor and Dectin-1, in the interaction of FhESP with macrophages, which allows this parasite to induce immunoregulatory effects on these important innate immune cells and may constitute a crucial event for extending its survival in the host. PMID:21595685

Guasconi, Lorena; Serradell, Marianela C; Garro, Ana P; Iacobelli, Luciana; Masih, Diana T

2011-01-01

6

Assessment of Immunomodulatory Activity of Euphorbia hirta L.  

PubMed

Immune system is the major target for development of treatment strategies to improve the management of infections. Many species of Indian medicinal plants have been reported to possess active principles with immunomodulating properties. Euphorbia hirta, a pantropic herb has been reported to be pharmacologically active. This study reports one another not widely reported property of the plant, immunomodulatory activity, which has been proved using simple techniques like the macrophage activity testing, carbon clearance test and mast cell de-granulation assay. PMID:21694995

Ramesh, K Vijaya; Padmavathi, K

2010-09-01

7

Assessment of Immunomodulatory Activity of Euphorbia hirta L.  

PubMed Central

Immune system is the major target for development of treatment strategies to improve the management of infections. Many species of Indian medicinal plants have been reported to possess active principles with immunomodulating properties. Euphorbia hirta, a pantropic herb has been reported to be pharmacologically active. This study reports one another not widely reported property of the plant, immunomodulatory activity, which has been proved using simple techniques like the macrophage activity testing, carbon clearance test and mast cell de-granulation assay. PMID:21694995

Ramesh, K. Vijaya; Padmavathi, K.

2010-01-01

8

Immunomodulatory activity of polysaccharides isolated from Alchornea cordifolia  

PubMed Central

Ethnopharmacological relevance Extracts of leaves from different species of the genus Alchornea have been used for centuries to treat a variety of medicinal problems in tropical Africa. However, little is known about the high-molecular weight active components conferring therapeutic properties to these extracts. Objective The aim of this study was to evaluate the immunomodulatory activity of polysaccharides isolated from the leaves of Alchornea cordifolia. Materials and methods Water-soluble polysaccharides from leaves of A. cordifolia were extracted and fractionated by DEAE-cellulose, Diaion HP-20, and size-exclusion chromatography. Molecular weight, sugar analysis, and other physical and chemical characterization of the fractions were performed. Immunomodulatory activity of the polysaccharide fractions was evaluated by determining their ability to induce monocyte/macrophage nitric oxide (NO) and cytokine production. Activation of mitogen activated protein kinases (MAPK) was also assessed using a phospho-MAPK array. Activation of nuclear factor ?B (NF-?B) was measured using an alkaline phosphatase reporter gene assay in THP1-Blue monocytic cells. Results Six polysaccharide fractions from A. cordifolia were isolated. Fractions containing type II arabinogalactan had potent immunomodulatory activity. Particularly, the parent fraction AP-AU and its high-molecular weight sub-fraction AP-AU1 (average Mr was estimated to be 39.5 kDa) induced production of NO and cytokines [interleukin (IL)-1?, -6, -10, tumor necrosis factor (TNF)-?, and granulocyte macrophage-colony stimulating factor (GM-CSF)] in human peripheral blood mononuclear cells and human and murine monocyte/macrophages cell lines in vitro. Furthermore, treatment with AP-AU1 induced phosphorylation of Akt2, p38?/p38?, p70S6K1, RSK2, and mTOR, as well as stimulation of NF-?B transcriptional activity. Conclusion Our results provide a molecular basis to explain a portion of the beneficial therapeutic properties of water extracts from A. cordifolia leaves in traditional folk medicine of Africa. PMID:23291534

Kouakou, Koffi; Schepetkin, Igor A.; Yapi, Ahoua; Kirpotina, Liliya N.; Jutila, Mark A.; Quinn, Mark T.

2013-01-01

9

Antitumor activity of the immunomodulatory lead Cumaside.  

PubMed

A new immunomodulatory lead Cumaside that is a complex of monosulfated triterpene glycosides from the sea cucumber Cucumaria japonica and cholesterol possesses significantly less cytotoxic activity against sea urchin embryos and Ehrlich carcinoma cells than the corresponding glycosides. Nevertheless Cumaside has an antitumor activity against different forms of experimental mouse Ehrlich carcinoma in vivo both independently and in combination with cytostatics. The highest effect occurs at a treatment once a day for 7 days before the tumor inoculation followed by Cumaside treatment once a day for 7 days. Prophylactic treatment with Cumaside and subsequent therapeutic application of 5-fluorouracil suppressed the tumor growth by 43%. PMID:20227525

Aminin, D L; Chaykina, E L; Agafonova, I G; Avilov, S A; Kalinin, V I; Stonik, V A

2010-06-01

10

Immunomodulatory Role of Ocimum gratissimum and Ascorbic Acid against Nicotine-Induced Murine Peritoneal Macrophages In Vitro  

PubMed Central

The aim of this present study was to evaluate the immune functions and immune responses in nicotine-induced (10?mM) macrophages and concurrently establish the immunomodulatory role of aqueous extract of Ocimum gratissimum (Ae-Og) and ascorbic acid. In this study, nitrite generations and some phenotype functions by macrophages were studied. Beside that, release of Th1 cytokines (TNF-?, IL-12) and Th2 cytokines (IL-10, TGF-?) was measured by ELISA, and the expression of these cytokines at mRNA level was analyzed by real-time PCR. Ae-Og, at a dose of 10??g/mL, significantly reduced the nicotine-induced NO generation and iNOSII expression. Similar kinds of response were observed with supplementation of ascorbic acid (0.01?mM). The administration of Ae-Og and ascorbic acid increased the decreased adherence, chemotaxis, phagocytosis, and intracellular killing of bacteria in nicotine-treated macrophages. Ae-Og and ascorbic acid were found to protect the murine peritoneal macrophages through downregulation of Th1 cytokines in nicotine-treated macrophages with concurrent activation of Th2 responses. These findings strongly enhanced our understanding of the molecular mechanism leading to nicotine-induced suppression of immune functions and provide additional rationale for application of anti-inflammatory therapeutic approaches by O. gratissimum and ascorbic acid for different inflammatory disease prevention and treatment during nicotine toxicity. PMID:22220218

Mahapatra, Santanu Kar; Chakraborty, Subhankari Prasad; Roy, Somenath

2011-01-01

11

Antimicrobial and Immunomodulatory Activities of PR-39 Derived Peptides  

PubMed Central

The porcine cathelicidin PR-39 is a host defence peptide that plays a pivotal role in the innate immune defence of the pig against infections. Besides direct antimicrobial activity, it is involved in immunomodulation, wound healing and several other biological processes. In this study, the antimicrobial- and immunomodulatory activity of PR-39, and N- and C-terminal derivatives of PR-39 were tested. PR-39 exhibited an unexpected broad antimicrobial spectrum including several Gram positive strains such as Bacillus globigii and Enterococcus faecalis. Of organisms tested, only Staphylococcus aureus was insensitive to PR-39. Truncation of PR-39 down to 15 (N-terminal) amino acids did not lead to major loss of activity, while peptides corresponding to the C-terminal part of PR-39 were hampered in their antimicrobial activity. However, shorter peptides were all much more sensitive to inhibition by salt. Active peptides induced ATP leakage and loss of membrane potential in Bacillus globigii and Escherichia coli, indicating a lytic mechanism of action for these peptides. Finally, only the mature peptide was able to induce IL-8 production in porcine macrophages, but some shorter peptides also had an effect on TNF-? production showing differential regulation of cytokine induction by PR-39 derived peptides. None of the active peptides showed high cytotoxicity highlighting the potential of these peptides for use as an alternative to antibiotics. PMID:24755622

Veldhuizen, Edwin J. A.; Schneider, Viktoria A. F.; Agustiandari, Herfita; van Dijk, Albert; Tjeerdsma-van Bokhoven, Johanna L. M.; Bikker, Floris J.; Haagsman, Henk P.

2014-01-01

12

Immunomodulatory activity of ?malaki Ras?yana: An experimental evaluation  

PubMed Central

Background: Ayurvedic system of medicine holds a number of drugs that improves the immunity. ?malaki (Emblica officinalis) is one such drug. Researches with crude extracts of ?malaki have proven the antioxidant and immunomodulatory activities. But, works on ?malaki Ras?yana are not found reported. Aims: Considering this, two samples of ?malaki Ras?yana (AR7 and AR21) were studied to evaluate comparative immunomodulatory activity against the cyclophosphamide immunosuppression in rats. Materials and Methods: Test drugs were prepared by following classical guidelines. Wistar strain albino rats of either sex were used in the study. Statistical Analysis: For comparison of data from cyclophosphamide control group with remaining cyclophosphamide plus test drug administered groups one way ANOVA with Dunnett's multiple t-test (DMTT) was employed. Results and Conclusions: ?malaki Ras?yana possesses significant immunostimulant activity and moderate cytoprotective activity. AR21 was found to have better activity profile in terms of both immunostimulant as well as cytoprotective activity. PMID:24167334

Rajani, Jignesh; Ashok, B.K.; Galib; Patgiri, B.J.; Prajapati, P.K.; Ravishankar, B.

2012-01-01

13

Development of QSAR model for immunomodulatory activity of natural coumarinolignoids  

PubMed Central

Immunomodulation is the process of alteration in immune response due to foreign intrusion of molecules inside the body. Along with the available drugs, a large number of herbal drugs are promoted in traditional Indian treatments, for their immunomodulating activity. Natural coumarinolignoids isolated from the seeds of Cleome viscose have been recognized as having hepatoprotective action and have recently been tested preclinically for their immunomodulatory activity affecting both cell-mediated and humoral immune response. To explore the immunomodulatory compound from derivatives of coumarinolignoids, a quantitative structure activity relationship (QSAR) and molecular docking studies were performed. Theoretical results are in accord with the in vivo experimental data studied on Swiss albino mice. Immunostimulatory activity was predicted through QSAR model, developed by forward feed multiple linear regression method with leave-one-out approach. Relationship correlating measure of QSAR model was 99% (R2 = 0.99) and predictive accuracy was 96% (RCV2 = 0.96). QSAR studies indicate that dipole moment, steric energy, amide group count, lambda max (UV-visible), and molar refractivity correlates well with biological activity, while decrease in dipole moment, steric energy, and molar refractivity has negative correlation. Docking studies also showed strong binding affinity to immunomodulatory receptors. PMID:20856844

Yadav, Dharmendra K; Meena, Abha; Srivastava, Ankit; Chanda, D; Khan, Feroz; Chattopadhyay, SK

2010-01-01

14

Isolation and characterization of exopolysaccharide with immunomodulatory activity from fermentation broth of Morchella conica  

PubMed Central

Background and the purpose of this study Mushroom polysaccharides have traditionally been used for the prevention and treatment of a multitude of disorders like infectious illnesses, cancers and various autoimmune diseases. In vitro and in vivo studies suggest that certain polysaccharides affect immune system function. Morchella conica (M. conica) is a species of rare edible mushroom whose multiple medicinal functions have been proven. Thus, the objective of this study is to isolate and characterize of exopolysaccharide from submerged mycelial culture of M. conica, and to evaluate its immunomodulatory activity. Methods A water-soluble Morchella conica Polysaccharides (MCP) were extracted and isolated from the fermentation broth of M. conica through a combination of DEAE-cellulose and Sephacryl S-300 HR chromatograph. NMR and IR spectroscopy has played a developing role in identification of polysaccharide with different structure and composition from fungal and plant sources, as well as complex glycosaminoglycans of animal origin. Thus, NMR and IR spectroscopy were used to analyze the chemical structure and composition of the isolated polysaccharide. Moreover, the polysaccharide was tested for its immunomodulatory activity at different concentrations using in vitro model. Results The results showed that MCP may significantly modulate nitric oxide production in macrophages, and promote splenocytes proliferation. Analysis from HPLC, infrared spectra and nuclear magnetic resonance spectroscopy showed that MCP was a homogeneous mannan with an average molecular weight of approximately 81.2 kDa. The glycosidic bond links is ?6)-?-D-Man p-(1?. Conclusion The results suggested that the extracted MCP may modulate nitric oxide production in macrophages and promote splenocytes proliferation, and it may act as a potent immunomodulatory agent. PMID:23351529

2013-01-01

15

Bacillus clausii probiotic strains: antimicrobial and immunomodulatory activities.  

PubMed

The clinical benefits observed with probiotic use are mainly attributed to the antimicrobial substances produced by probiotic strains and to their immunomodulatory effects. Currently, the best-documented probiotic bacteria used in human therapy are lactic acid bacteria. In contrast, studies aiming to characterize the mechanisms responsible for the probiotic beneficial effects of Bacillus are rare. The current work seeks to contribute to such characterization by evaluating the antimicrobial and immunomodulatory activities of probiotic B. clausii strains. B. clausii strains release antimicrobial substances in the medium. Moreover, the release of these antimicrobial substances was observed during stationary growth phase and coincided with sporulation. These substances were active against Gram-positive bacteria, in particular against Staphylococcus aureus, Enterococcus faecium, and Clostridium difficile. The antimicrobial activity was resistant to subtilisin, proteinase K, and chymotrypsin treatment, whereas it was sensitive to pronase treatment. The evaluation of the immunomodulatory properties of probiotic B. clausii strains was performed in vitro on Swiss and C57 Bl/6j murine cells. The authors demonstrate that these strains, in their vegetative forms, are able to induce NOS II synthetase activity, IFN-gamma production, and CD4 T-cell proliferation. PMID:15220667

Urdaci, Maria C; Bressollier, Philippe; Pinchuk, Irina

2004-07-01

16

[Interaction of the synthetic immunomodulatory dipeptide bestim with murine macrophages and thymocytes].  

PubMed

The tritium-labeled dipeptide bestim (gamma-D-Glu-L-Trp) with a specific activity of 45 Ci/mmol was obtained by high-temperature solid-state catalytic isotope exchange. It was found that [3H]bestim binds with a high affinity to murine peritoneal macrophages (Kd 2.1 +/- 0.1 nM) and thymocytes (Kd 3.1 +/- 0.2 nM), as well as with plasma membranes isolated from these cells (Kd 18.6 +/- 0.2 and 16.7 +/- 0.3 nM, respectively). The specific binding of [3H]bestim to macrophages and thymocytes was inhibited by the unlabeled dipeptide thymogen (L-Glu-L-Trp) (Ki 0.9 +/- 0.1 and 1.1 +/- 0.1 nM, respectively). After treatment with trypsin, macrophages and thymocytes lost the ability to bind [3H]bestim. Bestim in the concentration range of 10(-10) to 10(-6) M reduced the adenylate cyclase activity in the membranes of murine macrophages and thymocytes. PMID:18365736

Kolobov, A A; Kolodkin, N I; Zolotarev, Iu A; Tathill, C; Navolotskaia, E V

2008-01-01

17

Immunomodulatory activity of orphan drug Elmiron® in female B6C3F1/N mice.  

PubMed

Interstitial cystitis (IC) is a chronic disorder characterized by bladder discomfort and urinary urgency in the absence of identifiable infection. Despite the expanding use in IC treatment and other chronic conditions, the effects of Elmiron® treatment on immune system remain unknown. Therefore, female B6C3F1/N mice were orally administered Elmiron® daily for 28-days at doses of 63, 125, 250, 500 or 1000mg/kg to evaluate its immunomodulatory effects. Mice treated with Elmiron® had a significant increase in absolute numbers of splenic macrophages (63, 500 and 1000mg/kg) and natural killer (NK) cells (250 and 1000mg/kg). Elmiron® treatment did not affect the humoral immune response or T cell proliferative response. However, innate immune responses such as phagocytosis by liver macrophages (1000mg/kg) and NK cell activity were enhanced (500 and 1000mg/kg). Further analysis using a disease resistance model showed that Elmiron®-treated mice demonstrated significantly increased anti-tumor activity against B16F10 melanoma cells at the 500 and 1000mg/kg doses. Collectively, we conclude that Elmiron® administration stimulates the immune system, increasing numbers of specific cell populations and enhancing macrophage phagocytosis and NK cell activity in female B6C3F1/N mice. This augmentation may have largely contributed to the reduced number of B16F10 melanoma tumors. PMID:24657363

Thakur, Sheetal A; Nyska, Abraham; White, Kimber L; Smith, Matthew J; Auttachoat, Wimolnut; Germolec, Dori R

2014-06-01

18

Immunomodulatory activity of Vachadhatryadi Avaleha in albino rats  

PubMed Central

The present study is carried out to evaluate the immuno-modulatory activity of Vacha Dhatryadi Avaleha in albino rats. Vacha Dhatryadi Avaleha was prepared by classical method and evaluated for humoral antibody formation and cell-medicated immunity in established experimental models. Test formulation was administered at the dose of 900 mg/kg and parameters like hemagglutination titer, ponderal changes, histopathology of immunological organs and immunological paw edema were recorded. Vacha Dhatryadi Avaleha significantly enhanced antibody formation and moderately suppressed the immunological edema. The present study concludes that Vachadhatryadi Avaleha has immunopotentiating activity. PMID:22408316

Rajagopala, S.; Ashok, B.K.; Ravishankar, B.

2011-01-01

19

Anti-tumour and immunomodulatory activities of oligosaccharides isolated from Panax ginseng C.A. Meyer.  

PubMed

Water-soluble ginseng oligosaccharides (WGOS) composed of D-glucose with a degree of polymerisation ranging from 2 to 14 were obtained from Panax ginseng C.A. Meyer. In this study, the anti-tumour and immunoregulatory effects of WGOS were evaluated in Hepatoma-22 (H22)-bearing mice. Treatment with WGOS inhibited tumour growth in vivo and significantly increased relative spleen and thymus weight, serum tumour necrosis factor-? level, spleen lymphocyte proliferation, natural killer cell activity, phagocytic function and nitric oxide production secreted by macrophage in H22-bearing mice. However, no direct cytotoxicity was detected. Therefore, the anti-tumour activity of WGOS may be related to their immunomodulatory effects. PMID:24468047

Jiao, Lili; Zhang, Xiaoyu; Li, Bo; Liu, Zhen; Wang, Mingzhu; Liu, Shuying

2014-04-01

20

Immunomodulatory activity of polysaccharides isolated from Clerodendrum splendens: Beneficial effects in experimental autoimmune encephalomyelitis  

PubMed Central

Background Extracts of leaves from Clerodendrum have been used for centuries to treat a variety of medicinal problems in tropical Africa. However, little is known about the high-molecular weight active components conferring therapeutic properties to these extracts. Methods Polysaccharides from the leaves of Clerodendrum splendens were extracted and fractionated by ion exchange and size-exclusion chromatography. Molecular weight determination, sugar analysis, degree of methyl esterification, and other chemical characterization of the fractions were performed. Immunomodulatory activity of the fractions was evaluated by determining their ability to induce monocyte/macrophage nitric oxide (NO), cytokine production, and mitogen-activated protein kinase (MAPK) phosphorylation. Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice, and severity of EAE was monitored in mice treated with intraperitoneal (i.p.) injections of the most active polysaccharide fraction. Lymph nodes (LN) and spleen were harvested, and levels of cytokines in supernatants from LN cells and splenocytes challenged with myelin oligodendrocyte glycoprotein peptide were determined. Results Fractions containing type II arabinogalactan had potent immunomodulatory activity. Specifically, the high-molecular weight sub-fraction CSP-AU1 (average of 38.5 kDa) induced NO and cytokine [interleukin (IL)-1?, -1?, -6, -10, tumor necrosis factor (TNF; designated previously as TNF-?), and granulocyte macrophage-colony stimulating factor (GM-CSF)] production by human peripheral blood mononuclear cells (PBMCs) and monocyte/macrophages. CSP-AU1-induced secretion of TNF was prevented by Toll-like receptor 4 (TLR4) antagonist LPS-RS, indicating a role for TLR4 signaling. Treatment with CSP-AU1 also induced phosphorylation of a number of MAPKs in human PBMC and activated AP-1/NF-?B. In vivo treatment of mice with CSP-AU1 and CSP-NU1 resulted in increased serum IL-6, IL-10, TNF, monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1?/CCL3, and MIP-1?/CCL4. CSP-AU1 treatment of mice with EAE (50 mg/kg, i.p., daily, 13 days) resulted in significantly reduced disease severity in this experimental model of multiple sclerosis. Levels of IL-13, TNF, interferon (IFN)-?, IL-17, and GM-CSF were also significantly decreased, whereas transforming growth factor (TGF)-? was increased in LN cells from CSP-AU1-treated EAE mice. Conclusions Polysaccharide CSP-AU1 is a potent natural innate immunomodulator with a broad spectrum of agonist activity in vitro and immunosupressive properties after chronic administration in vivo. PMID:23806004

2013-01-01

21

Antibody Constant Region Peptides Can Display Immunomodulatory Activity through Activation of the Dectin-1 Signalling Pathway  

PubMed Central

We previously reported that a synthetic peptide with sequence identical to a CDR of a mouse monoclonal antibody specific for difucosyl human blood group A exerted an immunomodulatory activity on murine macrophages. It was therapeutic against systemic candidiasis without possessing direct candidacidal properties. Here we demonstrate that a selected peptide, N10K, putatively deriving from the enzymatic cleavage of the constant region (Fc) of human IgG1, is able to induce IL-6 secretion and pIkB-? activation. More importantly, it causes an up-regulation of Dectin-1 expression. This leads to an increased activation of ?-glucan-induced pSyk, CARD9 and pIkB-?, and an increase in the production of pro-inflammatory cytokines such as IL-6, IL-12, IL-1? and TNF-?. The increased activation of this pathway coincides with an augmented phagocytosis of non opsonized Candida albicans cells by monocytes. The findings suggest that some Fc-peptides, potentially deriving from the proteolysis of immunoglobulins, may cause an unexpected immunoregulation in a way reminiscent of innate immunity molecules. PMID:22952831

Cenci, Elio; Monari, Claudia; Magliani, Walter; Ciociola, Tecla; Conti, Stefania; Gatti, Rita; Bistoni, Francesco; Polonelli, Luciano; Vecchiarelli, Anna

2012-01-01

22

Immunomodulatory function of murine NK cell activity by alginate.  

PubMed

The in vivo immunomodulatory function of the activity of murine natural killer (NK) cells induced by high mannuronic acid-containing alginate (HMA) was examined. HMA was injected i.p at doses of 25 and 100 mg/kg. The NK activity was 3 times higher with 100 mg/kg HMA than the baseline. In addition, in vitro studies of splenocytes cultured with HMA for 20 h showed a significant increase in NK activity at E:T ratio of 100:1; a 160% and 210% increase at 10 and 100 microg/mL, respectively. There was a six fold increase in interferon-gamma production in a postculture of splenocytes with 100 microg/mL HMA. HMA had no suppressive effects on the lymphocyte function in the presence or absence of mitogens. This suggests that HMA is useful in cancer immunotherapy. PMID:16350856

Son, Eun-Wha; Yang, Kwang-Hee; Rhee, Dong-Kwon; Pyo, Suhkneung

2005-11-01

23

Effect of ultrasonic extraction conditions on antioxidative and immunomodulatory activities of a Ganoderma lucidum polysaccharide originated from fermented soybean curd residue.  

PubMed

A crude Ganoderma lucidum polysaccharide (GLPL) was extracted from fermented soybean curd residue by ultrasonic assisted extraction. The optimal extraction conditions were 30 min at 80 °C with 80 W and water to solid ratio of 10, and with this method 115.47 ± 2.95 mg/g of GLPL yield was obtained. Additionally, the antioxidant and immunomodulatory activities of GLPL were investigated. The results showed that GLPL exhibited strong antioxidant effects, which included scavenging activities against DPPH radicals, hydrogen oxide and ABTS radicals with IC50 values of 0.23, 0.48 and 0.69 mg/mL, respectively. For immunomodulatory activities, GLPL was shown to strongly stimulate the proliferation of macrophages (158.02 ± 13.12%), the production of nitric oxide and phagocytosis (21.16 ± 1.65 ?M), and, at 40.00 ?g/mL, protected macrophage from Doxorubicin (DOX) (0.16 ± 0.003). PMID:24594153

Shi, Min; Yang, Yingnan; Hu, Xuansheng; Zhang, Zhenya

2014-07-15

24

Flavonol Glycosides from Euphorbia microsciadia Bioss. with their Immunomodulatory Activities  

PubMed Central

Four known flavonoids: quercetin 3-O-?-D-rutinoside (Q3Rut), myricetin 3-O-?-D-galactopyranoside (M3Gal), quercetin 3-O-?-D-galactopyranoside (Q3Gal) and quercetin 3-O-?-D-glucopyranoside (Q3Glc), for the first time were isolated from aerial parts of Euphorbia microsciadia. The chemical structure of them was elucidated on the basis of 1 and 2 D-NMR spectra and different spectroscopic techniques. The immunomodulatory activities of isolated compounds were compared using standard T-cell proliferation assay. These data showed that lymphocyte suppression activity of flavonoids (1-4) were comparatively lower than prednisolon as a standard drug. Immunosuppressive activity of flavonoids with hydroxyl groups at both 3?-and 4?-positions in their B-ring (Q3Gal) were more than those with 3?-,4?-and 5?-hydroxyl substitution (M3Gal). In these compounds, Q3Gal showed the most inhibitory activity, whereas M3Gal showed the least lymphocyte antiprolifeartive activity. PMID:24250520

Ghanadian, Syed Mustafa; Ayatollahi, Abdul Majid; Afsharypour, Suleiman; Hareem, Sumaira; Abdalla, Omer Mohamed; Jules Kezetas Bankeu, Jean

2012-01-01

25

Galactofuranosyl glycosides: immunomodulatory effects on macrophages and in vivo enhancement of lethality on sepsis.  

PubMed

Galactofuranoside derivatives were synthesised by the classic Fischer glycosydation method, and their immune modulation properties were studied in vitro and in vivo. NMR spectroscopic and ESI-MS analyses confirmed the purity and authenticity of all derivatives. Their phagocyte capacities were tested in resident macrophages. Methyl ?-galactofuranoside (GFB-Me) and n-octyl ?-galactofuranoside (GFB-O) had an immune stimulant effect at 25?molml(-1) with an enhancement of 35.12%±0.06 SD and 17.49%±0.11 SD, respectively, but Methyl ?-galactofuranoside (GFA-Me) and n-octyl ?-galactofuranoside (GFA-O) gave a low immune response. Methyl ?-galactofuranoside 5,6-O-isopropylidene (GFA-IP) and Methyl ?-galactofuranoside 5,6-O-isopropylidene (GFB-IP) had negative values relative to the control group of minus 4.96%±0.10 SD and -40.72%±0.07 SD, respectively. Furthermore, GFB-Me and GFB-Me-IP were evaluated in vivo on the lethality induced by cecal ligation and puncture. Cytokine levels and iNOS expression were determined and correlated to mortality data. The results showed that the free HO-5 and HO-6 and the ?-configuration are essential for the induction of phagocytic activity by the galactofuranosyl units. The methyl ?-galactofuranosides also enhanced lethality during sepsis, increasing the levels of pro-inflammatory cytokines and iNOS expression. PMID:23756126

Sassaki, Guilherme L; Rattmann, Yanna D; Santana-Filho, Arquimedes P; Riter, Daniel S; Iagher, Fabíola; Trindade, Edvaldo S; da Silva, Morgana D; Santos, Adair R S; de Souza, Lauro Mera; Iacomini, Marcello; Gorin, Philip A J

2013-09-01

26

Immunomodulatory activity and partial characterisation of polysaccharides from Momordica charantia.  

PubMed

Momordica charantia Linn. is used as an edible and medicinal vegetable in sub-tropical areas. Until now, studies on its composition and related activities have been confined to compounds of low molecular mass, and no data have been reported concerning the plant's polysaccharides. In this work, a crude polysaccharide of M. charantia (MCP) fruit was isolated by hot water extraction and then purified using DEAE-52 cellulose anion-exchange chromatography to produce two main fractions MCP1 and MCP2. The immunomodulatory effects and physicochemical characteristics of these fractions were investigated in vitro and in vivo. The results showed that intragastric administration of 150 or 300 mg·kg-·d?ą of MCP significantly increased the carbolic particle clearance index, serum haemolysin production, spleen index, thymus index and NK cell cytotoxicity to normal control levels in cyclophosphamide (Cy)-induced immunosuppressed mice. Both MCP1 and MCP2 effectively stimulated normal and concanavalin A-induced splenic lymphocyte proliferation in vitro at various doses. The average molecular weights of MCP1 and MCP2, which were measured using high-performance gel permeation chromatography, were 8.55×10? Da and 4.41×10? Da, respectively. Both fractions exhibited characteristic polysaccharide bands in their Fourier transform infrared spectrum. MCP1 is mainly composed of glucose and galactose, and MCP2 is mainly composed of glucose, mannose and galactose. The results indicate that MCP and its fractions have good potential as immunotherapeutic adjuvants. PMID:25178064

Deng, Yuan-Yuan; Yi, Yang; Zhang, Li-Fang; Zhang, Rui-Fen; Zhang, Yan; Wei, Zhen-Cheng; Tang, Xiao-Jun; Zhang, Ming-Wei

2014-01-01

27

Structure and Antitumor and Immunomodulatory Activities of a Water-Soluble Polysaccharide from Dimocarpus longan Pulp  

PubMed Central

A new water-soluble polysaccharide (longan polysaccharide 1 (LP1)) was extracted and successfully purified from Dimocarpus longan pulp via diethylaminoethyl (DEAE)-cellulose anion-exchange and Sephacryl S-300 HR gel chromatography. The chemical structure was determined using Infrared (IR), gas chromatography (GC) and nuclear magnetic resonance (NMR) analysis. The results indicated that the molecular weight of the sample was 1.1 × 105 Da. Monosaccharide composition analysis revealed that LP1 was composed of Glc, GalA, Ara and Gal in a molar ratio of 5.39:1.04:0.74:0.21. Structural analysis indicated that LP1 consisted of a backbone of ?4)-?-d-Glcp-(1?4)-?-d-GalpA-(1?4)-?-d-Glcp-(1?4)-?-d-Glcp-(1? units with poly saccharide side chains composed of ?2)-?-d-Fruf-(1?2)-l-sorbose-(1? attached to the O-6 position of the ?-d-Glcp residues. In vitro experiments indicated that LP1 had significantly high antitumor activity against SKOV3 and HO8910 tumor cells, with inhibition percentages of 40% and 50%, respectively. In addition, LP1 significantly stimulated the production of the cytokine interferon-? (IFN-?), increased the activity of murine macrophages and enhanced B- and T-lymphocyte proliferation. The results of this study demonstrate that LP1 has potential applications as a natural antitumor agent with immunomodulatory activity. PMID:24663085

Meng, Fa-Yan; Ning, Yuan-Ling; Qi, Jia; He, Zhou; Jie, Jiang; Lin, Juan-Juan; Huang, Yan-Jun; Li, Fu-Sen; Li, Xue-Hua

2014-01-01

28

In vitro and in vivo immunomodulatory activity of sulfated polysaccharides from Enteromorpha prolifera.  

PubMed

Water-soluble sulfated polysaccharides extracted from Enteromorpha prolifera and fractionated using ion-exchange chromatography (crude, F(1), F(2) and F(3) fractions) were investigated to determine their in vitro and in vivo immunomodulatory activities. The sulfated polysaccharides, especially the F(1) and F(2) fractions, stimulated a macrophage cell line, Raw 264.7, inducing considerable nitric oxide (NO) and various cytokine production via up-regulated mRNA expression. The in vivo experiment results show that the sulfated polysaccharides (the crude and F(2) fractions) significantly increased Con A-induced splenocyte proliferation, revealing their potential comitogenic activity. In addition, IFN-? and IL-2 secretions were considerably increased by the F(2) fraction without altering the release of IL-4 and IL-5. This implies that the F(2) fraction can activate T cells by up-regulating Th-1 response and that Th-1 cells might be the main target cells of the F(2) fraction. These in vitro and in vivo results suggest that the sulfated polysaccharides are strong immunostimulators. PMID:21907732

Kim, Jin-Kyung; Cho, Myoung Lae; Karnjanapratum, Supatra; Shin, Il-Shik; You, Sang Guan

2011-12-01

29

In vivo evidence of the immunomodulatory activity of orally administered Aloe vera gel.  

PubMed

The gels of Aloe species contain immunomodulatory components such as aloctin A and acemannan. Most studies on these gels were performed in in vitro cell culture systems. Although several studies examined their immunomodulatory activity in vivo, the route of administration was intraperitoneal or intramuscular. Here, we evaluated the in vivo immunomodulatory activity of processed Aloe vera gel (PAG) in mice. Oral administration of PAG significantly reduced the growth of C. albicans in the spleen and kidney following intravenous injection of C. albicans in normal mice. PAG administration also reduced the growth of C. albicans in streptozotocin-induced diabetic mice. PAG administration did not increase ovalbumin (OVA)-specific cytotoxic T lymphocyte (CTL) generation in normal mice, but did increase it in high-fat-diet induced diabetic mice. These findings provide the first clear evidence for the immunomodulatory activity of orally administered Aloe vera gel. PMID:20361311

Im, Sun-A; Lee, Young-Ran; Lee, Young-Hee; Lee, Myung-Koo; Park, Young In; Lee, Sungwon; Kim, Kyungjae; Lee, Chong-Kil

2010-03-01

30

Schistosoma mansoni Hemozoin Modulates Alternative Activation of Macrophages via Specific Suppression of Retnla Expression and Secretion  

PubMed Central

The trematode Schistosoma mansoni is one of the etiological agents of schistosomiasis, a key neglected tropical disease responsible for an estimated annual loss of 70 million disability-adjusted life years. Hematophagy represents the primary nutrient acquisition pathway of this parasite, but digestion of hemoglobin also liberates toxic heme. Schistosomes detoxify heme via crystallization into hemozoin, which is subsequently regurgitated into the host's circulation. Here we demonstrate that during experimental schistosomiasis, hemozoin accumulating in the mouse liver is taken up by phagocytes at a time coincident with the development of the egg-induced T-helper 2 (Th2) granulomatous immune response. Furthermore, the uptake of hemozoin also coincides with the hepatic expression of markers of alternative macrophage activation. Alternatively activated macrophages are a key effector cell population associated with protection against schistosomiasis, making hemozoin well placed to play an important immunomodulatory role in this disease. To systematically explore this hypothesis, S. mansoni hemozoin was purified and added to in vitro bone marrow-derived macrophage cultures concurrently exposed to cytokines chosen to reflect the shifting state of macrophage activation in vivo. Macrophages undergoing interleukin-4 (IL-4)-induced alternative activation in the presence of hemozoin developed a phenotype specifically lacking in Retnla, a characteristic alternatively activated macrophage product associated with regulation of Th2 inflammatory responses. As such, in addition to its important detoxification role during hematophagy, we propose that schistosome hemozoin also provides a potent immunomodulatory function in the coevolved network of host-parasite relationships during schistosomiasis. PMID:23090958

Truscott, Martha; Evans, D. Andrew; Gunn, Matt

2013-01-01

31

Macrophage immunomodulatory activity of polysaccharides isolated from Opuntia polyacantha  

Microsoft Academic Search

Opuntia polyacantha (prickly pear cactus) has been used extensively for its nutritional properties; however, less is known regarding medicinal properties of Opuntia tissues. In the present study, we extracted polysaccharides from O. polyacantha and used size-exclusion chromatography to fractionate the crude polysaccharides into four polysaccharide fractions (designated as Opuntia polysaccharides C-I to C-IV). The average Mr of fractions C-I through

Igor A. Schepetkin; Gang Xie; Liliya N. Kirpotina; Robyn A. Klein; Mark A. Jutila; Mark T. Quinn

2008-01-01

32

Comparison of physicochemical properties and immunomodulatory activity of polysaccharides from fresh and dried litchi pulp.  

PubMed

Drying is commonly used for preservation and processing of litchi. However, its polysaccharide structure may be altered by the drying process, resulting in biological activity changes. Polysaccharides from fresh and dried litchi pulp (denoted as LPF and LPD, respectively) were isolated, investigated by GC-MS, GPC and UV/IR spectrum analysis and their antitumor and immunomodulatory activities were evaluated in vitro. LPD, the molecular weight of which was lower than that of LPF, contained more protein, uronic acid, arabinose, galactose and xylose. Compared with LPF, LPD exhibited a higher inhibitory effect on the proliferation of HepG2, Hela and A549 cells from 50-750 ?g/mL. LPD was also a better stimulator of spleen lymphocyte proliferation, NK cells cytotoxicity and macrophage phagocytosis from 50-400 ?g/mL. In summary, drying could change the physicochemical properties and enhance the bioactivity of polysaccharides from litchi pulp. This finding is supported by the fact that dried litchi pulps are used in Traditional Chinese Medicine. PMID:24691064

Huang, Fei; Zhang, Ruifen; Yi, Yang; Tang, Xiaojun; Zhang, Mingwei; Su, Dongxiao; Deng, Yuanyuan; Wei, Zhencheng

2014-01-01

33

Immunomodulatory activity of acidic polysaccharides isolated from Tanacetum vulgare L.  

PubMed

Tanacetum vulgare L. (Tansy) has been extensively used in folk medicine for treatment of a variety of medical disorders. In the present study, we isolated and purified four acidic polysaccharide fractions (designated T-I to T-IV) from Tansy florets by the sequential use of hot-water extraction, ethanol precipitation, ultra-filtration, anion-exchange, and size-exclusion chromatography. The average M(r) of fractions T-I through T-IV was estimated to be 326, 151, 64 and 9 kDa, respectively, as determined by high performance size-exclusion chromatography analysis. Sugar composition analysis revealed that Tansy polysaccharides consisted primarily of galacturonic acid, galactose, arabinose, and rhamnose. Fractions T-II through T-IV contained an arabinogalactan type II structure, as determined by reaction with Yariv reagent. High M(r) fractions T-I and T-II exhibited potent macrophage/monocyte-activating activity, enhancing production of reactive oxygen species (ROS), nitric oxide (NO), and tumor necrosis factor alpha (TNF-alpha) by J774.A1 murine macrophages, and activating nuclear factor kappaB (NF-kappaB) in THP-1 human monocytes. In addition, Tansy polysaccharides stimulated human neutrophil function by greatly enhancing neutrophil myeloperoxidase (MPO) release. Furthermore, the low M(r) fraction T-IV had potent complement-fixing activity, which may also contribute to the anti-inflammatory and would-healing properties of Tansy extracts. Taken together, our results provide a molecular basis to explain at least part of the beneficial therapeutic effects of Tansy extracts, and support the concept of using Tansy polysaccharides as an immunotherapeutic adjuvant. PMID:17996673

Xie, Gang; Schepetkin, Igor A; Quinn, Mark T

2007-12-15

34

TLR4-mediated activation of mouse macrophages by Korean mistletoe lectin-C (KML-C)  

Microsoft Academic Search

Korean mistletoe lectin (KML-C) is an adjuvant that activates systemic and mucosal immune cells to release cytokines including TNF-?, which induces immunity against viruses and cancer cells. Although the immunomodulatory activity of KML-C has been well established, the underlying mechanism of action of KML-C has yet to be explored. When mouse peritoneal macrophages were treated with KML-C, both transcription and

Hong-Jai Park; Ju-ho Hong; Hyung-Joon Kwon; Youngchan Kim; Kwan-Hee Lee; Jong-Bae Kim; Seong K. Song

2010-01-01

35

In vitro activation of macrophages by a novel proteoglycan isolated from corms of Crocus sativus L  

Microsoft Academic Search

Saffron corms contain a proteoglycan that is highly cytotoxic on human tumor cells. The present work was undertaken to study the possible immunomodulatory and anti-invasive properties of this compound. Non-cytotoxic concentrations of this glycoconjugate promoted significant macrophage activation, detected by the release of nitric oxide. A rapid activation of protein kinase C and NF-?B was obtained after proteoglycan treatment, which

Julio Escribano; M. José M. D??az-Guerra; Hans H. Riese; Jesús Ontańón; Damián Garc??a-Olmo; Dolores C. Garc??a-Olmo; Angela Rubio; José A. Fernández

1999-01-01

36

Immunomodulatory Activity of Oenothein B Isolated from Epilobium angustifolium1  

PubMed Central

Epilobium angustifolium has been traditionally used to treat of a number of diseases; however, not much is known regarding its effect on innate immune cells. Here, we report that extracts of E. angustifolium activated functional responses in neutrophils and monocyte/macrophages. Activity-guided fractionation, followed by mass spectroscopy and NMR analysis, resulted in the identification of oenothein B as the primary component responsible for phagocyte activation. Oenothein B, a dimeric hydrolysable tannin, dose-dependently induced a number of phagocyte functions in vitro, including intracellular Ca2+ flux, production of reactive oxygen species (ROS), chemotaxis, nuclear factor (NF)-?B activation, and proinflammatory cytokine production. Furthermore, oenothein B was active in vivo, inducing keratinocyte chemoattractant (KC) production and neutrophil recruitment to the peritoneum after intraperitoneal administration. Biological activity required the full oenothein B structure, as substructures of oenothein B (pyrocatechol, gallic acid, pyrogallol, 3,4-dihydroxybenzoic acid) were all inactive. The ability of oenothein B to modulate phagocyte functions in vitro and in vivo suggests that this compound is responsible for at least part of the therapeutic properties of E. angustifolium extracts. PMID:19846877

Schepetkin, Igor A.; Kirpotina, Liliya N.; Jakiw, Larissa; Khlebnikov, Andrei I.; Blaskovich, Christie L.; Jutila, Mark A.; Quinn, Mark T.

2009-01-01

37

Immunomodulatory activity of oenothein B isolated from Epilobium angustifolium.  

PubMed

Epilobium angustifolium has been traditionally used to treat of a number of diseases; however, not much is known regarding its effect on innate immune cells. In this study, we report that extracts of E. angustifolium activated functional responses in neutrophils and monocyte/macrophages. Activity-guided fractionation, followed by mass spectroscopy and NMR analysis, resulted in the identification of oenothein B as the primary component responsible for phagocyte activation. Oenothein B, a dimeric hydrolysable tannin, dose-dependently induced a number of phagocyte functions in vitro, including intracellular Ca(2+) flux, production of reactive oxygen species, chemotaxis, NF-kappaB activation, and proinflammatory cytokine production. Furthermore, oenothein B was active in vivo, inducing keratinocyte chemoattractant production and neutrophil recruitment to the peritoneum after intraperitoneal administration. Biological activity required the full oenothein B structure, as substructures of oenothein B (pyrocatechol, gallic acid, pyrogallol, 3,4-dihydroxybenzoic acid) were all inactive. The ability of oenothein B to modulate phagocyte functions in vitro and in vivo suggests that this compound is responsible for at least part of the therapeutic properties of E. angustifolium extracts. PMID:19846877

Schepetkin, Igor A; Kirpotina, Liliya N; Jakiw, Larissa; Khlebnikov, Andrei I; Blaskovich, Christie L; Jutila, Mark A; Quinn, Mark T

2009-11-15

38

Lactobacillus acidophilus L-92 Cells Activate Expression of Immunomodulatory Genes in THP-1 Cells  

PubMed Central

To understand the immunomodulatory effects of Lactobacillus acidophilus L-92 cells suggested from our previous study of in vivo anti-allergy and anti-virus effects, host immune responses in macrophage-like THP-1 cells after 4?h (the early phase) and 24?h (the late phase) of cocultivation with L-92 cells were investigated by transcriptome analysis. In the early phase of L-92 treatment, various transcription regulator genes, such as, NFkB1, NFkB2, JUN, HIVEP2 and RELB, and genes encoding chemokines and cytokines, such as CCL4, CXCL11, CCL3 and TNF, were upregulated. Two transmembrane receptor genes, TLR7 and ICAM1, were also upregulated in the early phase of treatment. In contrast, many transmembrane receptor genes, such as IL7R, CD80, CRLF2, CD86, CD5, HLA-DQA1, IL2RA, IL15RA and CSF2RA, and some cytokine genes, including IL6, IL23A and CCL22, were significantly upregulated in the late phase after L-92 exposure. Some genes encoding cytokines, such as IL1A, IL1B and IL8, and the enzyme IDO1 were upregulated at both the early and the late phases of treatment. These results suggest that probiotic L-92 might promote Th1 and regulatory T-cell responses by activation of the MAPK signaling pathway, followed by the NOD-like receptor signaling pathway in THP-1 cells. PMID:25379363

YANAGIHARA, Sae; GOTO, Hiroaki; HIROTA, Tatsuhiko; FUKUDA, Shinji; OHNO, Hiroshi; YAMAMOTO, Naoyuki

2014-01-01

39

Immunomodulatory activity of biopolymeric fraction BOS 2000 from Boswellia serrata.  

PubMed

Oral administration of BOS 2000 (1-10 mg/kg) elicited a dose related increase in the delayed hypersensitivity reaction (early 24 h and delayed 48 h) in mice. It also stimulated the IgM and IgG titre expressed in the form of plaques (PFC) and complement fixing antibody titre. The concentration of cytokines (IL-4, IFN-gamma and TNF-alpha) in serum with respect to T cell interactions, i.e. (CD4/CD8) and the proliferation of lymphocytes were significantly increased at 10 mg/kg compared with the control. The results in these studies demonstrated the immunostimulatory effect of BOS 2000 in a dose-dependent manner with respect to the macrophage activation possibly expressing the phagocytosis and nitrite production by the enhancement of TNF-alpha and IFN-gamma production as a mode of action. PMID:18167047

Khajuria, Anamika; Gupta, Amit; Suden, Pankaj; Singh, Surjeet; Malik, Fayaz; Singh, Jaswant; Gupta, B D; Suri, K A; Srinivas, V K; Ella, Krishna; Qazi, G N

2008-03-01

40

Novel insights into the immunomodulatory role of the dendritic cell and macrophage-expressed C-type lectin MGL.  

PubMed

Based on their ability to balance tolerance and inflammation, antigen presenting cells, such as dendritic cells and macrophages contribute to the maintenance of immune homeostasis as well as the instigation of immune activation. Acting as key sensors of tissue integrity and pathogen invasion, they are well equipped with a wide variety of pattern recognition receptors, to which the C-type lectin family also belongs. C-type lectins are glycan-binding receptors that mediate cell-cell communication and pathogen recognition, besides participating in the endocytosis of antigens for presentation to T cells and the fine-tuning of immune responses. Here we review the current state-of-the-art on the dendritic cell and macrophage-expressed C-type lectin macrophage galactose-type lectin (MGL), highlighting the binding specificities, signaling properties and modulation of innate and adaptive immunity by its human and murine orthologues. PMID:25454488

van Kooyk, Yvette; Ilarregui, Juan M; van Vliet, Sandra J

2015-02-01

41

QSAR and Docking Studies on Capsazepine Derivatives for Immunomodulatory and Anti-Inflammatory Activity  

PubMed Central

Capsazepine, an antagonist of capsaicin, is discovered by the structure and activity relationship. In previous studies it has been found that capsazepine has potency for immunomodulation and anti-inflammatory activity and emerging as a favourable target in quest for efficacious and safe anti-inflammatory drug. Thus, a 2D quantitative structural activity relationship (QSAR) model against target tumor necrosis factor-? (TNF-?) was developed using multiple linear regression method (MLR) with good internal prediction (r2?=?0.8779) and external prediction (r2pred?=?0.5865) using Discovery Studio v3.5 (Accelrys, USA). The predicted activity was further validated by in vitro experiment. Capsazepine was tested in lipopolysaccharide (LPS) induced inflammation in peritoneal mouse macrophages. Anti-inflammatory profile of capsazepine was assessed by its potency to inhibit the production of inflammatory mediator TNF-?. The in vitro experiment indicated that capsazepine is an efficient anti-inflammatory agent. Since, the developed QSAR model showed significant correlations between chemical structure and anti-inflammatory activity, it was successfully applied in the screening of forty-four virtual derivatives of capsazepine, which finally afforded six potent derivatives, CPZ-29, CPZ-30, CPZ-33, CPZ-34, CPZ-35 and CPZ-36. To gain more insights into the molecular mechanism of action of capsazepine and its derivatives, molecular docking and in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) studies were performed. The results of QSAR, molecular docking, in silico ADMET screening and in vitro experimental studies provide guideline and mechanistic scope for the identification of more potent anti-inflammatory & immunomodulatory drug. PMID:25003344

Shukla, Aparna; Sharma, Pooja; Prakash, Om; Singh, Monika; Kalani, Komal; Khan, Feroz; Bawankule, Dnyaneshwar Umrao; Luqman, Suaib; Srivastava, Santosh Kumar

2014-01-01

42

Immunomodulatory effects of clove (Syzygium aromaticum) constituents on macrophages: In vitro evaluations of aqueous and ethanolic components.  

PubMed

Abstract The present work sought to investigate potential suppressive effects on mouse macrophages by in vitro treatment with clove (Syzygium aromaticum) ethanolic extracted essential oil (containing eugenol) or its water-soluble extract. Using doses (ranging from 0.001-1000?µg/ml) of each material freshly prepared in the laboratory, cell survival and production of nitric oxide (NO), tumor necrosis factor (TNF)-?, interleukin (IL)-6, and IL-12 by the treated cells (that in all cases also had received LPS stimulation) were measured. Results indicated that, except at doses ?100?µg/ml, viability was unaffected in all groups. NO release by LPS-stimulated macrophages was generally significantly suppressed by either material; in contrast, low (i.e. 0.001-1?µg/ml) doses of either extract class appeared to enhance NO release by non-LPS (unstimulated)-treated macrophages. Among LPS-stimulated cells, TNF? release was also significantly affected by each extract; the ethanolic extract was suppressive at all doses tested, while the aqueous material was so up to 1?µg/ml and then became stimulatory. In contrast, nearly every dose of either extract appeared to stimulate IL-6 release from the LPS-treated cells. Effects on IL-12 production were overall inconsistent; in general, the ethanolic extract tended to be stimulatory of production by the LPS-treated cells. The data for the aqueous material showed no discernable pattern of effect. The results suggest that clove extracts do not have a distinct cytotoxic activity, but do impart potential anti- and pro-oxidant effects in cells, depending on their concentrations and on the activation state of the macrophages themselves at the time of exposure to the extracts. The impact of the extracts on macrophage cytokine release also displays a pattern of dose-relatedness. PMID:24873744

Dibazar, Shaghayegh Pishkhan; Fateh, Shirin; Daneshmandi, Saeed

2015-04-01

43

Molecular characterization and immunomodulatory activity of sulfated fucans from Agarum cribrosum.  

PubMed

The sulfated-fucans, known as fucoidans, were isolated from Agarum cribrosum and fractionated using ion-exchange chromatography to determine their molecular characteristics and in vitro immunomodulatory activity. The crude and fractionated fucoidans (F1 and F2) consisted mostly of carbohydrates (52.4-56.0%), sulfates (12.7-23.0%) and uronic acid (14.1-21.8%), with a small amount of proteins (3.9-9.3%), and included various levels of fucose (44.0-46.7%), mannose (18.9-26.8%), galactose (16.8-33.0%), xylose (10.7-17.0%) and glucose (3.5-9.5%). The crude and fractionated fucans contained one or two subfractions with average molecular weights (Mw) ranging from 110.1 × 10(3) to 2420 × 10(3)g/mol. The fractionated fucoidan, especially the F1 fraction, strongly stimulated murine macrophages (Raw 264.7 cells), producing a considerable amount of nitric oxide (NO) and inducing expression of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2) and interleukin-10 (IL-10) transcripts by activation of nuclear factor-kappa B (NF-?B) and mitogen-activated protein kinases (MAPKs) pathways. The maximally immunoenhancing F1 fraction was mainly composed of (1 ? 3)-linked fucose, (1 ? 2)-linked mannose and (1 ? 4)-linked glucuronic acid with sulfates at C-2 or both the C-2 and C-4 positions in (1 ? 2,3)- and (1 ? 2,3,4)-linked fucose residues. PMID:25256513

Cho, MyoungLae; Lee, Dong-Jin; Kim, Jin-Kyung; You, SangGuan

2014-11-26

44

Macrophage Activation Syndrome in Autoimmune Disease  

Microsoft Academic Search

Macrophage activation syndrome (MAS) is a phenomenon characterized by cytopenia, organ dysfunction, and coagulopathy associated with an inappropriate activation of macrophages. Current diagnostic criteria are imprecise, but the syndrome is now recognized as a form of hemophagocytic lymphohistiocytosis that is characteristically associated with autoimmune diatheses. The diagnosis of incipient MAS in patients with autoimmune disease requires a high index of

Sean Deane; Carlo Selmi; Suzanne S. Teuber; M. Eric Gershwin

2010-01-01

45

Different Effects of the Immunomodulatory Drug GMDP Immobilized onto Aminopropyl Modified and Unmodified Mesoporous Silica Nanoparticles upon Peritoneal Macrophages of Women with Endometriosis  

PubMed Central

The aim of the present work was to compare in vitro the possibility of application of unmodified silica nanoparticles (UMNPs) and modified by aminopropyl groups silica nanoparticles (AMNPs) for topical delivery of immunomodulatory drug GMDP to the peritoneal macrophages of women with endometriosis. The absence of cytotoxic effect and high cellular uptake was demonstrated for both types of silica nanoparticles. The immobilization of GMDP on the UMNPs led to the suppression of the stimulatory effect of GMDP on the membrane expression of scavenger receptors SR-AI and SR-B, mRNAs expression of NOD2 and RAGE, and synthesis of proteolytic enzyme MMP-9 and its inhibitor TIMP-1. GMDP, immobilized onto AMNPs, enhanced the initially reduced membrane expression of SRs and increased NOD2, RAGE, and MMP-9 mRNAs expression by macrophages. Simultaneously high level of mRNAs expression of factors, preventing undesirable hyperactivation of peritoneal macrophages (SOCS1 and TIMP-1), was observed in macrophages incubated in the presence of GMDP, immobilized onto AMNPs. The effect of AMNPs immobilized GMDP in some cases exceeded the effect of free GMDP. Thus, among the studied types of silica nanoparticles, AMNPs are the most suitable nanoparticles for topical delivery of GMDP to the peritoneal macrophages. PMID:24455738

Antsiferova, Yuliya; Sotnikova, Nataliya

2013-01-01

46

Lymphokine regulation of macrophage effector activities.  

PubMed

Our concept of the regulation of macrophage activation is ever expanding and contracting. In regard to the number of LK that regulate macrophages killing activities, we have entered a new phase. In the beginning there was one macrophage activation factor, MIF; then there were many macrophage activation factors, most uncharacterized and bearing a variety of names. Then came IFN, a genetically cloned single reagent that induced destruction of virtually every target assessed; all activities of macrophages were assumed to be regulated by IFN. Once again, however, the LK universe is expanding: the number of single, cloned reagents that induce macrophage killing activities is amazing. With just two targets, a fibrosarcoma cell and an intracellular amastigote of L. major, we can identify 5 different macrophage activation factors, four of which are cloned and sequenced. As more recombinant reagents become available, the story of macrophage activation is likely to become even more complex. It is fascinating not only that certain of the LK are capable of inducing single effector reactions in the absence of effects on other effector activities, but also that at least one effector reaction requires the cooperation of several molecularly distinct LK. The complexity of LK activation factors that regulate a single effector reaction in vitro is compounded by the complexity in effector cell populations. For example, inflammatory macrophages exposed to LK kill the fibrosarcoma tumor target 5 to 10-fold better than an equal number of resident peritoneal macrophages. In contrast, LK treated resident macrophages eliminate intracellular amastigotes of leishmania far more efficiently than inflammatory cells. Thus, changes in cell populations dramatically affect the capacity to demonstrate a single effector reaction. Further, simple changes in assay conditions also determine whether an effector reaction can be observed in vitro. And superimposed upon all these layers of complexity is the target itself. The mechanisms a macrophages uses to block the replication of a virus may be totally ineffective in the destruction of a multicellular helminth, such as Schistosoma mansoni. And there is no reason to suspect that the extracellular destruction of a tumor target occurs by the same means that the macrophage uses to kill an intracytoplasmic bacterium, such as a rickettsia.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:3059762

Nacy, C A; Belosevic, M; Crawford, R M; Healy, A T; Schreiber, R D; Meltzer, M S

1988-01-01

47

Immunomodulatory activities of medicinal mushroom Grifola frondosa extract and its bioactive constituent.  

PubMed

Grifola frondosa (GF), a high value medicinal mushroom in China and Japan, is popularly consumed as traditional medicines and health foods, especially for enhancing immune functions. In this study, our aim was to examine the immunomodulatory activities of GF and its bioactive compound ergosterol peroxide (EPO) in lipopolysaccharide (LPS)-induced human monocytic (THP-1) cells. At low concentrations, EPO but not other extracts showed a full protection against LPS-induced cell toxicity. EPO significantly blocked MyD88 and VCAM-1 expression, and cytokine (IL-1?, IL-6 and TNF-?) production in LPS-stimulated cells. It also effectively inhibited NF-?B activation, which was further confirmed with siRNA treatment. These results conclude that EPO may play an important role in the immunomodulatory activity of GF through inhibiting the production of pro-inflammatory mediators and activation of NF-?B signaling pathway. PMID:23336512

Wu, Shu-Jing; Lu, Tzy-Ming; Lai, Min-Nan; Ng, Lean-Teik

2013-01-01

48

Novel thalidomide analogues display anti-angiogenic activity independently of immunomodulatory effects  

Microsoft Academic Search

The anti-tumour effects of thalidomide have been associated with its anti-angiogenic properties. Second generation thalidomide analogues are distinct compounds with enhanced therapeutic potential. Although these compounds are beginning to enter trials for the treatment of cancer there is very little information regarding the anti-angiogenic activity of these clinically relevant compounds. Furthermore, it is not known how the various immunomodulatory activities

K Dredge; J B Marriott; C D Macdonald; H-W Man; R Chen; G W Muller; D Stirling; A G Dalgleish

2002-01-01

49

TLR4-mediated activation of mouse macrophages by Korean mistletoe lectin-C (KML-C).  

PubMed

Korean mistletoe lectin (KML-C) is an adjuvant that activates systemic and mucosal immune cells to release cytokines including TNF-alpha, which induces immunity against viruses and cancer cells. Although the immunomodulatory activity of KML-C has been well established, the underlying mechanism of action of KML-C has yet to be explored. When mouse peritoneal macrophages were treated with KML-C, both transcription and translation of TLR4 were upregulated. KML-C-induced TLR4 downstream events were similar to those activated by LPS: the upregulation of interleukin-1 receptor-associated kinase-1 (IRAK1); resulting in macrophage activation and TNF-alpha production. When TLR4 was blocked using a TLR4-specific neutralizing antibody, TNF-alpha production from the macrophages was significantly inhibited. Moreover, TLR4-deficient mouse macrophages treated with KML-C also secreted greatly reduced level of TNF-alpha secretion. Finally, TLR4 molecules were co-precipitated with KML-C, to which agarose beads were conjugated, indicating that those molecules are associated. These data indicate that KML-C activates mouse macrophages to secrete TNF-alpha by interacting with the TLR4 molecule and activating its signaling pathways. PMID:20450885

Park, Hong-Jai; Hong, Ju-ho; Kwon, Hyung-Joon; Kim, Youngchan; Lee, Kwan-Hee; Kim, Jong-Bae; Song, Seong K

2010-06-01

50

Enhancement of ATP generation capacity, antioxidant activity and immunomodulatory activities by Chinese Yang and Yin tonifying herbs  

PubMed Central

Chinese tonifying herbs such as Herba Cistanche, Ganoderma and Cordyceps, which possess antioxidant and/or immunomodulatory activities, can be useful in the prevention and treatment of age-related diseases. Pharmacological studies on Yang and Yin tonifying herbs suggest that Yang tonifying herbs stimulate mitochondrial adenosine triphosphate (ATP) generation, presumably through the intermediacy of reactive oxidant species, leading to the enhancement of cellular/mitochondrial antioxidant status. Yin tonifying herbs, however, apart from possessing antioxidant properties, exert mainly immunomodulatory functions that may boost a weak immune system and may also suppress overreactive immune responses. The abilities of Yang and Yin Chinese tonifying herbs to enhance ATP generation and to exhibit antioxidant and/or immunomodulatory actions are the pharmacological basis for their beneficial effects on the retardation of aging. PMID:17386115

Ko, Kam Ming; Leung, Hoi Yan

2007-01-01

51

Phagocytic activity of LPS tolerant macrophages.  

PubMed

Endotoxin tolerance is defined as a reduced capacity of the host to respond to LPS activation following a first exposure to this stimulus. It affects all leukocytes and regarding macrophages, most studies focus on the reduced ability of these cells to secrete pro-inflammatory cytokines. Therefore, we evaluated other macrophages functions (fungicidal capacity, reactive oxygen species production and antigen presentation) in cells from tolerant mice. We have performed a tolerance model in our laboratory that does not stimulate directly the place from where the cells will be removed (peritoneal cavity). Mouse received subcutaneous injections of LPS in the scruff for 5 days and we analyze the capacity of peritoneal macrophages to phagocyte using three different receptors: Fc, C3b and mannose receptors. We found a reduction in the phagocytosis of erythrocytes and Candida albicans related to the Fc and mannose receptors. These differences can be due to a macrophage reprogramming, as demonstrated by altered expression of cytokines and chemokines. Despite this reduction in phagocytosis capacity, macrophages from tolerant animals exhibited enhanced hydrogen peroxide production and expression of antigen presentation molecules, suggesting that their ability to combat an infection is improved. In summary, our data indicates that LPS tolerance drives macrophages from a predominant release of proinflammatory mediators that amplify inflammation and host damage toward a better killing and antigen presentation state. PMID:24732064

de Lima, Thais Martins; Sampaio, Sandra Coccuzzo; Petroni, Ricardo; Brigatte, Patrícia; Velasco, Irineu Tadeu; Soriano, Francisco Garcia

2014-07-01

52

Immunomodulatory activity and chemical characterisation of sangre de drago (dragon's blood) from Croton lechleri.  

PubMed

The immunomodulatory activity of the latex from Croton lechleri (sangre de drago) was determined by in vitro assays. Classical (CP) and alternative (AP) complement pathways activities were determined in human serum. Intracellular generation of reactive oxygen species (ROS) by human polymorphonuclear leukocytes (PMNs) and monocytes, and phagocytosis of opsonised fluorescent microspheres were measured by flow cytometry. Free radical scavenging activity was evaluated using 1,1-diphenyl-2-picrylhydrazyl (DPPH). Activity on proliferation of murine lymphocytes was also investigated. In addition, anti-inflammatory activity was assayed in vivo by carrageenan-induced rat paw oedema test. Some of the activities were compared with those of the isolated alkaloid taspine. Sangre de drago from Croton lechleri showed immunomodulatory activity. It exhibited a potent inhibitory activity on CP and AP of complement system and inhibited the proliferation of activated T-cells. The latex showed free radical scavenging capacity. Depending on the concentration, it showed antioxidant or prooxidant properties, and stimulated or inhibited the phagocytosis. Moreover, the latex has strong anti-inflammatory activity when administered i. p. Taspine cannot be considered the main responsible for these activities, and other constituents, probably proanthocyanidins, should be also involved. PMID:14598201

Risco, Ester; Ghia, Felipe; Vila, Roser; Iglesias, José; Alvarez, Elida; Cańigueral, Salvador

2003-09-01

53

Immunomodulatory activity of petroleum ether extract of flower heads of Sphaeranthus indicus Linn.  

PubMed

The petroleum ether extract from the flower heads of Sphaeranthus indicus Linn. was found to be effective in increasing phagocytic activity, hemagglutination antibody titer and delayed type hypersensitivity when tested in mice. Activity of the petroleum extract was tested at five different dosing levels to establish a dose-response relationship. It was found that 200 mg/kg dose was the optimum dose, and at higher doses the activity was either reduced or showed no further increase. The present study, therefore, reveals that the drug shows good promise as an immunomodulatory agent, which acts by stimulating both humoral and cellular immunity as well as phagocytic function. PMID:17594985

Bafna, A R; Mishra, S H

2007-01-01

54

Effect of Tityus serrulatus venom on cytokine production and the activity of murine macrophages.  

PubMed

THE purpose of this study was to investigate the effects of Tityus serrulatus venom (TSV) on murine peritoneal macrophages evaluated in terms of activation. The effects of crude TSV were analysed by detection of cytokines, oxygen intermediate metabolites (H2O2) and nitric oxide (NO) in supernatants of peritoneal macrophages. Several functional bioassays were employed including an in vitro model for envenomating: cytotoxicity of TSV was assessed using the lyses percentage. Tumor necrosis factor (TNF) activity was assayed by measuring its cytotoxic activity on L-929 cells, and interleukin-6 (IL-6) and interferon-gamma (IFN-gamma) were assayed by enzyme-linked immunosorbent assay, whereas NO levels were detected by Griess colorimetric reactions in culture supernatant of macrophages incubated with TSV and subsequently exposed to either lipopolysaccharide or IFN-gamma. Incubation of macrophages with TSV increased production of IL-6 and IFN-gamma in a dose-dependent manner. TNF production was not detected in supernatants treated with TSV at any concentration. The increase in IL-6 secretion was not associated with concentration-dependent cytoxicity of TSV on these cells. These data suggest that the cytotoxicity does not appear to be the main cause of an increased cytokine production by these cells. Although NO is an important effector molecule in macrophage microbicidal activity, the inducing potential of the test compounds for its release was found to be very moderate, ranging from 125 to 800 mM. Interestingly, NO levels of peritoneal macrophages were increased after IFN-gamma. Moreover, NO production had an apparent effect on macrophage activity. The results obtained here also shown that the TSV induces an important elevation in H2O2 release. These results combined with NO production suggest that TSV possesses significant immunomodulatory activities capable of stimulating immune functions in vitro. PMID:11926592

Petricevich, Vera L

2002-02-01

55

Immunomodulatory action of triterpene glycosides isolated from the sea cucumber Actinocucumis typica. Structure-activity relationships.  

PubMed

Stimulation of lysosomal activity and ROS formation in mouse peritoneal macrophages by five triterpene glycosides, typicosides A1 (1), A2 (2), B1 (3), C1 (4) and C2 (5) has been studied and compared with their cytotoxic activities. Glycosides 1-3 possess moderate activities, but the most cytotoxic glycoside 5 is not active. Typicoside C1 (4), with low toxicity, was proved to be the most active concerning stimulation of ROS formation. This is the first example of a triterpene glycoside from sea cucumbers with low cytotoxicity, but which demonstrates a strong immunostimulatory effect on mouse peritoneal macrophages in vitro. PMID:25115075

Pislyagin, Evgeny A; Aminin, Dmitry L; Silchenko, Alexandra S; Avilov, Sergey A; Andryjashchenko, Pelageya V; Kalinin, Vladimir I; Padmakumar, Krishna

2014-06-01

56

Immunomodulatory activity of boswellic acids of Boswellia serrata Roxb.  

PubMed

Extract of gum resin of B. serrata containing 60% acetyl 11-keto beta boswellic acid (AKBA) along with other constituents such as 11-keto beta-boswellic acid (KBA), acetyl beta-boswellic acid and beta-boswellic acid has been evaluated for antianaphylactic and mast cell stabilizing activity using passive paw anaphylaxis and compound 48/80 induced degranulation of mast cell methods. The extract inhibited the passive paw anaphylaxis reaction in rats in dose-dependant manner (20, 40 and 80 mg/kg, po). However, the standard dexamethasone (0.27 mg/kg, po) revealed maximum inhibition of edema as compared to the extract. A significant inhibition in the compound 48/80 induced degranulation of mast cells in dose-dependant manner (20, 40 and 80 mg/kg, po) was observed thus showing mast cell stabilizing activity. The standard disodium cromoglycate (50 mg/kg, ip) was found to demonstrate maximum per cent protection against degranulation as compared to the extract containing 60% AKBA. The results suggest promising antianaphylactic and mast cell stabilizing activity of the extract. PMID:15320503

Pungle, Pratibha; Banavalikar, M; Suthar, A; Biyani, M; Mengi, S

2003-12-01

57

Immunomodulatory activity of plant residues on ovine neutrophils.  

PubMed

Neutrophils play an essential role in host defense and inflammation. Plants have long been used to improve the immune function, but for most of them specific investigations on animal health are lacking. In the present study, water and hydroethanolic extracts from 11 plant wastes have been screened on immune responses of ovine neutrophils. Eight sheep clinically healthy, not lactating, non-pregnant were selected and used for the experiment. Freshly isolated neutrophils were incubated with the extracts of the residues at increasing doses, and then they were tested for adhesion and superoxide production induced with PMA. The residues of Larix decidua, Thymus vulgaris, Salix alba, Sinupret, Helianthus annuus, Mangifera indica modulated the neutrophil immune functions, moreover, Larix decidua, Thymus vulgaris and Salix alba presented the highest anti-inflammatory activity. PMID:18667240

Farinacci, Maura; Colitti, Monica; Sgorlon, Sandy; Stefanon, Bruno

2008-11-15

58

Immunostimulatory Activity of Protein Hydrolysate from Oviductus Ranae on Macrophage In Vitro  

PubMed Central

Oviductus Ranae is the dry oviduct of Rana chensinensis, which is also called R. chensinensis oil. Oviductus Ranae is a valuable Chinese crude drug and is recorded in the Pharmacopoeia of the People's Republic of China. The aim of this study was to investigate the immunostimulatory activity of protein hydrolysate of Oviductus Ranae (ORPH) and to assess its possible mechanism. Immunomodulatory activity of ORPH was examined in murine macrophage RAW 264.7 cells. The effect of ORPH on the phagocytic activity of macrophages was determined by the neutral red uptake assay. After treatment with ORPH, NO production levels in the culture supernatant were investigated by Griess assay. The mRNA and protein expressions of inducible nitric oxide synthase (iNOS) were detected by RT-PCR and Western blotting. The production of TNF-?, IL-1?, and IL-6 after treatment with ORPH was measured using ELISA assay. In addition, NF-?B levels were also investigated by Western blot. The results showed that ORPH enhanced the phagocytosis of macrophage, increased productions of TNF-?, IL-1?, IL-6, and NO in RAW 264.7 cells, and upregulated the mRNA and protein expression of iNOS. Besides, NF-?B, levels in RAW 264.7 cells were elevated after ORPH treatment. These findings suggested that ORPH might stimulate macrophage activities by activating the NF-?B pathway. PMID:25610475

Huang, Di; Yang, Lubing; Wang, Chenlu; Ma, Sihui; Cui, Li; Huang, Shiyang; Sheng, Xia; Weng, Qiang; Xu, Meiyu

2014-01-01

59

Mycobacterium indicus pranii and Mycobacterium bovis BCG lead to differential macrophage activation in Toll-like receptor-dependent manner.  

PubMed

Mycobacterium indicus pranii (MIP) is an atypical mycobacterial species possessing strong immunomodulatory properties. It is a potent vaccine candidate against tuberculosis, promotes Th1 immune response and protects mice from tumours. In previous studies, we demonstrated higher protective efficacy of MIP against experimental tuberculosis as compared with bacillus Calmette-Guérin (BCG). Since macrophages play an important role in the pathology of mycobacterial diseases and cancer, in the present study, we evaluated the MIP in live and killed form for macrophage activation potential, compared it with BCG and investigated the underlying mechanisms. High levels of tumour necrosis factor-?, interleukin-12p40 (IL-12p40), IL-6 and nitric oxide were produced by MIP-stimulated macrophages as compared with BCG-stimulated macrophages. Prominent up-regulation of co-stimulatory molecules CD40, CD80 and CD86 was also observed in response to MIP. Loss of response in MyD88-deficient macrophages showed that both MIP and BCG activate the macrophages in a MyD88-dependent manner. MyD88 signalling pathway culminates in nuclear factor-?B/activator protein-1 (NF-?B/AP-1) activation and higher activation of NF-?B/AP-1 was observed in response to MIP. With the help of pharmacological inhibitors and Toll-like receptor (TLR) -deficient macrophages, we observed the role of TLR2, TLR4 and intracellular TLRs in MIP-mediated macrophage activation. Stimulation of HEK293 cells expressing TLR2 in homodimeric or heterodimeric form showed that MIP has a distinctly higher level of TLR2 agonist activity compared with BCG. Further experiments suggested that TLR2 ligands are well exposed in MIP whereas they are obscured in BCG. Our findings establish the higher macrophage activation potential of MIP compared with BCG and delineate the underlying mechanism. PMID:24766519

Kumar, Pawan; Tyagi, Rohit; Das, Gobardhan; Bhaskar, Sangeeta

2014-10-01

60

Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide.  

PubMed

Thalidomide and the immunomodulatory drug, lenalidomide, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as the primary teratogenic target of thalidomide. Our studies demonstrate that thalidomide, lenalidomide and another immunomodulatory drug, pomalidomide, bound endogenous CRBN and recombinant CRBN-DNA damage binding protein-1 (DDB1) complexes. CRBN mediated antiproliferative activities of lenalidomide and pomalidomide in myeloma cells, as well as lenalidomide- and pomalidomide-induced cytokine production in T cells. Lenalidomide and pomalidomide inhibited autoubiquitination of CRBN in HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBN(YW/AA). Overexpression of CRBN wild-type protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplified pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21(WAF-1) expression. Long-term selection for lenalidomide resistance in H929 myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both pomalidomide and lenalidomide, CRBN protein was undetectable. Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and pomalidomide. PMID:22552008

Lopez-Girona, A; Mendy, D; Ito, T; Miller, K; Gandhi, A K; Kang, J; Karasawa, S; Carmel, G; Jackson, P; Abbasian, M; Mahmoudi, A; Cathers, B; Rychak, E; Gaidarova, S; Chen, R; Schafer, P H; Handa, H; Daniel, T O; Evans, J F; Chopra, R

2012-11-01

61

Brazilian Green Propolis: Anti-Inflammatory Property by an Immunomodulatory Activity  

PubMed Central

The immunomodulatory and anti-inflammatory activities of green propolis extracts from Apis mellifera were investigated using acute and chronic inflammation models. Swiss mice were anesthetized and a cotton pellet granuloma was implanted in subcutaneous tissue. Then the mice were divided into six groups and received apyrogenic water or different propolis extracts by oral route (5?mg/kg). According to the treatment the groups were designated as E1A, E1B, E10, E11, and E12. The control group received apyrogenic water. The treatment was performed by six days when the mice were killed. The blood and the bronchoalveolar lavage (BAL) were collected to measure the leukocyte recruitment. In acute pulmonary inflammation, Balb/c mice received lipopolysaccharide (LPS) of Escherichia coli by intranasal route for three days. Concomitantly the mice received by oral route apyrogenic water (control) or E10 and E11 propolis extracts. BAL was performed to assess the inflammatory infiltrate and cytokine quantification. The results showed that the E11 extract has anti-inflammatory property in both models by the inhibition of proinflammatory cytokines and increase of anti-inflammatory cytokines suggesting an immunomodulatory activity. PMID:23320022

Machado, Joleen Lopes; da Silva, Mayara Cristina Pinto; dos Reis, Aramys Silva; Costa, Graciomar Conceiçăo; Arruda, Dięgo de Sousa; Rocha, Bruno Alves; Vaz, Mirela Mara de Oliveira Lima Leite; Paes, Antonio Marcus de Andrade; Guerra, Rosane Nassar Meireles; Berretta, Andresa Aparecida; do Nascimento, Flávia Raquel Fernandes

2012-01-01

62

Macrophage activation and leishmanicidal activity by galactomannan and its oxovanadium (IV/V) complex in vitro.  

PubMed

Compounds that activate macrophage antimicrobial activity are potential targets for treatment of leishmaniasis. The present study investigated the in vitro immunomodulatory effects of a galactomannan (GALMAN-A) isolated from seeds of Mimosa scabrella and its oxovanadium (IV/V) complex (GALMAN-A:VO(2+)/VO(3+)) on macrophage activity. GALMAN-A increased nitric oxide levels by ~33% at a concentration of 250?g/ml, while GALMAN-A:VO(2+)/VO(3+) decreased nitric oxide levels by ~33% at a concentration of 50?g/ml. Furthermore, GALMAN-A increased interleukin-1 beta (IL-1?) and interleukin-6 (IL-6) levels by 5.5 and 2.3 times, respectively, at a concentration of 25?g/ml; at the same concentration, GALMAN-A:VO(2+)/VO(3+) promoted an increase in IL-1? and IL-6 production by 8 and 5.5 times, respectively. However, neither GALMAN-A nor GALMAN-A:VO(2+)/VO(3+) affected tumor necrosis factor alpha (TNF-?) or interleukin-10 (IL-10) levels. Importantly, both GALMAN-A and GALMAN-A:VO(2+)/VO(3+) exhibited leishmanicidal activity on amastigotes of Leishmania (L.) amazonensis, reaching ~60% activity at concentrations of 100 and 25?g/ml, respectively. These results indicate that GALMAN-A is three times more potent and its oxovanadium complex is twelve times more potent than Glucantime (300?g/ml), which is the drug of choice in leishmaniasis treatment. The IC50 value for GALMAN-A:VO(2+)/VO(3+) was 74.4?g/ml (0.58?g/ml of vanadium). Thus, the significant activation of macrophages and the noted leishmanicidal effect demonstrate the need for further studies to clarify the mechanisms of action of these compounds. PMID:24169303

Adriazola, Izabela Ono; Evangelista do Amaral, Alex; Amorim, Juliana Carolina; Correia, Beatriz Lourenço; Petkowicz, Carmen Lúcia Oliveira; Mercę, Ana Lucia Ramalho; Noleto, Guilhermina Rodrigues

2014-03-01

63

In vitro immunomodulatory activity of plants used by the Tacana ethnic group in Bolivia.  

PubMed

One hundred and seventy-eight ethanolic plant extracts from the pharmacopoeia of the Tacana, an ethnic group from Bolivia, were screened for immunomodulatory activity using complement cascade inhibition and ADP-induced platelet aggregation inhibition assays. Six impaired both complement pathways (classical and alternative): stem bark from Astronium urundeuvea (Anacardiaceae), Cochlospermum vitifolium (Cochlospermaceae), Terminalia amazonica (Combretaceae), Triplaris americana (Polygonaceae), Uncaria tomentosa (Rubiaceae) and Euterpe precatoria (Arecaceae) roots. Inhibition of complement cascade was independent of essential ion complexation, and was not due to direct hemolytic activity on target red blood cells. For A. urundeuvea, C. vitifolium, and T. amazonica, anti-inflammatory activity relied on cyclo-oxygenase inhibition. Four of these species (A. urundeuva, T. americana, U. tomentosa and E. precatoria) are used traditionally to treat inflammatory processes. PMID:15500263

Deharo, E; Baelmans, R; Gimenez, A; Quenevo, C; Bourdy, G

2004-09-01

64

Novel thalidomide analogues display anti-angiogenic activity independently of immunomodulatory effects  

PubMed Central

The anti-tumour effects of thalidomide have been associated with its anti-angiogenic properties. Second generation thalidomide analogues are distinct compounds with enhanced therapeutic potential. Although these compounds are beginning to enter trials for the treatment of cancer there is very little information regarding the anti-angiogenic activity of these clinically relevant compounds. Furthermore, it is not known how the various immunomodulatory activities of these compounds relate to anti-angiogenic activity. In this study we assessed the anti-angiogenic activity of compounds from both IMiD™ and SelCID™ classes of analogues using a novel in vitro multicellular human assay system and the established rat aorta assay. Our results show that both the IMiDs and SelCIDs tested are significantly more potent than thalidomide. The anti-angiogenic potency of the analogues was not related to inhibition of endothelial cell proliferation, nor their TNF-?/PDE type 4 inhibitory properties. However, anti-migratory effects in vitro and inhibition of tumour growth in vivo was observed with the analogue IMiD-1 (clinically known as REVIMID™). Our results show that anti-angiogenic activity spans both currently defined classes of thalidomide analogue and is not related to their previously described immunomodulatory properties. Identification of the differential effects of these compounds will enable targeting of such compounds into the appropriate clinical setting. British Journal of Cancer (2002) 87, 1166–1172. doi:10.1038/sj.bjc.6600607 www.bjcancer.com © 2002 Cancer Research UK PMID:12402158

Dredge, K; Marriott, J B; Macdonald, C D; Man, H-W; Chen, R; Muller, G W; Stirling, D; Dalgleish, A G

2002-01-01

65

The macrophage in HIV-1 infection: From activation to deactivation?  

PubMed Central

Macrophages play a crucial role in innate and adaptative immunity in response to microorganisms and are an important cellular target during HIV-1 infection. Recently, the heterogeneity of the macrophage population has been highlighted. Classically activated or type 1 macrophages (M1) induced in particular by IFN-? display a pro-inflammatory profile. The alternatively activated or type 2 macrophages (M2) induced by Th-2 cytokines, such as IL-4 and IL-13 express anti-inflammatory and tissue repair properties. Finally IL-10 has been described as the prototypic cytokine involved in the deactivation of macrophages (dM). Since the capacity of macrophages to support productive HIV-1 infection is known to be modulated by cytokines, this review shows how modulation of macrophage activation by cytokines impacts the capacity to support productive HIV-1 infection. Based on the activation status of macrophages we propose a model starting with M1 classically activated macrophages with accelerated formation of viral reservoirs in a context of Th1 and proinflammatory cytokines. Then IL-4/IL-13 alternatively activated M2 macrophages will enter into the game that will stop the expansion of the HIV-1 reservoir. Finally IL-10 deactivation of macrophages will lead to immune failure observed at the very late stages of the HIV-1 disease. PMID:20380696

2010-01-01

66

Immunomodulatory and Hemagglutinating Activities of Acidic Polysaccharides Isolated from Combretum racemosum  

PubMed Central

Extracts of leaves of different species of the genus Combretum have been used historically to treat a variety of medicinal problems. However, little is known about the active components conferring therapeutic properties to these extracts. In the present studies, we evaluated biochemical properties and immunomodulatory activity of polysaccharides isolated from the leaves of Combretum racemosum. Water-soluble polysaccharides from leaves of C. racemosum were extracted and fractionated by DEAE-cellulose and Diaion HP-20 to obtain a Diaion-bound fraction, designated Combretum polysaccharide-acidic bound or CP-AB, which was eluted with methanol, and an unbound fraction, designated as CP-AU. Molecular weight determination, sugar analysis, and other physical and chemical characterization of the fractions were performed. Fraction CP-AU (mol. weight 5.0 kDa) contained type II arabinogalactan and had potent immunomodulatory activity, inducing the production of interleukin (IL)-1?, -6, -10, and tumor necrosis factor-? (TNF-?) by human peripheral blood mononuclear cells (PBMC) and MonoMac-6 monocytic cells. Likewise, intraperitoneal administration of CP-AU increased in vivo serum levels of IL-6 and monocyte chemoattractant protein-1 (MCP-1) in mice. CP-AU-induced secretion of TNF-? in PBMC was prevented by Toll-like receptor 4 (TLR4) antagonist LPS-RS. Treatment with CP-AU induced phosphorylation of Akt2, Akt3, GSK-3?, HSP27, mTOR, and all p38 MAPK isoforms (?, ?, ?, and ?), as well as stimulation of AP-1/NF-?B transcriptional activity. In addition, CP-AU effectively agglutinated erythrocytes from several species, including human, mouse, and rabbit. In contrast, fraction CP-AB was inactive in all biological tests, including cytokine production and hemagglutination. These data suggest that at least part of the beneficial therapeutic effects reported for the water extracts of leaves from C. racemosum are due to modulation of leukocyte functions. PMID:23380150

Schepetkin, Igor A.; Kouakou, Koffi; Yapi, Ahoua; Kirpotina, Liliya N.; Jutila, Mark A.; Quinn, Mark T.

2013-01-01

67

Immunomodulatory and hemagglutinating activities of acidic polysaccharides isolated from Combretum racemosum.  

PubMed

Extracts of leaves of different species of the genus Combretum have been used historically to treat a variety of medicinal problems. However, little is known about the active components conferring therapeutic properties to these extracts. In the present studies, we evaluated biochemical properties and immunomodulatory activity of polysaccharides isolated from the leaves of Combretum racemosum. Water-soluble polysaccharides from leaves of C. racemosum were extracted and fractionated by DEAE-cellulose and Diaion HP-20 to obtain a Diaion-bound fraction, designated Combretum polysaccharide-acidic bound or CP-AB, which was eluted with methanol, and an unbound fraction, designated as CP-AU. Molecular weight determination, sugar analysis, and other physical and chemical characterization of the fractions were performed. Fraction CP-AU (mol. weight 5.0 kDa) contained type II arabinogalactan and had potent immunomodulatory activity, inducing the production of interleukin (IL)-1?, -6, -10, and tumor necrosis factor-? (TNF-?) by human peripheral blood mononuclear cells (PBMC) and MonoMac-6 monocytic cells. Likewise, intraperitoneal administration of CP-AU increased in vivo serum levels of IL-6 and monocyte chemoattractant protein-1 (MCP-1) in mice. CP-AU-induced secretion of TNF-? in PBMC was prevented by Toll-like receptor 4 (TLR4) antagonist LPS-RS. Treatment with CP-AU induced phosphorylation of Akt2, Akt3, GSK-3?, HSP27, mTOR, and all p38 MAPK isoforms (?, ?, ?, and ?), as well as stimulation of AP-1/NF-?B transcriptional activity. In addition, CP-AU effectively agglutinated erythrocytes from several species, including human, mouse, and rabbit. In contrast, fraction CP-AB was inactive in all biological tests, including cytokine production and hemagglutination. These data suggest that at least part of the beneficial therapeutic effects reported for the water extracts of leaves from C. racemosum are due to modulation of leukocyte functions. PMID:23380150

Schepetkin, Igor A; Kouakou, Koffi; Yapi, Ahoua; Kirpotina, Liliya N; Jutila, Mark A; Quinn, Mark T

2013-03-01

68

Enhanced Immunomodulatory Activity of Gelatin-Encapsulated Rubus coreanus Miquel Nanoparticles  

PubMed Central

The aim of this work was to investigate the immunomodulatory activities of Rubus coreanus Miquel extract-loaded gelatin nanoparticles. The mean size of the produced nanoparticles was 143 ± 18 nm with a bandwidth of 76 nm in the size distribution and a maximum size of ~200 nm, which allows effective nanoparticle uptake by cells. Confocal imaging confirmed this, since the nanoparticles were internalized within 30 min and heterogeneously distributed throughout the cell. Zeta-potential measurements showed that from pH = 5 onwards, the nanoparticles were highly negatively charged, which prevents agglomeration to clusters by electrostatic repulsion. This was confirmed by TEM imaging, which showed a well dispersed colloidal solution. The encapsulation efficiency was nearly 60%, which is higher than for other components encapsulated in gelatin nanoparticles. Measurements of immune modulation in immune cells showed a significant effect by the crude extract, which was only topped by the nanoparticles containing the extract. Proliferation of B-, T- and NK cells was notably enhanced by Rubus coreanus-gelatin nanoparticles and in general ~2–3 times higher than control and on average ~2 times higher than ferulic acid. R. coreanus-gelatin nanoparticles induced cytokine secretion (IL-6 and TNF-?) from B- and T-cells on average at a ~2–3 times higher rate compared with the extract and ferulic acid. In vivo immunomodulatory activity in mice fed with R. coreanus-gelatin nanoparticles at 1 mL/g body weight showed a ~5 times higher antibody production compared to control, a ~1.3 times higher production compared to the extract only, and a ~1.6 times higher production compared to ferulic acid. Overall, our results suggest that gelatin nanoparticles represent an excellent transport vehicle for Rubus coreanus extract and extracts from other plants generally used in traditional Asian medicine. Such nanoparticles ensure a high local concentration that results in enhancement of immune cell activities, including proliferation, cytokine secretion, and antibody production. PMID:22272118

Seo, Yong Chang; Choi, Woon Yong; Lee, Choon Geun; Cha, Seon Woo; Kim, Young Ock; Kim, Jin-Chul; Drummen, Gregor P. C.; Lee, Hyeon Yong

2011-01-01

69

The FGL2/fibroleukin prothrombinase is involved in alveolar macrophage activation in COPD through the MAPK pathway  

SciTech Connect

Fibrinogen-like protein 2 (FGL2)/fibroleukin has been reported to play a vital role in the pathogenesis of some critical inflammatory diseases by possessing immunomodulatory activity through the mediation of 'immune coagulation' and the regulation of maturation and proliferation of immune cells. We observed upregulated FGL2 expression in alveolar macrophages from peripheral lungs of chronic obstructive pulmonary disease (COPD) patients and found a correlation between FGL2 expression and increased macrophage activation markers (CD11b and CD14). The role of FGL2 in the activation of macrophages was confirmed by the detection of significantly decreased macrophage activation marker (CD11b, CD11c, and CD71) expression as well as the inhibition of cell migration and inflammatory cytokine (IL-8 and MMP-9) production in an LPS-induced FGL2 knockdown human monocytic leukemia cell line (THP-1). Increased FGL2 expression co-localized with upregulated phosphorylated p38 mitogen-activated protein kinase (p38-MAPK) in the lung tissues from COPD patients. Moreover, FGL2 knockdown in THP-1 cells significantly downregulated LPS-induced phosphorylation of p38-MAPK while upregulating phosphorylation of c-Jun N-terminal kinase (JNK). Thus, we demonstrate that FGL2 plays an important role in macrophage activation in the lungs of COPD patients through MAPK pathway modulation.

Liu, Yanling; Xu, Sanpeng; Xiao, Fei; Xiong, Yan; Wang, Xiaojin; Gao, Sui; Yan, Weiming [Department and Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030 (China)] [Department and Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030 (China); Ning, Qin, E-mail: qning@tjh.tjmu.edu.cn [Department and Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030 (China)] [Department and Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030 (China)

2010-05-28

70

Influence of Alternatively and Classically Activated Macrophages on Fibrogenic Activities of Human Fibroblasts  

Microsoft Academic Search

Activated macrophages regulate fibrogenesis by providing cytokines and growth factors that modulate the proliferation and collagen synthesis of fibroblasts. However, macrophages can be activated in a classical pathway induced by LPS or IFN-? and an alternative pathway induced by IL-4 or glucocorticoid. Differently activated macrophages display distinct biological features. To clarify the difference between these two subsets of macrophages in

Erwei Song; Nengtai Ouyang; Markus Hörbelt; Balazs Antus; Minghui Wang; Michael S. Exton

2000-01-01

71

Sulfated modification of longan polysaccharide and its immunomodulatory and antitumor activity in vitro.  

PubMed

A water-soluble polysaccharide fraction (LP1) was prepared from Dimocarpus longan Lour. by hot water extraction, DEAE-cellulose and Sephadex G-100 chromatography. Its sulfated derivative (LP1-S) was prepared by the sulfuric acid method. Preliminary tests in vitro showed LP1 and LP1-S could stimulate murine lymphocytes proliferation, increase pinocytic activity of murine macrophages and production of nitric oxide (NO), interleukin 6 (IL-6), IL-1? and tumor necrosis factor-alpha (TNF-?) in macrophages. Furthermore, LP1-S exhibited higher antiproliferative activity against human nasopharyngeal carcinoma HONE1 cells in vitro than LP1, which might be caused by the sulfate group in its structures. These results indicated that the LP1-S might be useful for developing safe antitumor drugs or health food. PMID:24680807

Jiang, Jie; Meng, Fa-Yan; He, Zhou; Ning, Yuan-Ling; Li, Xue-Hua; Song, Hui; Wang, Jing; Zhou, Rui

2014-06-01

72

Screening of immunomodulatory activity of total and protein extracts of some Moroccan medicinal plants.  

PubMed

Herbal and traditional medicines are being widely used in practice in many countries for their benefits of treating different ailments. A large number of plants in Morocco were used in folk medicine to treat immune-related disorders. The objective of this study is to evaluate the immunomodulatory activity of protein extracts (PEs) of 14 Moroccan medicinal plants. This activity was tested on the proliferation of immune cells. The prepared total and PEs of the plant samples were tested using MTT (3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide) assay on the splenocytes with or without stimulation by concanavalin-A (Con-A), a mitogenic agent used as positive control. The results of this study indicated different activity spectra. Three groups of activities were observed. The first group represented by Citrullus colocynthis, Urtica dioica, Elettaria cardamomum, Capparis spinosa and Piper cubeba showed a significant immunosuppressive activity. The second group that showed a significant immunostimulatory activity was represented by Aristolochia longa, Datura stramonium, Marrubium vulgare, Sinapis nigra, Delphynium staphysagria, Lepidium sativum, Ammi visnaga and Tetraclinis articulata. The rest of the plant extracts did not alter the proliferation induced by Con-A. This result was more important for the PE than for the total extract. In conclusion, this study revealed an interesting immunomodulating action of certain PEs, which could explain their traditional use. The results of this study may also have implications in therapeutic treatment of infections, such as prophylactic and adjuvant with cancer chemotherapy. PMID:22301818

Daoudi, Abdeljlil; Aarab, Lotfi; Abdel-Sattar, Essam

2013-04-01

73

Evaluation of a topical herbal drug for its in-vivo immunomodulatory effect on cytokines production and antibacterial activity in bovine subclinical mastitis  

PubMed Central

Background: Antibiotics have been in use in the treatment of bovine mastitis since decades; however, their use is associated with cost issues and human health concern. Use of herbal drugs does not generally carry these disadvantages. Many plants/herbs have been evaluated in the treatment of bovine mastitis with additional property of immunomodulation in affected mammary gland. Aim: To evaluate a topical herbal drug in two breeds of cattle for its in-vivo immunomodulatory effect on cytokines production and antibacterial activity in bovine subclinical mastitis. Materials and Methods: The response to treatment was evaluated by enumerating somatic cell count (SCC), determining total bacterial load, and studying the expression of different cytokines (interleukin [IL]-6, IL-8, IL-12, granulocyte macrophage-colony stimulating factor, interferon (IFN)-? and tumor necrosis factor [TNF]-?). Results: The pre- and post-treatment SCC in mastitic quarters statistically did not differ significantly, however, total bacterial load declined significantly from day 0 onwards in both the breeds. Highly significant differences (P < 0.01) were observed in all the cytokines on day 0, 5, and 21 postlast treatment in both the breeds. The expression level of all the cytokines showed a significant increase on day 5, while a decrease was noticed on day 21 in both the breeds of cattle. The comparison of cytokine expression profiles between crossbred and Gir cattle revealed a significant difference in expression of IL-6 and TNF-?. However, other cytokines exhibited a similar pattern of expression in both breeds, which was non-significant. Conclusion: The topical herbal drug exhibited antibacterial and immunomodulatory activities in subclinical mastitis and thus the work supports its use as alternative herbal therapy against subclinical udder infection in bovines.

Bhatt, Vaibhav D.; Shah, Tejas M.; Nauriyal, Dev S.; Kunjadia, Anju P.; Joshi, Chaitanya G.

2014-01-01

74

In vitro immunomodulatory activity of Bo-yang-hwan-o-tang.  

PubMed

Bo-yang-hwan-o-tang (BHT), an herbal decoction has been mainly used for improvement of blood flow in oriental medicine. Its in vivo immunomodulation was recently demonstrated but the effective mechanisms have not been described. This study was carried out to evaluate in vitro immunomodulatory activity of BHT. Water extract of BHT significantly promoted in vitro proliferative responses of mouse spleen cells (SPC) and also further enhanced the proliferation of SPC stimulated with anti-CD3 antibody. Unexpectedly, addition of BHT extract did not affect proliferation of both resting and CD3-activated T cells, whereas it showed a strong mitogenic activity on B cells. Flow cytometric analysis of CFSE-stained SPC showed that BHT-mediated enhancement of CD3-activated SPC proliferation is due to T cell, but not B cell, division. Mixed culture experiment combining T and mitomycin C-treated B cells demonstrated that BHT-mediated enhancement of CD3-activated T cell proliferation was dependent on the presence of B cells. However, B cell-derived factors were not involved in BHT effect on T cell proliferation. In the presence of B cells, BHT treatment resulted in a great enhancement in IL-2 production of CD3-activated T cells, and BHT effect on T cell proliferation was completely abrogated by addition of exogenous IL-2, indicating that IL-2 plays a critical role in BHT-mediated enhancement of CD3-activated T cell proliferation. Taken together, our data revealed that BHT possesses a potent B cell mitogenic activity and also can enhance activated T cell response through B cell regulation. PMID:15658611

Kim, Young-Hyun; Ha, Jong-Cheon; Do, Jeong-Su; Choi, Youn-Hwa; Choo, Young Kug; Woo, Won-Hong; Yi, Ho Keun; Hwang, Pyung Han; Nam, Sang-Yun

2004-01-01

75

Anti-Inflammatory and Immunomodulatory Activities of Stevioside and Its Metabolite Steviol on THP-1 Cells.  

PubMed

Stevioside, a natural noncaloric sweetener isolated from Stevia rebaudiana Bertoni, possesses anti-inflammatory and antitumor promoting properties; however, no information is available to explain its activity. The aim of this study was to elucidate the anti-inflammatory and immunomodulatory activities of stevioside and its metabolite, steviol. Stevioside at 1 mM significantly suppressed lipopolysaccharide (LPS)-induced release of TNF-alpha and IL-1beta and slightly suppressed nitric oxide release in THP-1 cells without exerting any direct toxic effect, whereas steviol at 100 microM did not. Activation of IKKbeta and transcription factor NF-kappaB were suppressed by stevioside, as demonstrated by Western blotting. Furthermore, only stevioside induced TNF-alpha, IL-1beta, and nitric oxide release in unstimulated THP-1 cells. Release of TNF-alpha could be partially neutralized by anti-TLR4 antibody. This study suggested that stevioside attenuates synthesis of inflammatory mediators in LPS-stimulated THP-1 cells by interfering with the IKKbeta and NF-kappaB signaling pathway, and stevioside-induced TNF-alpha secretion is partially mediated through TLR4. PMID:16448183

Boonkaewwan, Chaiwat; Toskulkao, Chaivat; Vongsakul, Molvibha

2006-02-01

76

JUNB Is a Key Transcriptional Modulator of Macrophage Activation.  

PubMed

Activated macrophages are crucial for restriction of microbial infection but may also promote inflammatory pathology in a wide range of both infectious and sterile conditions. The pathways that regulate macrophage activation are therefore of great interest. Recent studies in silico have putatively identified key transcription factors that may control macrophage activation, but experimental validation is lacking. In this study, we generated a macrophage regulatory network from publicly available microarray data, employing steps to enrich for physiologically relevant interactions. Our analysis predicted a novel relationship between the AP-1 family transcription factor Junb and the gene Il1b, encoding the pyrogen IL-1?, which macrophages express upon activation by inflammatory stimuli. Previously, Junb has been characterized primarily as a negative regulator of the cell cycle, whereas AP-1 activity in myeloid inflammatory responses has largely been attributed to c-Jun. We confirmed experimentally that Junb is required for full expression of Il1b, and of additional genes involved in classical inflammation, in macrophages treated with LPS and other immunostimulatory molecules. Furthermore, Junb modulates expression of canonical markers of alternative activation in macrophages treated with IL-4. Our results demonstrate that JUNB is a significant modulator of both classical and alternative macrophage activation. Further, this finding provides experimental validation for our network modeling approach, which will facilitate the future use of gene expression data from open databases to reveal novel, physiologically relevant regulatory relationships. PMID:25472994

Fontana, Mary F; Baccarella, Alyssa; Pancholi, Nidhi; Pufall, Miles A; Herbert, De'Broski R; Kim, Charles C

2015-01-01

77

Characterization of Two Homogalacturonan Pectins with Immunomodulatory Activity from Green Tea  

PubMed Central

Two natural homogalacturonan (HG) pectins (MW ca. 20 kDa) were isolated from green tea based on their immunomodulatory activity. The crude tea polysaccharides (TPS1 and TPS2) were obtained from green tea leaves by hot water extraction and followed by 40% and 70% ethanol precipitation, respectively. Two homogenous water soluble polysaccharides (TPS1-2a and TPS1-2b) were obtained from TPS1 after purification with gel permeation, which gave a higher phagocytic effect than TPS2. A combination of composition, methylation and configuration analyses, as well as NMR (nuclear magnetic resonance) spectroscopy revealed that TPS1-2a and TPS1-2b were homogalacturonan (HG) pectins consisting of a backbone of 1,4-linked ?-d-galacturonic acid (GalA) residues with 28.4% and 26.1% of carboxyl groups as methyl ester, respectively. The immunological assay results demonstrated that TPS1-2, which consisted mainly of HG pectins, showed phagocytosis-enhancing activity in HL-60 cells. PMID:24901527

Wang, Huijun; Wei, Guodong; Liu, Fei; Banerjee, Gautam; Joshi, Manoj; Bligh, S. W. Annie; Shi, Songshan; Lian, Hui; Fan, Hongwei; Gu, Xuelan; Wang, Shunchun

2014-01-01

78

Evaluation of the immunomodulatory activities of royal jelly components in vitro.  

PubMed

In this work the effect of different components isolated from royal jelly (RJ) was studied using an in vitro rat T-cell proliferation assay. We found that lower concentrations of MEL 174 (final water extract of RJ) and MEL 147 (3-10-dihydroxydecanoic acid) stimulated T-cell proliferation, triggered by concanavalin A (Con-A) and the process was followed by an increase in the production of interleukin-2 (IL-2). Higher concentrations of MEL 174, MEL 247 (dry powder of RJ) and MEL 138 (trans-10-hydroxydec-2-enoic acid) inhibited T-cell proliferation. The inhibition of T-cell proliferation in the presence of MEL 174 was followed by a decrease in IL-2 production, which was partly abrogated by exogenous IL-2, a decrease in nitric oxide (NO) production and increased apoptosis. In conclusion, our results showed the complexity of biological activity of RJ and suggest that its water extract possesses the most potent immunomodulatory activity in vitro. PMID:18075862

Gasic, Sonja; Vucevic, Dragana; Vasilijic, Sasa; Antunovic, Mirjana; Chinou, Ioanna; Colic, Miodrag

2007-01-01

79

Characterization of two homogalacturonan pectins with immunomodulatory activity from green tea.  

PubMed

Two natural homogalacturonan (HG) pectins (MW ca. 20 kDa) were isolated from green tea based on their immunomodulatory activity. The crude tea polysaccharides (TPS1 and TPS2) were obtained from green tea leaves by hot water extraction and followed by 40% and 70% ethanol precipitation, respectively. Two homogenous water soluble polysaccharides (TPS1-2a and TPS1-2b) were obtained from TPS1 after purification with gel permeation, which gave a higher phagocytic effect than TPS2. A combination of composition, methylation and configuration analyses, as well as NMR (nuclear magnetic resonance) spectroscopy revealed that TPS1-2a and TPS1-2b were homogalacturonan (HG) pectins consisting of a backbone of 1,4-linked ?-D-galacturonic acid (GalA) residues with 28.4% and 26.1% of carboxyl groups as methyl ester, respectively. The immunological assay results demonstrated that TPS1-2, which consisted mainly of HG pectins, showed phagocytosis-enhancing activity in HL-60 cells. PMID:24901527

Wang, Huijun; Wei, Guodong; Liu, Fei; Banerjee, Gautam; Joshi, Manoj; Bligh, S W Annie; Shi, Songshan; Lian, Hui; Fan, Hongwei; Gu, Xuelan; Wang, Shunchun

2014-01-01

80

The immunomodulatory activity of Staphylococcus aureus products derived from biofilm and planktonic cultures.  

PubMed

Biofilms are probably one of the most common structures formed by microorganisms in various environments. The higher resistance of such microbial communities to stress conditions, including antibiotics and host immune response, is recently extensively studied. However, the weak activity of phagocytic cells against microbial biofilm is not yet fully understood and explained. The aim of this study was: (1) a qualitative and quantitative comparison of cell components/products released from Staphylococcus aureus biofilm or planktonic cultures, (2) evaluation of the influence of such cell components/products on murine leukocytes secretory function. For this, mouse peritoneal leukocytes were stimulated with biofilm or planktonic staphylococcal cultures or their acellular filtrates, and then the production of cytokines (TNF-?, IL-6, IL-10, MCP-1 and MIP-1?), hemolytic activity and staphylokinase (SAK) production was determined. It was found that similar staphylococcal components/products possessing the immunomodulatory properties, were present in both, biofilm and planktonic filtrates. Moreover, these compounds were similarly active in the stimulation of TNF-? and MCP-1 release from leukocytes. The hemolytic activity and SAK release by planktonic and biofilm cultures were also comparable. What is interesting, stronger stimulatory activity of biofilm-derived components/products of clinical S. aureus strains in the case of MIP-1?, IL-6 and IL-10 was noticed. On the other hand, taking into consideration the reference strains, MIP-1? production was enhanced by "planktonic filtrates". Thus, in our study it was proved, first of all, that biofilm is not a structure fully separated from the external environment. Second, the influence of these S. aureus constituents/metabolites on leukocytes seems to be more strain-dependent than culture phenotype-dependent. The lack of one common profile of biofilm and planktonic S. aureus cultures/filtrates biological activity indicates that the disturbances in cytokines' production could not be the only reason for the so-called "frustrated phagocytosis", connected with enhanced biofilm resistance. PMID:23925370

Sadowska, Beata; Wi?ckowska-Szakiel, Marzena; Paszkiewicz, Ma?gorzata; Ró?alska, Barbara

2013-10-01

81

Effect of ultra high pressure processing on immuno-modulatory activities of the fruits of Rubus coreanus Miquel  

Microsoft Academic Search

In this study, the most optimal extraction conditions as regards to the immuno-modulatory activity of Rubus coreanus were determined to be 500MPa with water at 60°C for 15min (HPE15). The extraction yield under these conditions was estimated to be 17.3%, which was higher than the yield obtained from the conventional extraction process (13.9%) with water at 100°C (NE100). For most

Yong Chang Seo; Woon Yong Choi; Ji Seon Kim; Chang Soon Yoon; Hye Won Lim; Jeong Sub Cho; Ju hee Ahn; Hyeon Yong Lee

2011-01-01

82

Immunomodulatory activity of methanolic fruit extract of Aegle marmelos in experimental animals  

PubMed Central

Aim The aim of the present study was to investigate the immunomodulatory action of methanolic extract of Aegle marmelos fruit (FEAM) in experimental model of immunity. Methods Cellular immunity was carried out by neutrophil adhesion test and carbon clearance assay, whereas, humoral immunity was analyzed by mice lethality test and indirect haemagglutination assay. FEAM dose was selected by Stair case method (up and down) and administered at 100 and 500 mg/kg orally. The Ocimum sanctum (OSE, 100 mg/kg, p.o) was used as standard. Results FEAM at 100 and 500 mg/kg produced significant increases in adhesion of neutrophils and an increase in phagocytic index in carbon clearance assay. Both high and low doses of FEAM significantly prevented the mortality induced by bovine Pasteurella multocida in mice. Treatment of animals with FEAM and OSE significantly increased the circulating antibody titre in indirect haemagglunation test. Among the different doses, low one was more effective in cellular immunity models than the high. However, all the doses exhibited similar protection in humoral immunity procedures. Conclusion From the above findings, it is concluded that FEAM possesses potential for augmenting immune activity by cellular and humoral mediated mechanisms more at low dose (100 mg/kg) than high dose (500 mg/kg). PMID:23964175

Patel, Phatru; Asdaq, Syed Mohammed Basheeruddin

2010-01-01

83

Toll-like receptor 4-mediated ROS signaling pathway involved in Ganoderma atrum polysaccharide-induced tumor necrosis factor-? secretion during macrophage activation.  

PubMed

Ganoderma atrum has been used as Chinese traditional medicine and healthful mushroom for thousands of years. The polysaccharide is regarded as the major bioactive substances in G. atrum. To delineate the underlying mechanism and signaling cascade involved in the immunomodulatory property of G. atrum polysaccharide (PSG-1). Specifically, this study is designed to examine the possibility of TLR4 as a candidate receptor interacted with G. atrum polysaccharide (PSG-1) and elucidate the role of reactive oxygen species (ROS) in PSG-1-induced tumor necrosis factor-? (TNF-?) production during macrophage activation. Flow cytometric and confocal laser-scanning microscopy analysis showed that fluorescence-labeled PSG-1 bind specifically to the macrophages. Moreover, PSG-1 stimulated TNF-? secretion of peritoneal macrophages from C3H/HeN mice, but not from C3H/HeJ mice. PSG-1-indcued TNF-? production was suppressed by anti-TLR4 mAb. Furthermore, ROS production was mediated by TLR4, and NADPH oxidase-derived ROS act as upstream of phosphoinositide 3-kinase(PI3K)/Akt/mitogen-activated protein kinases(MAPKs)/nuclear factor(NF)-?B signaling pathway in the regulation of PSG-1 stimulated TNF-? production. Taken together, we conclude that PSG-1 induces TNF-? secretion through TLR4/ROS/PI3K/Akt/MAPKs/NF-?B pathways during macrophage activation. Our findings provide a molecular basis for the potential of PSG-1 as a novel immunomodulatory agent. PMID:24447977

Yu, Qiang; Nie, Shao-Ping; Wang, Jun-Qiao; Yin, Peng-Fei; Huang, Dan-Fei; Li, Wen-Juan; Xie, Ming-Yong

2014-04-01

84

Immunomodulatory mechanisms of lactobacilli  

PubMed Central

Abstract Over the past decade it has become clear that lactobacilli and other probiotic and commensal organisms can interact with mucosal immune cells or epithelial cells lining the mucosa to modulate specific functions of the mucosal immune system. The most well understood signalling mechanisms involve the innate pattern recognition receptors such as Toll-like receptors, nucleotide oligomerization domain-like receptors and C-type lectin receptors. Binding of microbe-associated molecular patterns with these receptors can activate antigen presenting cells and modulate their function through the expression of surface receptors, secreted cytokines and chemokines. In vitro the cytokine response of human peripheral blood mononuclear cells and dendritic cells to lactobacilli can be strikingly different depending on both the bacterial species and the strain. Several factors have been identified in lactobacilli that influence the immune response in vitro and in vivo including cell surface carbohydrates, enzymes modifying the structure of lipoteichoic acids and metabolites. In mice mechanistic studies point to a role for the homeostatic control of inducible T regulatory cells in the mucosal tissues as one possible immunomodulatory mechanism. Increasing evidence also suggests that induction of epithelial signalling by intestinal lactobacilli can modulate barrier functions, defensin production and regulate inflammatory signalling. Other probiotic mechanisms include modulation of the T cell effector subsets, enhancement of humoral immunity and interactions with the epithelial-associated dendritic cells and macrophages. A major challenge for the future will be to gain more knowledge about the interactions occurring between lactobacilli and the host in vivo and to understand the molecular basis of innate signalling in response to whole bacteria which trigger multiple signalling pathways. PMID:21995674

2011-01-01

85

Maternal immune activation leads to activated inflammatory macrophages in offspring  

PubMed Central

Several epidemiological studies have shown an association between infection or inflammation during pregnancy and increased risk of autism in the child. In addition, animal models have illustrated that maternal inflammation during gestation can cause autism-relevant behaviors in the offspring; so called maternal immune activation (MIA) models. More recently, permanent changes in T cell cytokine responses were reported in children with autism and in offspring of MIA mice; however, the cytokine responses of other immune cell populations have not been thoroughly investigated in these MIA models. Similar to changes in T cell function, we hypothesized that following MIA, offspring will have long-term changes in macrophage function. To test this theory, we utilized the poly (I:C) MIA mouse model in C57BL/6J mice and examined macrophage cytokine production in adult offspring. Pregnant dams were given either a single injection of 20 mg/kg polyinosinic–polycytidylic acid, poly (I:C), or saline delivered intraperitoneally on gestational day 12.5. When offspring of poly (I:C) treated dams reached 10 weeks of age, femurs were collected and bone marrow-derived macrophages were generated. Cytokine production was measured in bone marrow-derived macrophages incubated for 24 h in either growth media alone, LPS, IL-4/LPS, or IFN-?/LPS. Following stimulation with LPS alone, or the combination of IFN-?/LPS, macrophages from offspring of poly (I:C) treated dams produced higher levels of IL-12(p40) (p < 0.04) suggesting an increased M1 polarization. In addition, even without the presence of a polarizing cytokine or LPS stimulus, macrophages from offspring of poly (I:C) treated dams exhibited a higher production of CCL3 (p = 0.05). Moreover, CCL3 levels were further increased when stimulated with LPS, or polarized with either IL-4/LPS or IFN-?/LPS (p < 0.05) suggesting a general increase in production of this chemokine. Collectively, these data suggest that MIA can produce lasting changes in macrophage function that are sustained into adulthood. PMID:24566386

Onore, Charity E.; Schwartzer, Jared J.; Careaga, Milo; Bennan, Robert F.; Ashwood, Paul

2015-01-01

86

Antiorthostatic suspension stimulates profiles of macrophage activation in mice  

NASA Technical Reports Server (NTRS)

The antiorthostatic suspension model simulates certain physiological effects of spaceflight. We have previously reported BDF1 mice suspended by the tail in the antiorthostatic orientation for 4 days express high levels of resistance to virulent Listeria monocytogenesinfection. In the present study, we examined whether the increased resistance to this organism correlates with profiles of macrophage activation, given the role of the macrophage in killing this pathogen in vivo. We infected BDF1 mice with a lethal dose of virulent L. monocytogenes on day 4 of antiorthostatic suspension and 24 h later constructed profiles of macrophage activation. Viable listeria could not be detected in mice suspended in the antiorthostatic orientation 24 h after infection. Flow cytometric analysis revealed the numbers of granulocytes and mononuclear phagocytes in the spleen of infected mice were not significantly altered as a result of antiorthostatic suspension. Splenocytes from antiorthostatically suspended infected mice produced increased titers of IL-1. Serum levels of neopterin, a nucleotide metabolite secreted by activated macrophages, were enhanced in mice infected during antiorthostatic suspension, but not in antiorthostatically suspended naive mice. Splenic macrophages from mice infected on day 4 of suspension produced enhanced levels of lysozyme. In contrast to the results from antiorthostatically suspended infected mice, macrophages from antiorthostatically suspended uninfected mice did not express enhanced bactericidal activities. The collective results indicate that antiorthostatic suspension can stimulate profiles of macrophage activation which correlate with increased resistance to infection by certain classes of pathogenic bacteria.

Miller, E. S.; Bates, R. A.; Koebel, D. A.; Sonnenfeld, G.

1999-01-01

87

Liver enzyme-mediated oxidation of Echinacea purpurea alkylamides: production of novel metabolites and changes in immunomodulatory activity.  

PubMed

The medicinal plant Echinacea is widely used to treat upper respiratory infections and is reported to stimulate the human immune system. A major constituent class of Echinacea, the alkylamides, has immunomodulatory effects. Recent studies show that alkylamides are oxidized by cytochrome P450 enzymes, but the immunomodulatory activity of these products is unknown. The objectives of this study were to characterize the products formed by incubation of an Echinacea extract and an isolated alkylamide with human liver microsomes, and to evaluate the influence of Echinacea alkylamides and metabolites on cytokine production by Jurkat human T cells. A novel class of carboxylic acid alkylamide metabolites was identified and shown to be the major constituents present after 2-h incubation of alkylamides with human liver microsomes. Echinacea alkylamides suppressed IL-2 secretion by stimulated T cells, and this effect was significantly lessened upon oxidation of the alkylamides to carboxylic acids and hydroxylated metabolites. These findings highlight the importance of considering the influence of liver enzyme metabolism when evaluating the immunomodulatory effects of alkylamides. PMID:17054047

Cech, Nadja B; Tutor, Katrina; Doty, Bethany A; Spelman, Kevin; Sasagawa, Masa; Raner, Gregory M; Wenner, Cynthia A

2006-12-01

88

Teriflunomide, an immunomodulatory drug, exerts anticancer activity in triple negative breast cancer cells.  

PubMed

Triple-negative breast cancer (TNBC) is defined as a group of primary breast cancers lacking expression of estrogen, progesterone, and human epidermal growth factor receptor-2 (HER-2) receptors, characterized by higher relapse rate and lower survival compared with other subtypes. Due to lack of identified targets and molecular heterogeneity, conventional chemotherapy is the only available option for treatment of TNBC, but non-discordant positive therapeutic efficacy could not be achieved. Here, we demonstrated that these TNBC cells were sensitive to teriflunomide, which was a well-known immunomodulatory drug for treatment of relapsing multiple sclerosis (MS). Potent anti-cancer effects in TNBC in vitro, including proliferation inhibition, cell cycle delay, cell apoptosis, and suppression of cell motility and invasiveness, could be achieved with this agent. Of note, we showed that multiple signals involved in TNBC proliferation, survival, migratory, and invasive potential were under regulation by teriflunomide. Among them, we identified down-regulation of growth factor receptors to abolish growth maintenance, suppression of c-Myc, and cyclin D1 to contribute to its anti-proliferative effect, modulation of components of cell cycle to induce S-phase arrest, degradation of Bcl-xL, and up-regulation of BAX via activation of MAPK pathway to induce apoptosis, and inhibition of epithelial-mesenchymal transition (EMT) process, matrix metalloproteinase-9 (MMP9) expression, and inactivation of Src/FAK to reduce TNBC migration and invasion. The results identified teriflunomide may be of therapeutic benefit for the more aggressive and difficult-to-treat breast cancer subtype, indicating the use of teriflunomide for clinical trials for treatment of TNBC patients. PMID:25304315

Huang, Ou; Zhang, Weili; Zhi, Qiaoming; Xue, Xiaofeng; Liu, Hongchun; Shen, Daoming; Geng, Meiyu; Xie, Zuoquan; Jiang, Min

2014-10-10

89

HDAC6 Deacetylase Activity Is Critical for Lipopolysaccharide-Induced Activation of Macrophages  

PubMed Central

Activated macrophages play an important role in both innate and adaptive immune responses, and aberrant activation of macrophages often leads to inflammatory and immune disorders. However, the molecular mechanisms of how macrophages are activated are not fully understood. In this study, we identify a novel role for histone deacetylse 6 (HDAC6) in lipopolysaccharide (LPS)-induced macrophage activation. Our data show that suppression of HDAC6 activity significantly restrains LPS-induced activation of macrophages and production of pro-inflammatory cytokines. Further study reveals that the regulation of macrophage activation by HDAC6 is independent of F-actin polymerization and filopodium formation; instead, it is mediated by the effects of HDAC6 on cell adhesion and microtubule acetylation. These data thus suggest that HDAC6 is an important regulator of LPS-induced macrophage activation and might be a potential target for the management of inflammatory disorders. PMID:25330030

Liu, Zhu; Ran, Jie; Li, Yuanyuan; Wang, Jian; Yang, Yang; Zhou, Jun; Li, Dengwen; Liu, Min

2014-01-01

90

Concomitant administration of fluoxetine and amantadine modulates the activity of peritoneal macrophages of rats subjected to a forced swimming test.  

PubMed

Recent studies show that administration of a non-competitive NMDA receptor antagonist, amantadine (AMA), potentiates the action of antidepressant drugs. Since antidepressants may modulate functioning of the immune system and activation of a pro-inflammatory response in depressive disorders is frequently reported, the aim of the present study was to examine whether a combined administration of AMA and the antidepressant, fluoxetine (FLU), to rats subsequently subjected to a forced swimming test (FST) modifies the parameters of macrophage activity, directly related to their immunomodulatory functions, i.e., arginase (ARG) activity and synthesis of nitric oxide (NO). We found that 10 mg/kg AMA and 10 mg/kg FLU, ineffective in FST for antidepressant-like activity when administered alone, increased the ARG/NO ratio in macrophages when administered concomitantly. This effect was accompanied by a decrease of cellular adherence. Concurrently, the basal metabolic activity of the cells measured with reduction of resazurin, and intracellular host defense as assessed by a synthesis of superoxide anion, were not affected by such antidepressive treatment. Our data indicate that co-administration of AMA and FLU decreases the pro-inflammatory properties of macrophages and causes a redirection of immune response toward anti-inflammatory activity, as one can anticipate in the case of an effective antidepressive treatment. PMID:20081242

Roman, Adam; Rogóz, Zofia; Kubera, Marta; Nawrat, Dominika; Nalepa, Irena

2009-01-01

91

Six immunosuppressive features from an ascomycete, Zopfiella longicaudata, found in a screening study monitored by immunomodulatory activity.  

PubMed

In a screening study on immunomodulatory fungal metabolites, three known anthraquinones, carviolin (roseo-purpurin) (1), 1-O-methylemodin (2), omega-hydroxyemodin (citreorosein) (4), and a new anthraquinone, omega-acetylcarviolin (3), together with a known steroid, ergosta-4,6,8(14),22-tetraen-3-one (5) and a new steroid, 25-hydroxyergosta-4,6,8(14),22-tetraen-3-one (6) were isolated from an Ascomycete, Zopfiella longicaudata, and found to have moderate immunosuppressive activities. The structure-activity relationships of these metabolites are discussed. PMID:15305003

Fujimoto, Haruhiro; Nakamura, Etsuko; Okuyama, Emi; Ishibashi, Masami

2004-08-01

92

The carotenoid lutein enhances matrix metalloproteinase-9 production and phagocytosis through intracellular ROS generation and ERK1/2, p38 MAPK, and RAR? activation in murine macrophages.  

PubMed

Early studies have demonstrated the ability of dietary carotenoids to enhance immune response, but the mechanism underlying their influence on macrophage activity remains unclear. Here, we investigated the effects of carotenoids on macrophage activity. Carotenoids, including lutein and lycopene, enhanced MMP-9 activity in RAW264.7 macrophages. Lutein was chosen as a representative and analyzed further in this study. It increased the synthesis, activity, and release of MMP-9 in murine RAW264.7 and primary-cultured peritoneal macrophages. MMP-9 induction by lutein was through the transcriptional regulation of mmp-9. It was blunted by the MAPK inhibitors targeting ERK1/2 and p38 MAPK, the reagents that inhibit free radical signaling, and the inhibitors and siRNA targeting RAR?. Moreover, lutein induced Nox activation and intracellular ROS production at an early stage of treatment. This carotenoid also caused ERK1/2 and p38 MAPK activation, RAR? expression, and RAR interaction with its responsive element in the promoter region. These findings suggest the involvement of ROS, MAPKs, and RAR? activation in lutein-driven MMP-9 expression and release. Interestingly, lutein enhanced the phagocytic activity of macrophages, and the secreted MMP-9 appeared to be involved in this process. In summary, we provide evidence here for the first time that the carotenoid lutein induces intracellular ROS generation and MAPK and RAR? activation in macrophages, leading to an increase in MMP-9 release and macrophage phagocytosis. Our results demonstrate that lutein exerts an immunomodulatory effect on macrophages. PMID:23431043

Lo, Huey-Ming; Chen, Chih-Li; Yang, Chuen-Mao; Wu, Pi-Hui; Tsou, Chih-Jen; Chiang, Kai-Wen; Wu, Wen-Bin

2013-05-01

93

Granuloma formation and in vitro macrophage activation in mice by mycoloyl glycolipids from Nocardia asteroides and related taxa.  

PubMed

Cord factor (trehalose 6,6'-dimycolate: TDM) is a well-known toxic glycolipid in Mycobacterium tuberculosis. We isolated various mycoloyl glycolipids from Nocardia asteroides 23,167 and related species which are closely related taxonomically to Mycobacterium. Since Nocardia is also an opportunistic pathogen co-infected with HIV, we examined in vivo granuloma formation and the in vitro macrophage activation in mice. We found that cord factor (TDM) and glucose monomycolate (GM) from Nocardia asteroides and Rhodococcus species with shorter chain mycolic acids also exhibited distinctive granuloma-forming activity in lungs, spleen and liver in mice and in vitro induction of prostaglandin E2 (PGE2) and interleukin 1 (IL-1) synthesis. We also found that mycoloyl glycolipids possessing trehalose or glucose as a carbohydrate moiety exhibited immunomodulatory activity, and that mycoloyl glycolipids with longer chain mycolic acids exhibited stronger activity in mice than did those with shorter chain mycolic acids. The mycoloyl glycolipids from Nocardia asteroides directly activated macrophages. Stimulation of above concentration with 0.16 microgram/ml of TDM or 0.8 microgram/ml of GM markedly enhanced production of PGE2 by mouse peritoneal macrophages. At higher concentrations above 100 micrograms/ml of TDM or 500 micrograms/ml of GM, IL-1 release was also enhanced. PMID:10097600

Han, Y; Kawada, N; Yano, I

1998-12-01

94

Characterization of the Placental Macrophage Secretome: Implications for Antiviral Activity  

PubMed Central

It is well documented that placental macrophages show lower levels of HIV-1 infection than monocyte-derived macrophages (MDM). We used proteomic methods to test the hypothesis that placental macrophages secrete different proteins as compared to MDM that may contribute to decreased HIV-1 replication. Placental macrophages and MDM were cultured for 12 days and supernatant was collected. To characterize supernatants, the protein profiles of placental macrophages and MDM were compared using the protein chip assay. Subsequently, proteins were separated by one-dimensional gel electrophoresis and identified by tandem mass spectrometry at the corresponding mass to charge (m/z) range of 5000–20,000. Significant differences were found between placental macrophages and MDM in seven protein peaks with m/z values of 6075, 6227, 11,662, 14,547, 6158, 7740, and 11,934 on the CM10 and IMAC chips. After sequencing and identification, five proteins were validated for differential expression in placental macrophages and MDM by Western blot analyses. Peroxiredoxin 5, found to be more abundant in placental macrophage supernatants, is important in the cellular antioxidant mechanisms, and other members of its family have shown antiviral activity. Cystatin B was less abundant in PM supernatant, and decreased intracellular levels have recently been shown to be associated with lower HIV-1 replication in placental macrophages than in MDM. This study elucidates for the first time the placental macrophage secretome corresponding to 5000–20,000 Da and advances our understanding of the proteins secreted in the placenta that can protect the fetus against HIV-1 and other viral infections. PMID:19070362

García, K.; García, V.; Laspiur, J.Pérez; Duan, F.; Meléndez, L.M.

2010-01-01

95

Macrophage activation by polysaccharide isolated from Astragalus membranaceus  

Microsoft Academic Search

We show that APS, a polysaccharide isolated from the roots of Astragalus membranaceus, significantly induces nitric oxide (NO) production and inducible NO synthase (iNOS) transcription through the activation of nuclear factor-?B\\/Rel (NF-?B\\/Rel). In vivo administration of APS induced NO production by peritoneal macrophages of B6C3F1 mice. APS also dose-dependently induced the production of NO in isolated mouse peritoneal macrophages and

Kun Yeong Lee; Young Jin Jeon

2005-01-01

96

Molecular characteristics of sulfated polysaccharides from Monostroma nitidum and their in vitro anticancer and immunomodulatory activities.  

PubMed

We investigated water-soluble sulfated polysaccharides isolated from Monostroma nitidum using ion-exchange chromatography to determine their molecular characteristics and biological activities. The crude and fractionated polysaccharides (F(1), F(2), and F(3)) consisted mostly of carbohydrates (58.3-91.9%), uronic acids (0-21.8%) and sulfates (1.8-17.7%) as well as varying amounts of proteins (1.6-9.4%). Their monosaccharide levels were significantly different including rhamnose (0-95.7%) and glucose (0-98.6%) content with small amounts of xylose (0.8-4.3%). These polysaccharides contained one or two subfractions with average molecular weights (M(w)) ranging from 94.4 to 1387×10(3) g/mol. The in vitro inhibitory activity (?75%) of the polysaccharides on a human cancer cell line (AGS) suggested that the polysaccharides had direct cytotoxic effects on the cancer cells. In addition, these hetero-polysaccharides (from the crude and F(1) and F(2) fractions) stimulated a macrophage cell line, Raw 264.7 cells, inducing considerable NO and PGE(2), production, which suggested that they could be strong immunomodulators. PMID:21145343

Karnjanapratum, Supatra; You, SangGuan

2011-03-01

97

Macrophages activated by Listeria monocytogenes induce organ-specific autoimmunity.  

PubMed Central

We have previously reported an experimental autoimmune model induced by the local infection of Listeria monocytogenes. The unilateral inoculation of virulent Listeria into a testis of a normal mouse induced a delayed-type hypersensitivity response against testicular antigen and caused autoimmune orchitis in the contralateral testis. The orchitis was transferred to naive mice by T cells from the intratesticularly infected mice. In this paper, we demonstrated that avirulent Listeria, which lacks the expression of listeriolysin O, failed to induce any anti-testicular responses or contralateral orchitis even when it was inoculated at a high dose into the testis. Furthermore, the intraperitoneal inoculation of virulent Listeria with testicular antigen induced the anti-testicular responses and orchitis although intraperitoneal inoculation of testicular antigen with avirulent Listeria failed to induce them. The difference between virulent and avirulent Listeria in the induction of anti-testicular responses was supposed to be dependent on the difference in macrophage activation by the two bacterial strains because, first, the anti-testicular responses were elicited in normal mice when macrophages from virulent Listeria-infected mice were intraperitoneally transferred with testicular antigen although no viable bacteria were detected from the macrophages, and secondly, in contrast, the intraperitoneal co-inoculation of macrophages from avirulent Listeria-infected mice and testicular antigen failed to elicit any anti-testicular responses. Finally, we found that the virulent Listeria-induced macrophages expressed a higher level of CD80 (B7-1) and CD86 (B7-2) molecules than did the avirulent Listeria-induced macrophages and naive peritoneal macrophages. These results thus suggest that virulent Listeria activates macrophages to induce autoreactive T cells while avirulent Listeria does not. The up-regulation of B7 molecules by virulent Listeria infection is a candidate of the mechanism for the activation of autoreactive T cells. Images Figure 2 Figure 4 PMID:9415037

Sonoda, K H; Matsuzaki, G; Nomura, A; Yamada, H; Hamano, S; Nakamura, T; Mukasa, A; Nomoto, K

1997-01-01

98

Anti-angiogenesis and immunomodulatory activities of an anti-tumor sesquiterpene bigelovin isolated from Inula helianthus-aquatica.  

PubMed

Bigelovin is a sesquiterpene lactone isolated from the plant Inula helianthus-aquatica which was traditionally used in cancer treatment in Yunnan, China. The potent apoptotic activities of bigelovin in human leukemia U937 cells were shown in our previous study. The present study investigated the anti-angiogenic and immunomodulatory effects of bigelovin using transgenic zebrafish Tg(fli1a:EGFP)y1 with fluorescent blood vessels and human peripheral blood mononuclear cells (PBMCs), respectively. Furthermore, the inhibitory activities of bigelovin on the human endothelial cell adhesion molecules (CAMs) were also examined. Our results showed that the growth of subintestinal vessels of the bigelovin-treated zebrafish embryos was significantly inhibited and the gene expressions in angiogenesis signaling pathways (e.g. Ang2 and Tie2) of the zebrafish were down-regulated after bigelovin treatment. Besides, the proliferation and Th1 cytokines productions (e.g. IFN-?, IL-2 and IL-12) were suppressed in bigelovin-treated PBMCs. On the other hand, bigelovin was shown to significantly inhibit the human monocyte adhesion to human endothelial cells and the gene expressions of inflammation-related CAMs (e.g. ICAM-1, VCAM-1 and E-selectin) were significantly down-regulated in bigelovin-treated human endothelial cells. In summary, our data provide the first evidence that bigelovin possesses anti-angiogenic and immunomodulatory activities, suggesting bigelovin may exert multi-target functions against cancer in animal models. PMID:23231968

Yue, Grace G L; Chan, Ben C L; Kwok, Hin-Fai; Wong, Yuk-Lau; Leung, Hoi-Wing; Ji, Chang-Jiu; Fung, Kwok-Pui; Leung, Ping-Chung; Tan, Ning-Hua; Lau, Clara B S

2013-01-01

99

Thymosin ?1 activates complement receptor-mediated phagocytosis in human monocyte-derived macrophages.  

PubMed

Thymosin ?1 (T?1) is a naturally occurring thymic peptide used worldwide in clinical trials for the treatment of infectious diseases and cancer. The immunomodulatory activity of T?1 on innate immunity effector cells has been extensively described, but its mechanism of action is not completely understood. We report that T?1-exposed human monocyte-derived macrophages (MDMs) assume the typical activated morphology also exhibited by lipopolysaccharide-activated MDMs, but show a comparatively higher ability of internalizing fluorescent beads and zymosan particles. T?1 exposure also promptly and dramatically stimulates MDM phagocytosis and killing of Aspergillus niger conidia starting as soon as 30 min after challenge. The effect is dose dependent and early coupled to low transcription of the proinflammatory cytokines tumor necrosis factor ? and interleukin-6 and unmodified Toll-like receptor expression. The T?1-stimulated phagocytosis is strictly dependent on the integrity of the microtubule network and protein kinase C activity and occurs by a variation in the classic zipper model, with recruitment of vinculin and actin at the phagosome exhibiting a punctate distribution. These findings indicate that, in human mature MDMs, T?1 implements pathogen internalization and killing via the stimulation of the complement receptor-mediated phagocytosis. Our observations document that T?1 is an early and potent activator of innate immunity and reinforce the concept of its pleiotropy. PMID:23797159

Serafino, Annalucia; Pica, Francesca; Andreola, Federica; Gaziano, Roberta; Moroni, Noemi; Moroni, Gabriella; Zonfrillo, Manuela; Pierimarchi, Pasquale; Sinibaldi-Vallebona, Paola; Garaci, Enrico

2014-01-01

100

Activation of peritoneal macrophages by berberine-type alkaloids in terms of induction of cytostatic activity.  

PubMed

The antitumour alkaloids, berberine and coralyne were investigated in terms of their ability to induce chemiluminescent responses and cytostatic activity in macrophages against tumour cells in vitro. Berberine hydrochloride and sulfate, and coralyne chloride, which had no direct tumoristatic activities at a concentration of less than 0.15 micrograms/ml, activated macrophages to inhibit the incorporation of tritiated thymidine into EL4 leukemic cells. The activation of cytostatic macrophages by berberine was not augmented by the addition of a suboptimal dose of macrophage activating factor (MAF). Furthermore, a marked chemiluminescent response of macrophages was induced by treatment with berberine as well as with MAF or lipopolysaccharide. These results show that berberine and coralyne are potent macrophage activators for inducing cytostatic activity against tumour cells in vitro. PMID:6392120

Kumazawa, Y; Itagaki, A; Fukumoto, M; Fujisawa, H; Nishimura, C; Nomoto, K

1984-01-01

101

Charcoal suspension for tumor labelling modifies macrophage activity in mice.  

PubMed

We have previously developed a charcoal suspension for injection into human breast cancers in order to facilitate their location during surgery. We observed that charcoal particles were ingested by intra and peritumoral macrophages, some of which carried the particles at some distance from the injection site. We studied the influence of the formulation parameters of the charcoal suspension for intratumoral injection on in vitro and in vivo activation and in vivo mobilization of mouse peritoneal macrophages after intra-peritoneal injection of 2 mL of each preparation. The influence of the charcoal origin (peat vs wood), granulometry, suspension vehicle (water for parenteral injection, vs saline), concentration and excipients were studied. Micronized peat charcoal in water for injection at the highest studied concentration reduced macrophage activation in vitro and in vivo. However, macrophage mobilization was weaker than after thioglycolate injection and did not seem to be charcoal dose-dependent. The additives incorporated in the charcoal suspension led in vivo to increased peritoneal macrophage activation and mobilization (mannitol, and glucose), only increased activation (polysorbate 80 and pluronic F68) or mobilization (dextran 40, egg lecithin, and cabosil), or inhibited both activation and mobilization (cremophor EL). PMID:10698356

Bonhomme-Faivre, L; Depraetere, P; Savelli, M P; Amdidouche, D; Bizi, E; Seiller, M; Orbach-Arbouys, S

2000-01-21

102

Umbilical cord-derived mesenchymal stem cells retain immunomodulatory and anti-oxidative activities after neural induction?  

PubMed Central

The immunomodulatory and anti-oxidative activities of differentiated mesenchymal stem cells contribute to their therapeutic efficacy in cell-replacement therapy. Mesenchymal stem cells were isolated from human umbilical cord and induced to differentiate with basic fibroblast growth factor, nerve growth factor, epidermal growth factor, brain-derived neurotrophic factor and forskolin. The mesenchymal stem cells became rounded with long processes and expressed the neural markers, Tuj1, neurofilament 200, microtubule-associated protein-2 and neuron-specific enolase. Nestin expression was significantly reduced after neural induction. The expression of immunoregulatory and anti-oxidative genes was largely unchanged prior to and after neural induction in mesenchymal stem cells. There was no significant difference in the effects of control and induced mesenchymal stem cells on lymphocyte proliferation in co-culture experiments. However, the expression of human leukocyte antigen-G decreased significantly in induced neuron-like cells. These results suggest that growth factor-based methods enable the differentiation of mesenchymal stem cell toward immature neuronal-like cells, which retain their immunomodulatory and anti-oxidative activities. PMID:25337112

Li, Jianjun; Li, Dong; Ju, Xiuli; Shi, Qing; Wang, Dakun; Wei, Fengcai

2012-01-01

103

Biotechnological Approach to Evaluate the Immunomodulatory Activity of Ethanolic Extract of Tinospora cordifolia Stem (Mango Plant Climber)  

PubMed Central

The present study was designed to investigate the immunomodulatory activity of the ethanolic extract of Tinospora cordifolia (Family: Menispermaceae) stem (climbing shrub, mango plant) at cellular level. For antioxidant study, the liver mitochondria were separated and the concentration of enzymes like lipid peroxidation (LPO), reduced glutathione (GSH), catalase (CAT) and superoxide Dismutase (SOD) were estimated; melatonin secretion characterization was carried out through SDS-PAGE. The spleen lymphocyte proliferation assay was performed through measuring its optical density at 570 nm using Elisa Reader. The cytokines viz. IL-2, IL-10 and TNF-? expression in spleen cells were determined through Real Time PCR. Tinospora cordifolia (Tc) ethanolic extract (100 mg/Kg/p.o.) increased the level of liver mitochondrial enzymes like GSH, CAT and SOD but decreased the level of LPO in liver as compared to the vehicle, SRBC and cyclophosphamide-treated groups. The secretion of melatonin via pineal gland was enhanced with Tc treatment. The extract also increased the spleen lymphocyte proliferation. In RT-PCR analysis, the expression of cytokines viz. IL-2, IL-10 and TNF-? was more in Tc-treated animals than vehicle and cyclophosphamide treatment. Hence, the study confirms the immunomodulatory activity of Tc stem through altering the concentration of antioxidant enzymes, increasing T and B cells and antibody which play an important role in immunity, enhancing the concentration of melatonin in pineal gland and increasing the level of cytokines like IL-2, IL-10 and TNF-? which plays an important role in immunity. PMID:24250513

Aher, Vaibhav; Kumar Wahi, Arun

2012-01-01

104

Periodontitis-activated monocytes/macrophages cause aortic inflammation  

PubMed Central

A relationship between periodontal disease and atherosclerosis has been suggested by epidemiological studies. Ligature-induced experimental periodontitis is an adequate model for clinical periodontitis, which starts from plaque accumulation, followed by inflammation in the periodontal tissue. Here we have demonstrated using a ligature-induced periodontitis model that periodontitis activates monocytes/macrophages, which subsequently circulate in the blood and adhere to vascular endothelial cells without altering the serum TNF-? concentration. Adherent monocytes/macrophages induced NF-?B activation and VCAM-1 expression in the endothelium and increased the expression of the TNF-? signaling cascade in the aorta. Peripheral blood-derived mononuclear cells from rats with experimental periodontitis showed enhanced adhesion and increased NF-?B/VCAM-1 in cultured vascular endothelial cells. Our results suggest that periodontitis triggers the initial pathogenesis of atherosclerosis, inflammation of the vasculature, through activating monocytes/macrophages. PMID:24893991

Miyajima, Shin-ichi; Naruse, Keiko; Kobayashi, Yasuko; Nakamura, Nobuhisa; Nishikawa, Toru; Adachi, Kei; Suzuki, Yuki; Kikuchi, Takeshi; Mitani, Akio; Mizutani, Makoto; Ohno, Norikazu; Noguchi, Toshihide; Matsubara, Tatsuaki

2014-01-01

105

Periodontitis-activated monocytes/macrophages cause aortic inflammation.  

PubMed

A relationship between periodontal disease and atherosclerosis has been suggested by epidemiological studies. Ligature-induced experimental periodontitis is an adequate model for clinical periodontitis, which starts from plaque accumulation, followed by inflammation in the periodontal tissue. Here we have demonstrated using a ligature-induced periodontitis model that periodontitis activates monocytes/macrophages, which subsequently circulate in the blood and adhere to vascular endothelial cells without altering the serum TNF-? concentration. Adherent monocytes/macrophages induced NF-?B activation and VCAM-1 expression in the endothelium and increased the expression of the TNF-? signaling cascade in the aorta. Peripheral blood-derived mononuclear cells from rats with experimental periodontitis showed enhanced adhesion and increased NF-?B/VCAM-1 in cultured vascular endothelial cells. Our results suggest that periodontitis triggers the initial pathogenesis of atherosclerosis, inflammation of the vasculature, through activating monocytes/macrophages. PMID:24893991

Miyajima, Shin-ichi; Naruse, Keiko; Kobayashi, Yasuko; Nakamura, Nobuhisa; Nishikawa, Toru; Adachi, Kei; Suzuki, Yuki; Kikuchi, Takeshi; Mitani, Akio; Mizutani, Makoto; Ohno, Norikazu; Noguchi, Toshihide; Matsubara, Tatsuaki

2014-01-01

106

Immunomodulatory activity of methanolic extracts of fruits and bark of Ficus glomerata Roxb. in mice and on human neutrophils  

PubMed Central

Objective: To evaluate the immunomodulatory activity of methanolic extracts of fruit and bark of Ficus glomerata Roxb. on cyclophosphamide-induced myelosuppression in mice and the phagocytic effect on human neutrophils. Materials and Methods: Methanolic extracts of fruits and bark of Ficus glomerata Roxb. at two dose levels of 250and 500 mg/kg p.o. were administered for 13 days to albino mice and cyclophosphamide (30 mg/kg i.p.) was administered on 11th,12th, and 13th days, 1 hour after the administration of the respective treatment. On 14th day blood was collected and the hematological parameters were evaluated. The two extracts in the concentration range 100,50,25,12 and 6.25 ?g were also tested for phagocytic effect on human neutrophils using the in vitro models–nitroblue tetrazolium (NBT) dye test, phagocytosis of Candida albicans, and chemotaxis assay. Results: Methanolic extracts of fruit and bark of Ficus glomerata Roxb. showed significant counteracting effect (P < 0.01) to cyclophosphamide-induced reduction in total WBC, differential leucocyte count, platelet counts, RBC counts, and hemoglobin levels. The extracts of the plant in the concentration range 100,50,25,12, and 6.25 ?g also showed significant (P < 0.01) phagocytic effect on human neutrophils in the parameters studied. Conclusion: Methanolic extracts of fruits and bark of Ficus glomerata Roxb. exhibited immunomodulatory property in both in vivo and in vitro models. PMID:23716887

Heroor, Sanjeev; Beknal, Arun Kumar; Mahurkar, Nitin

2013-01-01

107

Monocyte macrophage differentiation in vitro: Fibronectin-dependent upregulation of certain macrophage-specific activities.  

PubMed

Transendothelial migration of monocytes followed by their differentiation into macrophages involves interaction of monocytes with subendothelial matrix. The influence of extracellular matrix on monocyte-macrophage differentiation was studied using an in vitro model system with human PBMC maintained on different matrix protein substrata. Upregulation of macrophage specific marker activities such as endocytosis of modified proteins, changes in expression of cell surface antigen, and production of matrix metalloproteinases was studied. Cells maintained on Fibronectin (Fn) showed significantly higher rate of endocytosis and production of MMP2 and MMP9 when compared to other matrix protein substrata. Immunoblot analysis, ELISA, and zymography showed that Fn-dependent upregulation of MMPs was blocked by antibodies to alpha(5)beta(1) integrin indicating that the Fn effect was mediated by integrins. The Fn effect on mo-mPhi was blocked by genistein and herbimycin. As monocytes differentiate to macrophages there was an increase in the rate of production of Fn. These results indicate the influence of the microenvironment of the cell, particularly Fn, on mo-mPhi differentiation and integrin-mediated downstream signaling through focal adhesion kinase and Src type tyrosine kinase is involved in this. PMID:17115276

Sudhakaran, P R; Radhika, A; Jacob, S S

2007-01-01

108

Dysregulation of Macrophage Activation Profiles by Engineered Nanoparticles  

PubMed Central

Although the potential human health impacts from exposure to engineered nanoparticles (ENPs) are uncertain, past epidemiological studies have established correlations between exposure to ambient air pollution particulates and the incidence of pneumonia and lung infections. Using amorphous silica and superparamagnetic iron oxide (SPIO) as model high production volume ENPs, we examined how macrophage activation by bacterial lipopolysaccharide (LPS) or the lung pathogen Streptococcus pneumoniae is altered by ENP pre-treatment. Neither silica nor SPIO treatment elicited direct cytotoxic or pro-inflammatory effects in bone marrow-derived macrophages. However, pre-treatment of macrophages with SPIO caused extensive reprogramming of nearly 500 genes regulated in response to LPS challenge, hallmarked by exaggerated activation of oxidative stress response pathways and suppressed activation of both pro- and anti-inflammatory pathways. Silica pre-treatment altered regulation of only 67 genes, but there was strong correlation with gene sets affected by SPIO. Macrophages exposed to SPIO displayed a phenotype suggesting an impaired ability to transition from a M1 to M2-like activation state, characterized by suppressed IL-10 induction, enhanced TNF? production, and diminished phagocytic activity toward S. pneumoniae. Studies in macrophages deficient in scavenger receptor A (SR-A) showed SR-A participates in cell uptake of both the ENPs and S. pneumonia, and co-regulates the anti-inflammatory IL-10 pathway. Thus, mechanisms for dysregulation of innate immunity exist by virtue that common receptor recognition pathways are used by some ENPs and pathogenic bacteria, although the extent of transcriptional reprogramming of macrophage function depends on the physicochemical properties of the ENP after internalization. Our results also illustrate that biological effects of ENPs may be indirectly manifested only after challenging normal cell function. Nanotoxicology screening strategies should therefore consider how exposure to these materials alters susceptibility to other environmental exposures. PMID:23808590

Kodali, Vamsi; Littke, Matthew H.; Tilton, Susan C.; Teeguarden, Justin G.; Shi, Liang; Frevert, Charles W.; Wang, Wei; Pounds, Joel G.; Thrall, Brian D.

2013-01-01

109

Dysregulation of Macrophage Activation Profiles by Engineered Nanoparticles  

SciTech Connect

Although the potential human health impacts from exposure to engineered nanoparticles (ENPs) are uncertain, past epidemiological studies have established correlations between exposure to ambient air pollution particulates and the incidence of pneumonia and lung infections. Using amorphous silica and superparamagnetic iron oxide (SPIO) as model high production volume ENPs, we examined how macrophage activation by bacterial lipopolysaccharide (LPS) or the lung pathogen Streptococcus pneumoniae is altered by ENP pre-treatment. Neither silica nor SPIO treatment elicited direct cytotoxic or pro-inflammatory effects in bone marrow-derived macrophages. However, pre-treatment of macrophages with SPIO caused extensive reprogramming of nearly 500 genes regulated in response to LPS challenge, hallmarked by exaggerated activation of oxidative stress response pathways and suppressed activation of both pro- and anti-inflammatory pathways. Silica pre-treatment altered regulation of only 67 genes, but there was strong correlation with gene sets affected by SPIO. Macrophages exposed to SPIO displayed a phenotype suggesting an impaired ability to transition from a M1 to M2-like activation state, characterized by suppressed IL-10 induction, enhanced TNF? production, and diminished phagocytic activity toward S. pneumoniae. Studies in macrophages deficient in scavenger receptor A (SR-A) showed SR-A participates in cell uptake of both the ENPs and S. pneumonia, and co-regulates the anti-inflammatory IL-10 pathway. Thus, mechanisms for dysregulation of innate immunity exist by virtue that common receptor recognition pathways are used by some ENPs and pathogenic bacteria, although the extent of transcriptional reprogramming of macrophage function depends on the physicochemical properties of the ENP after internalization. Our results also illustrate that biological effects of ENPs may be indirectly manifested only after challenging normal cell function. Nanotoxicology screening strategies should therefore consider how exposure to these materials alters susceptibility to other environmental exposures.

Kodali, Vamsi K.; Littke, Matt H.; Tilton, Susan C.; Teeguarden, Justin G.; Shi, Liang; Frevert, Charles W.; Wang, Wei; Pounds, Joel G.; Thrall, Brian D.

2013-07-09

110

Formation of distinct chromatin conformation signatures epigenetically regulate macrophage activation.  

PubMed

Microbial-lipopolysacharide (LPS), interleukin 4 (IL-4) and interferon gamma (IFN-?) polarise macrophages into "innate", "alternative" and "classical", activation states by selective gene regulation. Expression of MARCO, CD200, CD200R1 (innate), MRC1 (alternative) and H2-Eb1 (classical) selectively marks these distinct activation states. Epigenetic events drive such activation upon stimuli and here we study one such mechanism, chromatin conformation signatures implicated in long-range chromatin interactions that regulate transcriptional switch and gene expression. The EpiSwitch™ technology was used to identify and analyse potential markers bordering such conformational signatures for these genes and juxtaposition of markers was compared between resting and activated macrophages. LPS, IL-4 and IFN-? selectively altered chromatin conformations of their responsive genes in wild type, but not in MyD88(-/-), IL-4R(-/-) and IFN-?R(-/-) macrophages. In addition, two distinct conformations were observed in CD200R1 after LPS and IFN-? stimulation. In summary, signal-specific alterations in chromatin conformation provide biomarkers that identify and determine distinct gene expression programmes during macrophage activation. PMID:24211766

Mukhopadhyay, Subhankar; Ramadass, Aroul Selvam; Akoulitchev, Alexandre; Gordon, Siamon

2014-01-01

111

Attenuated Activation of Macrophage TLR9 by DNA from Virulent Mycobacteria  

Microsoft Academic Search

Alveolar macrophages are the first line of host defence against mycobacteria, but an insufficient host response allows survival of bacteria within macrophages. We aimed to investigate the role of Toll-like receptor 9 (TLR9) activation in macrophage defence against mycobacteria. Human in vitrodifferentiated macrophages as well as human and mouse alveolar macrophages showed TLR9 mRNA and protein expression. The cells were

Alexandra K. Kiemer; Ryan H. Senaratne; Jessica Hoppstädter; Britta Diesel; Lee W. Riley; Koichi Tabeta; Stefan Bauer; Bruce Beutler; Bruce L. Zuraw

2009-01-01

112

Macrophage activation syndrome triggered by primary disseminated toxoplasmosis.  

PubMed

We report the case of a patient with disseminated toxoplasmosis who presented with cervical lymphadenopathies and pneumonia. Although the infection was successfully treated with co-trimoxazole, the patient developed reactive macrophage activation syndrome (rMAS). To our knowledge, this is the first reported case of rMAS triggered by toxoplasmosis in the medical literature. PMID:22803958

Arslan, Ferhat; Batirel, Ayse; Ramazan, Mehmet; Ozer, Serdar; Mert, Ali

2012-12-01

113

Diet Modifies the Neuroimmune System by Influencing Macrophage Activation  

ERIC Educational Resources Information Center

It has long been appreciated that adequate nutrition is required for proper immune function and it is now recognized that dietary components contribute to modulation of immune cells, subsequently impacting the whole body's response during an immune challenge. Macrophage activation plays a critical role in the immune system and directs the…

Sherry, Christina Lynn

2009-01-01

114

Proximal tubule cells stimulated by lipopolysaccharideinhibit macrophage activation  

Microsoft Academic Search

Proximal tubule cells stimulated by lipopolysaccharide inhibit macrophage activation.BackgroundTubule cells can produce a variety of cytokines, extracellular matrix (ECM) components, and adhesion molecules in vitro and in vivo. It is generally assumed that stimulated tubule cells are proinflammatory and at least partially responsible for interstitial inflammation. However, the overall effect of tubular cells on interstitial cells is unknown. In this

YIPING WANG; YUET-CHING TAY; DAVID C H HARRIS

2004-01-01

115

Dynamics of lung macrophage activation in response to helminth infection  

Technology Transfer Automated Retrieval System (TEKTRAN)

Most of our understanding of the development and phenotype of alternatively activated macrophages (AAM) has been obtained from studies investigating the response of bone marrow- and peritoneal-derived cells to IL-4 or IL-13 stimulation. Comparatively little is known about the development of the AAM...

116

Carbon nanotubes activate macrophages into a m1/m2 mixed status: recruiting naďve macrophages and supporting angiogenesis.  

PubMed

The potential of carbon nanotubes (CNTs) in medical applications has been attracting constant research interest as well as raising concerns related to toxicity. The immune system serves as the first line of defense against invasion. In this work, interactions of oxidized multiwalled carbon nanotubes (MWCNT) with macrophages were investigated to unravel the activation profile of macrophages, using cytokine array, ELISA assay, transwell assay, confocal microscopy, and reactive oxygen species examination. Results show that MWCNT initiate phagocytosis of macrophages and upregulate CD14, CD11b, TLR-4/MD2, and CD206, which does not alter the MHCII expression of the macrophages. The macrophages engulfing MWCNT (MWCNT-RAW) secrete a large amount of MIP-1? and MIP-2 to recruit naďve macrophages and produce angiogenesis-related cytokines MMP-9 and VEGF, while inducing much lower levels of proinflammatory cytokines than those activated by LPS. In conclusion, MWCNT activate macrophages into a M1/M2 mixed status, which allows the cells to recruit naďve macrophages and support angiogenesis. PMID:25591447

Meng, Jie; Li, Xiaojin; Wang, Chuan; Guo, Hua; Liu, Jian; Xu, Haiyan

2015-02-11

117

Immunomodulatory activity of geranial, geranial acetate, gingerol, and eugenol essential oils: evidence for humoral and cell-mediated responses  

PubMed Central

Objective: The immunomodulatory effect of geranial, geranial acetate, gingerol, and eugenol essential oils were evaluated by studying humoral and cell-mediated immune responses. Materials and Method: The essential oils were evaluated for immunomodulatory activity in in vivo studies, using rats as the animal model. The essential oils were tested for hypersensitivity and hemagglutination reactions, using sheep red blood cells (SRBC) as the antigen while sodium carboxy methyl cellulose (SCMC) served as the control in all the tests. Result: Orally administrated essential oils showed a significant increase of test parameters, viz., haemagglutinating antibody titre (HAT) and delayed type hypersensitivity (DTH) response. In rats immunized with sheep RBC, essential oils enhanced the humoral antibody response to the antigen and significantly potentiated the cellular immunity by facilitating the foot pad thickness response to sheep RBC in sensitized rats with doses of 50-800 mg/ml. Haemagglutination titre of geraniol showed the highest increase of 139.3±6.38 and with 5.9±0.7 DTH, respectively. For geranial acetate, the haemagglutination titre showed a moderate increase of 87.5±5.9 and highest increase in DTH with 5.9±0.8, respectively. Using gingerol, the haemagglutination titre showed a moderate increase with 88.2±6.306 and DTH 3.5±0.5, respectively and for eugenol, the haemaggulation titre showed a moderate increase with 112.06±6.169 and DTH 4.4±0.6, respectively. These differences were statistically significant. Conclusion: The essential oils were found to have a significant immunostimulant activity on both the specific and non-specific immune mechanisms. PMID:25050278

Farhath, Seema; Vijaya, PP; Vimal, Manivannan

2013-01-01

118

Transcriptional analysis of LPS-stimulated activation of trout (Oncorhynchus mykiss) monocyte/macrophage cells in primary culture treated with cortisol.  

PubMed

Primary immune responses to pathogen invasion are mediated by the innate immune system in which tissue macrophages play a key role. During infectious processes glucocorticoids generally may function to dampen inflammatory responses. In this study, the ability of cortisol to directly modulate the transcriptional response of rainbow trout macrophages to the cellular activator lipopolysaccharide (LPS) was investigated. The results indicate that cortisol significantly inhibits the well-described LPS-dependent induction of the expression of TNF-alpha2, a pro-inflammatory cytokine. In order to further characterize the molecular effects of LPS and the immunomodulatory role of cortisol, the in vitro macrophage response to LPS in the absence or presence of 12-h cortisol exposure was analyzed utilizing a salmonid-specific microarray platform. Genes that were stimulated or inhibited with LPS plus cortisol fell into several major functional groups. The first, a general "response" group comprising genes within ontology classes including the response to external stimuli, stress, humoral immunity and apoptosis, exhibited a significant increase after LPS stimulation, whereas suppression of this response was observed in the presence of cortisol. LPS stimulated other genes in a second group involved in cell signalling and also genes in a third group involved in the activation of transcription. Categories activated with cortisol were mainly related to various aspects of metabolism (including protein biosynthesis, binding and transport of ions) and structural proteins (mainly cytoskeleton and microtubules). The immunomodulatory action of cortisol on LPS-stimulated macrophages therefore appears more complex than simply the antagonism of LPS-induced transcriptional responses. PMID:16239032

MacKenzie, S; Iliev, D; Liarte, C; Koskinen, H; Planas, J V; Goetz, F W; Mölsä, H; Krasnov, A; Tort, L

2006-03-01

119

RIG-I activation inhibits HIV replication in macrophages  

PubMed Central

The RIG-I signaling pathway is critical in the activation of the type I IFN-dependent antiviral innate-immune response. We thus examined whether RIG-I activation can inhibit HIV replication in macrophages. We showed that the stimulation of monocyte-derived macrophages with 5?ppp-dsRNA, a synthetic ligand for RIG-I, induced the expression of RIG-I, IFN-?/?, and several IRFs, key regulators of the IFN signaling pathway. In addition, RIG-I activation induced the expression of multiple intracellular HIV-restriction factors, including ISGs, several members of the APOBEC3 family, tetherin and CC chemokines, the ligands for HIV entry coreceptor (CCR5). The inductions of these factors were associated with the inhibition of HIV replication in macrophages stimulated by 5?ppp-dsRNA. These observations highlight the importance of RIG-I signaling in macrophage innate immunity against HIV, which can be beneficial for the treatment of HIV disease, where intracellular immune defense is compromised by the virus. PMID:23744645

Wang, Yizhong; Wang, Xu; Li, Jieliang; Zhou, Yu; Ho, Wenzhe

2013-01-01

120

Modulation of nitric oxide synthase activity in macrophages  

PubMed Central

L-Arginine is converted to the highly reactive and unstable nitric oxide (NO) and L-citrulline by an enzyme named nitric oxide synthase (NOS). NO decomposes into other nitrogen oxides such as nitrite (NO2-) and nitrate (NO2-), and in the presence of superoxide anion to the potent oxidizing agent peroxynitrite (ONOO?). Activated rodent macrophages are capable of expressing an inducible form of this enzyme (iNOS) in response to appropriate stimuli, i.e., lipopolysaccharide (LPS) and interferon-? (IFN?). Other cytokines can modulate the induction of NO biosynthesis in macrophages. NO is a major effector molecule of the anti-microbial and cytotoxic activity of rodent macrophages against certain micro-organisms and tumour cells, respectively. The NO synthesizing pathway has been demonstrated in human monocytes and other cells, but its role in host defence seems to be accessory. A delicate functional balance between microbial stimuli, host-derived cytokines and hormones in the microenvironment regulates iNOS expression. This review will focus mainly on the known and proposed mechanisms of the regulation of iNOS induction, and on agents that can modulate NO release once the active enzyme has been expressed in the macrophage. PMID:18475620

Jorens, P. G.; Matthys, K. E.

1995-01-01

121

Crosstalk between circadian rhythmicity, mitochondrial dynamics and macrophage bactericidal activity.  

PubMed

Biological functions show rhythmic fluctuations with 24-hr periodicity regulated by circadian proteins encoded by the so-called 'clock' genes. The absence or deregulation of circadian proteins in mice leads to metabolic disorders and in vitro models have shown that the synthesis of pro-inflammatory cytokines by macrophages follows a circadian rhythm so showing a link between circadian rhythmicity, metabolism and immunity. Recent evidence reveals that mitochondrial shape, position and size, collectively referred to as mitochondrial dynamics, are related to both cell metabolism and immune function. However, studies addressing the simultaneous crosstalk between circadian rhythm, mitochondrial dynamics and cell immune function are scarce. Here, by using an in vitro model of synchronized murine peritoneal macrophages, we present evidence that the mitochondrial dynamics and the mitochondrial membrane potential (??m ) follow a circadian rhythmic pattern. In addition, it is shown that the fusion of mitochondria along with high ??m , indicative of high mitochondrial activity, precede the highest phagocytic and bactericidal activity of macrophages on Salmonella typhimurium. Taken together, our results suggest a timely coordination between circadian rhythmicity, mitochondrial dynamics, and the bactericidal capacity of macrophages. PMID:24903615

Oliva-Ramírez, Jacqueline; Moreno-Altamirano, María Maximina B; Pineda-Olvera, Benjamín; Cauich-Sánchez, Patricia; Sánchez-García, F Javier

2014-11-01

122

Guidance and Activation of Murine Macrophages by Nanometric Scale Topography  

Microsoft Academic Search

We studied the guidance and activation of macrophages from the P388D1 cell line and rat peritoneum by topographic features on a nanometric scale. Cells were plated on plain fused silica substrata or substrata with microfabricated grooves and steps, 30–282 nm deep. The contact of cells with the patterned surface activated cell spreading and adhesion and increased the number of protrusions

Beata Wójciak-Stothard; Adam Curtis; William Monaghan; Karen Macdonald; Chris Wilkinson

1996-01-01

123

Specific immunomodulatory and secretory activities of stevioside and steviol in intestinal cells.  

PubMed

Stevioside, isolated from Stevia rebaudiana, is a commercial sweetener. It was previously demonstrated that stevioside attenuates NF-kappaB-dependent TNF-alpha and IL-1beta synthesis in LPS-stimulated monocytes. The present study examined the effects of stevioside and its metabolite, steviol, on human colon carcinoma cell lines. High concentrations of stevioside (2-5 mM) and steviol (0.2-0.8 mM) decreased cell viability in T84, Caco-2, and HT29 cells. Stevioside (2 mM) potentiated TNF-alpha-mediated IL-8 release in T84 cells. However, steviol (0.01-0.2 mM) significantly suppressed TNF-alpha-induced IL-8 release in all three cell lines. In T84 cells, steviol attenuated TNF-alpha-stimulated IkappaB --> NF-kappaB signaling. Chloride transport was stimulated by steviol (0.1 mM) > stevioside (1 mM) at 30 min. Two biological effects of steviol in the colon are demonstrated for the first time: stimulation of Cl(-) secretion and attenuation of TNF-alpha-stimulated IL-8 production. The immunomodulatory effects of steviol appear to involve NF-kappaB signaling. In contrast, at nontoxic concentrations stevioside affects only Cl(-) secretion. PMID:18433103

Boonkaewwan, Chaiwat; Ao, Mei; Toskulkao, Chaivat; Rao, Mrinalini C

2008-05-28

124

Role of activated macrophages in experimental Fusarium solani keratitis.  

PubMed

Macrophages under the conjunctival tissue are the first line defender cells of the corneas. Elimination of these cells would lead to aggravation of fungal keratitis. To determine how the course of fungal keratitis would be altered after the activation of these macrophages, a murine model was achieved by intrastromal instillation of latex beads before the corneas were infected with Fusarium solani. The keratitis was observed and clinically scored daily. Infected corneas were homogenized for colony counts. The levels of the IL-12, IL-4, MPO, MIF and iNOS cytokines were measured in the corneas using real-time polymerase chain reactions and enzyme-linked immunosorbent assays. CD3+, CD4+ and CD8+ lymphocytes in the corneas, submaxillary lymph nodes and peripheral blood were detected using immunohistochemistry and flow cytometry, respectively. The latex bead-treated mice exhibited aggravated keratitis. Substantially increased macrophage and polymorphonuclear leukocyte infiltration was detected in the corneas, although few colonies were observed. There was a marked increase in the IL-12, IL-4, MPO, MIF and iNOS expression in the corneas. The numbers of CD3+, CD4+ and CD8+ lymphocytes and the CD4+/CD8+ ratio were significantly enhanced in the corneas and submaxillary lymph nodes. However, the number of CD4+ lymphocytes was decreased in the peripheral blood, while the number of CD8+ lymphocytes increased. Collectively, our data demonstrate that the activation of macrophages in the cornea may cause an excessive immune response. Macrophages appear to play a critical role in regulating the immune response to corneal infections with F. solani. PMID:25447809

Hu, Jianzhang; Hu, Yingfeng; Chen, Shikun; Dong, Chenhuan; Zhang, Jingjin; Li, Yanling; Yang, Juan; Han, Xiaoli; Zhu, Xuejun; Xu, Guoxing

2014-12-01

125

Macrophages in inflammatory multiple sclerosis lesions have an intermediate activation status  

PubMed Central

Background Macrophages play a dual role in multiple sclerosis (MS) pathology. They can exert neuroprotective and growth promoting effects but also contribute to tissue damage by production of inflammatory mediators. The effector function of macrophages is determined by the way they are activated. Stimulation of monocyte-derived macrophages in vitro with interferon-? and lipopolysaccharide results in classically activated (CA/M1) macrophages, and activation with interleukin 4 induces alternatively activated (AA/M2) macrophages. Methods For this study, the expression of a panel of typical M1 and M2 markers on human monocyte derived M1 and M2 macrophages was analyzed using flow cytometry. This revealed that CD40 and mannose receptor (MR) were the most distinctive markers for human M1 and M2 macrophages, respectively. Using a panel of M1 and M2 markers we next examined the activation status of macrophages/microglia in MS lesions, normal appearing white matter and healthy control samples. Results Our data show that M1 markers, including CD40, CD86, CD64 and CD32 were abundantly expressed by microglia in normal appearing white matter and by activated microglia and macrophages throughout active demyelinating MS lesions. M2 markers, such as MR and CD163 were expressed by myelin-laden macrophages in active lesions and perivascular macrophages. Double staining with anti-CD40 and anti-MR revealed that approximately 70% of the CD40-positive macrophages in MS lesions also expressed MR, indicating that the majority of infiltrating macrophages and activated microglial cells display an intermediate activation status. Conclusions Our findings show that, although macrophages in active MS lesions predominantly display M1 characteristics, a major subset of macrophages have an intermediate activation status. PMID:23452918

2013-01-01

126

Multimodality PET/MRI agents targeted to activated macrophages.  

PubMed

The recent emergence of multimodality imaging, particularly the combination of PET and MRI, has led to excitement over the prospect of improving detection of disease. Iron oxide nanoparticles have become a popular platform for the fabrication of PET/MRI probes owing to their advantages of high MRI detection sensitivity, biocompatibility, and biodegradability. In this article, we report the synthesis of dextran-coated iron oxide nanoparticles (DIO) labeled with the positron emitter (64)Cu to generate a PET/MRI probe, and modified with maleic anhydride to increase the negative surface charge. The modified nanoparticulate PET/MRI probe (MDIO-(64)Cu-DOTA) bears repetitive anionic charges on the surface that facilitate recognition by scavenger receptor type A (SR-A), a ligand receptor found on activated macrophages but not on normal vessel walls. MDIO-(64)Cu-DOTA has an average iron oxide core size of 7-8 nm, an average hydrodynamic diameter of 62.7 nm, an r1 relaxivity of 16.8 mM(-1) s(-1), and an r 2 relaxivity of 83.9 mM(-1) s(-1) (37 °C, 1.4 T). Cell studies confirmed that the probe was nontoxic and was specifically taken up by macrophages via SR-A. In comparison with the nonmodified analog, the accumulation of MDIO in macrophages was substantially improved. These characteristics demonstrate the promise of MDIO-(64)Cu-DOTA for identification of vulnerable atherosclerotic plaques via the targeting of macrophages. PMID:24166283

Tu, Chuqiao; Ng, Thomas S C; Jacobs, Russell E; Louie, Angelique Y

2014-02-01

127

Activation of RAW264.7 macrophages by the polysaccharide from the roots of Actinidia eriantha and its molecular mechanisms.  

PubMed

The polysaccharide from the roots of Actinidia eriantha (AEPS), a potent antitumor agent and immunological adjuvant, was investigated for the immunomodulatory effects on RAW264.7 macrophages and its molecular mechanisms. AEPS could significantly enhance the pinocytic and phagocytic activity, induce the production of NO, TNF-?, IL-10, IL-1? and IL-6, and promote the expression of accessory and costimulatory molecules in RAW264.7 cells. PCR array assay revealed that AEPS up-regulated 28 genes including TLRs (TLR2, TLR8, TLR9), proinflammatory factors (IL-1?, G-CSF, IL-1?, GM-CSF, IL-6, COX-2, TNF-?, IFN-?, CXCL10, CCL2, TNF-?, IL-10), and the genes involved in NF-?B signaling pathway, and down-regulated 6 genes such as TLR3, TLR4, PGLYRP1, EIF2?K2, MAP3K1 and IRF1. AEPS was further showed to promote cytoplasmic I?B-? degradation and increase nuclear NF-?B p65 levels in RAW264.7 cells. These results suggested that AEPS activated RAW264.7 macrophages and elicited a M1 and M2 response through TLRs/NF-?B signaling pathway. PMID:25659714

Sun, Hongxiang; Zhang, Juan; Chen, Fengyang; Chen, Xiangfeng; Zhou, Zhihua; Wang, Hui

2015-05-01

128

An immunomodulatory polysaccharide-rich substance from the fruit juice of Morinda citrifolia (noni) with antitumour activity.  

PubMed

The fruit juice of Morinda citrifolia (noni) contains a polysaccharide-rich substance (noni-ppt) with antitumour activity in the Lewis lung (LLC) peritoneal carcinomatosis model. Therapeutic administration of noni-ppt significantly enhanced the duration of survival of inbred syngeneic LLC tumour bearing mice. It did not exert significant cytotoxic effects in an adapted culture of LLC cells, LLC1, but could activate peritoneal exudate cells (PEC) to impart profound toxicity when co-cultured with the tumour cells. This suggested the possibility that noni-ppt may suppress tumour growth through activation of the host immune system. Concomitant treatment with the immunosuppressive agent, 2-chloroadenosine (C1-Ade) or cyclosporin (cys-A) diminished its activity, thereby substantiating an immunomodulatory mechanism. Noni-ppt was also capable of stimulating the release of several mediators from murine effector cells, including tumour necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-10, IL-12 p70, interferon-gamma (IFN-gamma) and nitric oxide (NO), but had no effect on IL-2 and suppressed IL-4 release. Improved survival time and curative effects occurred when noni-ppt was combined with sub-optimal doses of the standard chemotherapeutic agents, adriamycin (Adria), cisplatin (CDDP), 5-fluorouracil (5-FU), and vincristine (VCR), suggesting important clinical applications of noni-ppt as a supplemental agent in cancer treatment. PMID:10441776

Hirazumi, A; Furusawa, E

1999-08-01

129

Immunomodulatory activity of a potent thymopentin analog: disulphide bridged beta-mercaptopropionyl-arginyl-lysyl-aspartyl-valyl-tyrosyl-cysteine amide.  

PubMed

The immunomodulatory activity of the disulphide bridged heptapeptide Mpa-Arg-Lys-Asp-Val-Tyr-Cys-NH2 (CTP-1), containing the thymopentin (TP5) sequence (Arg-Lys-Asp-Val-Tyr), was investigated by different immunological tests. The activity of CTP-1 was compared with the activities of two other disulphide bridged TP5 analogs: Mpa-Arg-Lys-D-Pro-Val-Tyr-Cys-NH2 (CTP-2) and Mpa-Arg-Lys-Asp-Val-Pro-Cys-NH2 (CTP3). The results obtained indicate that from the whole series of TP5 analogs CTP-1 may be of interest from the point of view of its prospective medical use. The results of autologous rosette forming cells (ARFC-test), as well as the direct examination of the influence of CTP-1 on the interleukin-1 (IL-1) production by P-388 D1 cell line evidence that the mechanism of CTP-1 action involves stimulation of IL-1 production. The results of E-rosette assay, ARFC test, and imuran test show that the activity of CTP-1 is stronger than that of TP5. PMID:9112625

Wieczorek, Z; Zimecki, M; Trojnar, J; Siemion, I Z

1996-01-01

130

Activin A inhibits activities of lipopolysaccharide-activated macrophages via TLR4, not of TLR2.  

PubMed

Activin A, a member of TGF-? superfamily, is involved in either pro-inflammatory or anti-inflammatory responses. Our previous studies have reported that lipopolysaccharide (LPS) can simulate activin A secretion from macrophage, and activin A can induce rest macrophage activation in mice, but inhibit the activities of the activated macrophages. However, the relationship of activin and LPS actions and their mechanism are not well characterized. In the present study, the results showed that both activin A and LPS promoted the phagocytic activities of mouse peritoneal macrophages in vivo and in vitro, but activin A inhibited the phagocytosis of LPS-activated macrophages. Simultaneously, the results revealed that activin A inhibited the Toll-like receptor 4 (TLR4) expression on LPS-activated mouse peritoneal macrophages in vivo and in vitro, whereas there was no obvious change of TLR2 expression. Moreover, the results showed that activin A obviously reduced the TLR4 mRNA and protein expressions in LPS-activated macrophage cell line RAW264.7 cells, and the inhibitory effect of activin A on the TLR4 expression was significantly attenuated in Smad3 knock-down RAW264.7 cells. Interestingly, LPS promoted the expression of activin type IIA receptor (ActRIIA) on mouse peritoneal macrophages in vivo, and also up-regulated ActRIIA and activin signal molecules Smad2, 3 mRNA expressions. These data suggest that activin A inhibits LPS action on macrophages in vivo via suppressing TLR4 expression, and LPS further augments the negative feedback action of activin A via up-regulating activin signaling transduction. PMID:23665022

Li, Nan; Cui, Xueling; Ge, Jingyan; Li, Jiru; Niu, Liman; Liu, Haiyan; Qi, Yan; Liu, Zhonghui; Wang, Yinan

2013-05-31

131

In vitro immunoregulatory effects of Korean mistletoe lectin on functional activation of monocytic and macrophage-like cells.  

PubMed

Korean mistletoe lectin (KML) is one of the major active components in Viscum album var. (coloratum), displaying various biological effects such as anti-tumor and anti-metastatic activities. Even though it has been shown to boost host immune defense mechanisms, the immunomodulatory effects of KML on specific immune responses mediated by macrophages have not been fully elucidated. Therefore, in this study, we aimed to demonstrate KML's regulatory roles on macrophage-mediated immune responses. KML clearly blocked lipopolysaccharide (LPS)-induced events [expression of interleukin (IL)-10, nitric oxide (NO) production and phagocytic uptake], and suppressed the normal expression levels of IL-10 (at 2 ng/ml) and tumor necrosis factor (TNF)-alpha (at 10 ng/ml). In contrast, (1) the expression of cytokine (TNF-alpha) and (2) the generation of reactive oxygen species (ROS) induced by LPS were significantly up-regulated with KML co-treatment. In addition, KML itself increased the mRNA levels of IL-3 and IL-23; phagocytic uptake; the surface levels of co-stimulatory molecules (CD80 and CD86), pattern recognition receptors (PRRs) [such as dectin-1 and toll like receptor (TLR)-2] and adhesion molecules [beta1-integrins (CD29) and CD43]; and CD29-mediated cell adhesion events. Finally, according to co-treatment of D-galactose with KML under LPS-induced NO production conditions, KML inhibition seems to be mediated by binding to proteins with D-galactose. Therefore, these data suggest that KML may participate in regulating various macrophage-mediated innate and adaptive responses via binding to surface protein with D-galactose and that some of these may deserve in KML's therapeutic activities such as anti-tumor and anti-microbial effects. PMID:17978473

Lee, Ji Yeon; Kim, Joo Young; Lee, Yong Gyu; Byeon, Se Eun; Kim, Byung Hun; Rhee, Man Hee; Lee, Albert; Kwon, Moosik; Hong, Sungyoul; Cho, Jae Youl

2007-11-01

132

Delineation of Diverse Macrophage Activation Programs in Response to Intracellular Parasites and Cytokines  

PubMed Central

Background The ability to reside and proliferate in macrophages is characteristic of several infectious agents that are of major importance to public health, including the intracellular parasites Trypanosoma cruzi (the etiological agent of Chagas disease) and Leishmania species (etiological agents of Kala-Azar and cutaneous leishmaniasis). Although recent studies have elucidated some of the ways macrophages respond to these pathogens, the relationships between activation programs elicited by these pathogens and the macrophage activation programs elicited by bacterial pathogens and cytokines have not been delineated. Methodology/Principal Findings To provide a global perspective on the relationships between macrophage activation programs and to understand how certain pathogens circumvent them, we used transcriptional profiling by genome-wide microarray analysis to compare the responses of mouse macrophages following exposure to the intracellular parasites T. cruzi and Leishmania mexicana, the bacterial product lipopolysaccharide (LPS), and the cytokines IFNG, TNF, IFNB, IL-4, IL-10, and IL-17. We found that LPS induced a classical activation state that resembled macrophage stimulation by the Th1 cytokines IFNG and TNF. However, infection by the protozoan pathogen L. mexicana produced so few transcriptional changes that the infected macrophages were almost indistinguishable from uninfected cells. T. cruzi activated macrophages produced a transcriptional signature characterized by the induction of interferon-stimulated genes by 24 h post-infection. Despite this delayed IFN response by T. cruzi, the transcriptional response of macrophages infected by the kinetoplastid pathogens more closely resembled the transcriptional response of macrophages stimulated by the cytokines IL-4, IL-10, and IL-17 than macrophages stimulated by Th1 cytokines. Conclusions/Significance This study provides global gene expression data for a diverse set of biologically significant pathogens and cytokines and identifies the relationships between macrophage activation states induced by these stimuli. By comparing macrophage activation programs to pathogens and cytokines under identical experimental conditions, we provide new insights into how macrophage responses to kinetoplastids correlate with the overall range of macrophage activation states. PMID:20361029

Zhang, Shuyi; Kim, Charles C.; Batra, Sajeev; McKerrow, James H.; Loke, P'ng

2010-01-01

133

Investigating the function of a novel protein from Anoectochilus formosanus which induced macrophage differentiation through TLR4-mediated NF-?B activation.  

PubMed

Anoectochilus formosanus is a therapeutic orchid appreciated as a traditional Chinese medicine in Asia. The extracts of A. formosanus have been reported to possess hepatoprotective, anti-inflammatory, and anti-tumor activates. A novel protein was isolated from A. formosanus, and its immunomodulatory effect on murine peritoneal macrophage was investigated. Macrophages obtained from ascites of thioglycollate-induced BALB/c were co-cultured with IPAF (0-20 ?g/ml) for 24 h and then harvested for flow cytometry analysis. The cytokine/chemokine production was measured by real time PCR and ELISA. The interaction between IPAF and toll like receptors (TLRs) was investigated by TLR gene knockout (KO) mice and fluorescence labeled IPAF. The activation of NF-?B was assessed by EMSA. IPAF stimulated the TNF-? and IL-1? production, upregulated the CD86 and MHC II expression, and enhanced the phagocytic activity of macrophages. IPAF induced gene expression of IL-12 and Th1-assosiated cytokines/chemokines. The stimulating effect of IPAF was impaired, and the IPAF-macrophage interaction was reduced in TLR4(-/-) C57BL/10ScNJ mice. In addition, IPAF stimulated expressions of TLR signal-related genes and the activation of NF-?B. IPAF could induce classical activated macrophage differentiation via TLR4-dependent NF-?B activation and had potential of IPAF to modulate the Th1 response. These findings provided valuable information regarding the immune modulatory mechanism of A. formosanus, and indicated the possibility of IPAF as a potential peptide drug. PMID:22749731

Kuan, Yen-Chou; Lee, Wan-Tzu; Hung, Chih-Liang; Yang, Ching; Sheu, Fuu

2012-09-01

134

Chain conformation and immunomodulatory activity of a hyperbranched polysaccharide from Cordyceps sinensis.  

PubMed

A polysaccharide, named as cordysinan, extracted from natural Cordyceps sinensis, was identified as a hyperbranched heteropolysaccharide from the results of FT-IR, GC-MS, and carbohydrate analysis by carbohydrate gel electrophoresis analysis, as well as the degree of branching of cordysinan was 43.3%. The solution properties of cordysinan were investigated by using size exclusion chromatography coupled with multi-angle laser light scattering and triple detector array, respectively. The molecular weights, the radius of gyration and the intrinsic viscosity of cordysinan were determined as 22.45±0.26 kDa and 22.37 kDa, 15.4±2.4 nm and 1.41 mL/g, respectively. By applying the polymer solution theory, the exponent (? and ?) values of g1/2=kMwv and [?]=kMw? were calculated as 0.28 and 0.42, respectively, which firstly revealed that cordysinan existed as a globular shape in 0.9% NaCl aqueous solution. Moreover, the results showed that cordysinan could obviously stimulate macrophages functions. PMID:24906773

Wu, Ding-Tao; Meng, Lan-Zhen; Wang, Lan-Ying; Lv, Guang-Ping; Cheong, Kit-Leong; Hu, De-Jun; Guan, Jia; Zhao, Jing; Li, Shao-Ping

2014-09-22

135

Comparative Screening of Immunomodulatory Activity of Hydro-alcoholic Extract of Hibiscus rosa sinensis Linn. and Ethanolic Extract of Cleome gynandra Linn  

Microsoft Academic Search

2 Abstract: The assesement of immunomodulatory activity of hydro-alcoholic extract of flowers of Hibiscus rosa sinensis Linn. (75, 150 and 300 mg\\/kg, p.o.) and ethanolic extracts of aerial parts of Cleome gynandra Linn. (50, 100 and 200 mg\\/kg, p.o.) were done by carbon clearance method for non-specific immunity, haemagglutination antibody titre method for humoral immunity and footpad swelling method for

Kalpesh Gaur; M. L. Kori; R. K. Nema

136

Recombinant Expression of a Novel Fungal Immunomodulatory Protein with Human Tumor Cell Antiproliferative Activity from Nectria haematococca  

PubMed Central

To our best knowledge, all of the fungal immunomodulatory proteins (FIPs) have been successfully extracted and identified in Basidomycetes, with only the exception of FIP from ascomycete Nectria haematococca (FIP-nha) discovered through homology alignment most recently. In this work, a gene encoding FIP-nha was synthesized and recombinantly expressed in an Escherichia coli expression system. SDS-PAGE and MALDI-MS analyses of recombinant FIP-nha (rFIP-nha) indicated that the gene was successfully expressed. The yield of the bioactive FIP-nha protein was 42.7 mg/L. In vitro assays of biological activity indicated that the rFIP-nha caused hemagglutination of human and rabbit red blood cells, significantly stimulated mouse spleen lymphocyte proliferation, and enhanced expression of interleukin-2 (IL-2) released from mouse splenocytes, revealing a strong antitumor effect against HL60, HepG2 and MGC823. Through this work, we constructed a rapid and efficient method of FIP production, and suggested that FIP-nha is a valuable candidate for use in future medical care and pharmaceutical products. PMID:25272229

Li, Shuying; Nie, Ying; Ding, Yang; Shi, Lijun; Tang, Xuanming

2014-01-01

137

Recombinant expression of a novel fungal immunomodulatory protein with human tumor cell antiproliferative activity from Nectria haematococca.  

PubMed

To our best knowledge, all of the fungal immunomodulatory proteins (FIPs) have been successfully extracted and identified in Basidomycetes, with only the exception of FIP from ascomycete Nectria haematococca (FIP-nha) discovered through homology alignment most recently. In this work, a gene encoding FIP-nha was synthesized and recombinantly expressed in an Escherichia coli expression system. SDS-PAGE and MALDI-MS analyses of recombinant FIP-nha (rFIP-nha) indicated that the gene was successfully expressed. The yield of the bioactive FIP-nha protein was 42.7 mg/L. In vitro assays of biological activity indicated that the rFIP-nha caused hemagglutination of human and rabbit red blood cells, signi?cantly stimulated mouse spleen lymphocyte proliferation, and enhanced expression of interleukin-2 (IL-2) released from mouse splenocytes, revealing a strong antitumor effect against HL60, HepG2 and MGC823. Through this work, we constructed a rapid and efficient method of FIP production, and suggested that FIP-nha is a valuable candidate for use in future medical care and pharmaceutical products. PMID:25272229

Li, Shuying; Nie, Ying; Ding, Yang; Shi, Lijun; Tang, Xuanming

2014-01-01

138

Lectin coated MgO nanoparticle: its toxicity, antileishmanial activity, and macrophage activation.  

PubMed

The purpose of this research was to evaluate toxicity of uncoated magnesium oxide nanoparticles (MgO NPs), MgO NPs coated with Peanut agglutinin (PNA) lectin, and PNA alone on the promastigotes of Leishmania major (L. major) and macrophages of BALB/c mice. On the other hand, antileishmanial property of uncoated MgO NPs, lectin coated MgO NPs, and PNA lectin alone was evaluated, and also macrophage activation was investigated after treatment with these materials by measurement of nitrite, H2O2, and some interleukins. This study showed that PNA lectin and lectin coated MgO NPs had approximately no toxicity on L. major and macrophages, but some toxic effects were observed for uncoated MgO NPs, especially at concentration of 500?µg/mL. Interestingly, lectin coated MgO NPs had the highest antileishmanial activity and macrophage activation, compared with uncoated MgO NPs and PNA lectin. PMID:24393043

Jebali, Ali; Hekmatimoghaddam, Seyedhossein; Kazemi, Bahram; Allaveisie, Azra; Masoudi, Alireza; Daliri, Karim; Sedighi, Najme; Ranjbari, Javad

2014-10-01

139

Multimodality PET/MR imaging agents targeted to activated macrophages  

PubMed Central

The recent emergence of multimodality imaging, particularly the combination of PET and MRI, has led to excitement over the prospect of improving detection of disease. Iron oxide nanoparticles (IONPs) have become a popular platform for the fabrication of PET/MRI probes due to their advantages of high MRI detection sensitivity, biocompatibility, and biodegradability. In this paper, we report the synthesis of dextran coated iron oxide nanoparticles labeled with the positron emitter 64Cu to generate a PET/MRI probe, and modified with small molecular maleic anhydride to increase negative surface charge. The modified nanoparticulate PET/MRI probe (MDIO-64Cu-DOTA) bears repetitive anionic charges on the surface that facilitate recognition by scavenger receptor type A (SR-A), a ligand-receptor found on activated macrophages but not on normal vessel walls. MDIO-64Cu-DOTA has an average iron oxide core size of 7-8 nm, an average hydrodynamic diameter of 62.7 nm, an r1 relaxivity of 16.8 mM?1·s?1, and an r2 relaxivity of 83.9 mM?1·s?1 (37 °C, 1.4 T). Cell studies confirmed that the probe was nontoxic and was specifically taken up by macrophages via SR-A. In comparison with the non-modified analog, the accumulation of maleylated DIO in macrophages was substantially improved. These characteristics demonstrate the promise of MDIO-64Cu-DOTA for identification of vulnerable atherosclerotic plaques (VAP) via the targeting of macrophages. PMID:24166283

Tu, Chuqiao; Ng, Thomas S. C.; Jacobs, Russell E.; Louie, Angelique Y.

2013-01-01

140

A Novel Immunomodulatory Hemocyanin from the Limpet Fissurella latimarginata Promotes Potent Anti-Tumor Activity in Melanoma  

PubMed Central

Hemocyanins, the huge oxygen-transporting glycoproteins of some mollusks, are used as immunomodulatory proteins with proven anti-cancer properties. The biodiversity of hemocyanins has promoted interest in identifying new anti-cancer candidates with improved immunological properties. Hemocyanins promote Th1 responses without known side effects, which make them ideal for long-term sustained treatment of cancer. In this study, we evaluated a novel hemocyanin from the limpet/gastropod Fissurella latimarginata (FLH). This protein has the typical hollow, cylindrical structure of other known hemocyanins, such as the keyhole limpet hemocyanin (KLH) and the Concholepas hemocyanin (CCH). FLH, like the KLH isoforms, is composed of a single type of polypeptide with exposed N- and O-linked oligosaccharides. However, its immunogenicity was significantly greater than that of KLH and CCH, as FLH induced a stronger humoral immune response and had more potent anti-tumor activity, delaying tumor growth and increasing the survival of mice challenged with B16F10 melanoma cells, in prophylactic and therapeutic settings. Additionally, FLH-treated mice demonstrated increased IFN-? production and higher numbers of tumor-infiltrating CD4+ lymphocytes. Furthermore, in vitro assays demonstrated that FLH, but not CCH or KLH, stimulated the rapid production of pro-inflammatory cytokines (IL-6, IL-12, IL-23 and TNF-?) by dendritic cells, triggering a pro-inflammatory milieu that may explain its enhanced immunological activity. Moreover, this effect was abolished when deglycosylated FLH was used, suggesting that carbohydrates play a crucial role in the innate immune recognition of this protein. Altogether, our data demonstrate that FLH possesses increased anti-tumor activity in part because it activates a more potent innate immune response in comparison to other known hemocyanins. In conclusion, FLH is a potential new marine adjuvant for immunization and possible cancer immunotherapy. PMID:24466345

Arancibia, Sergio; Espinoza, Cecilia; Salazar, Fabián; Del Campo, Miguel; Tampe, Ricardo; Zhong, Ta-Ying; De Ioannes, Pablo; Moltedo, Bruno; Ferreira, Jorge; Lavelle, Ed C.; Manubens, Augusto; De Ioannes, Alfredo E.; Becker, María Inés

2014-01-01

141

Review on medicinal uses, pharmacological, phytochemistry and immunomodulatory activity of plants.  

PubMed

Since ancient times, plants have been an exemplary source of medicine. Researchers have discovered some important compounds from plants. The present work constitutes a review of the medicinal plants whose immunomodulant activity has been proven. We performed PUBMED, EMBASE, Google scholar searches for research papers of medicinal plants having immunomodulant activity. Medicinal plants used by traditional physicians or reported as having immunomodulant activity include Acacia concocinna, Camellia sinensis, Lawsonia inermis Linn, Piper longum Linn, Gelidium amansii, Petroselinum crispum, Plantago major and Allium sativum. Immunomodulant activities of some of these medicinal plants have been investigated. The medicinal plants documented have immunomodulant activity and should be further investigated via clinical trial. PMID:25280022

Akram, M; Hamid, A; Khalil, A; Ghaffar, A; Tayyaba, N; Saeed, A; Ali, M; Naveed, A

2014-01-01

142

LPS-inducible factor(s) from activated macrophages mediates cytolysis of Naegleria fowleri amoebae  

SciTech Connect

Soluble cytolytic factors of macrophage origin have previously been described with respect to their tumoricidal activity. The purpose of this study was to investigate the mechanism and possible factor(s) responsible for cytolysis of the amoeba Naegleria fowleri by activated peritoneal macrophages from B6C3F1 mice. Macrophages or conditioned medium (CM) from macrophage cultures were incubated with /sup 3/H-Uridine labeled amoebae. Percent specific release of label served as an index of cytolysis. Bacille Calmette-Guerin (BCG) and Corynebacterium parvum macrophages demonstrated significant cytolysis of amoebae at 24 h with an effector to target ratio of 10:1. Treatment of macrophages with inhibitors of RNA or protein synthesis blocked amoebicidal activity. Interposition of a 1 ..mu..m pore membrane between macrophages and amoebae inhibited killing. Inhibition in the presence of the membrane was overcome by stimulating the macrophages with LPS. CM from SPS-stimulated, but not unstimulated, cultures of activated macrophages was cytotoxic for amoebae. The activity was heat sensitive and was recovered from ammonium sulfate precipitation of the CM. Results indicate that amoebicidal activity is mediated by a protein(s) of macrophage origin induced by target cell contact or stimulation with LPS.

Cleary, S.F.; Marciano-Cabral, F.

1986-03-01

143

A defect in the inflammation-primed macrophage-activation cascade in osteopetrotic rats.  

PubMed

Macrophages were activated by administration of lysophosphatidylcholine (lyso-Pc) or dodecylglycerol (DDG) to wild-type rats but not in osteopetrotic (op) mutant rats. In vitro treatment of wild-type rat peritoneal cells with lyso-Pc or DDG efficiently activated macrophages whereas treatment of op mutant rat peritoneal cells with lyso-Pc or DDG did not activate macrophages. The inflammation-primed macrophage activation cascade in rats requires participation of B lymphocytes and vitamin D binding protein (DBP). Lyso-Pc-inducible beta-galactosidase of wild-type rat B lymphocytes can convert DBP to the macrophage-activating factor (MAF), whereas B lymphocytes of the op mutant rats were shown to be deficient in lyso-Pc-inducible beta-galactosidase. DBP is conserved among mammalian species. Treatment of human DBP (Gc1 protein) with commercial glycosidases yields an extremely high titrated MAF as assayed on mouse and rat macrophages. Because the enzymatically generated MAF (GcMAF) bypasses the role of lymphocytes in macrophage activation, the op mutant rat macrophages were efficiently activated by administration of a small quantity (100 pg/rat) of GcMAF. Likewise, in vitro treatment of op rat peritoneal cells with as little as 40 pg GcMAF/ml activated macrophages. PMID:8176226

Yamamoto, N; Lindsay, D D; Naraparaju, V R; Ireland, R A; Popoff, S N

1994-05-15

144

Effect of phenothiazines on protein kinase C- and calcium-dependent activation of peritoneal macrophages.  

PubMed

The effects of some phenothiazines (promethazine, PMZ; chlorpromazine, CPZ; levomepromazine, LVPZ; thioridazine, TRDZ; trifluoperazine, TFPZ) on the activation and viability of rat peritoneal macrophages were investigated. The macrophage activation was estimated by measuring of luminol-dependent chemiluminescence, induced by phorbol-12-myristate-13-acetate (PMA) (a protein kinase C activator) or calcium ionophore A23187. The viability of macrophages was determined using ATP bioluminescence as a criterion of cell viability. It was observed that all drugs, in concentrations higher than 1 micromol/L, markedly decreased the chemiluminescent index of PMA-activated or A23187-activated macrophages. The inhibitory effect was dose-dependent. It was better expressed in the case of CPZ, followed by TFPZ and TRDZ, and less expressed in the case of PMZ and LVPZ. The suppression of chemiluminescence of PMA-/A23187-activated macrophages by phenothiazines was not a result of their cytotoxic effect. Moreover, it was found that all drugs dose-dependently enhanced the viability of macrophages, estimated by ATP production. The inhibitory effects of phenothiazines on the chemiluminescence of PMA-/A23187-activated macrophages were greater than their ability to decrease KO2-induced chemiluminescence as a result of interaction with superoxide radicals. It may be supposed that the inhibitory effect of phenothiazines on PMA-/A23187-induced chemiluminescence of macrophages is a result not only of interaction between drugs and superoxide radicals, generated during the "oxidative burst" of activated cells. Presumably the drugs have an immunomodulating effect on rat peritoneal macrophages. PMID:12661983

Hadjimitova, V; Bakalova, R; Traykov, T; Ohba, H; Ribarov, St

2003-02-01

145

Influence of hypercholesterolemia and cholesterol accumulation on rabbit carrageenan granuloma macrophage activation.  

PubMed Central

These experiments were designed to determine whether hypercholesterolemia and the accumulation of cholesterol or cholesteryl esters in rabbit carrageenan granuloma macrophages might influence selected markers of macrophage activation. Granulomas induced by subcutaneous injection of carrageenan into rabbits were harvested after 4, 14, and 28 days. Macrophages were isolated from granuloma tissues by collagenase digestion and cultured overnight. Secretion of lysosomal beta-glucuronidase, membrane 5'-nucleotidase, cellular plasminogen activator, and superoxide anion generation were measured as markers of activation. beta-Glucuronidase activity secreted into the media by granuloma macrophages from normocholesterolemic (NC) and hypercholesterolemic (HC) rabbits showed a trend toward an increase with time between 4 and 14 days in both groups. This was confirmed in a separate experiment with a significant increase by 14 days, together with a significantly greater secretion by NC macrophages and a significantly elevated level of cellular beta-glucuronidase activity in NC relative to HC macrophages. Activity of the membrane ectoenzyme 5'-nucleotidase was minimal in lysates of NC or HC macrophages, in contrast to freshly isolated human monocytes, indicating that both NC and HC granuloma macrophages were highly activated. Cellular plasminogen activator activity was significantly increased between 4 and 14 days, and was significantly greater in HC than in NC macrophages at 14 days. Stimulation of macrophages with phorbol myristate acetate increased superoxide anion generation by both NC and HC macrophages; however, no difference in superoxide anion generation was observed between macrophages from NC and HC rabbits. On the basis of the 5'-nucleotidase findings, it is concluded that both the NC and HC granuloma macrophages are highly activated, and further that hypercholesterolemia does not enhance macrophage generation of superoxide anion, either spontaneously or as the result of phorbol myristate acetate stimulation. Although hypercholesterolemia results in macrophage activation in terms of an increased cellular plasminogen activator activity, the secretion of the lysosomal enzyme beta-glucuronidase is diminished. Thus, hypercholesterolemia associated with macrophage cholesterol and cholesteryl ester accumulation has no consistent overall influence on activation, a finding of potential importance in the context of atherogenesis. PMID:2837904

Kelley, J. L.; Suenram, C. A.; Rozek, M. M.; Schwartz, C. J.

1988-01-01

146

Chicken cathelicidin-2-derived peptides with enhanced immunomodulatory and antibacterial activities against biological warfare agents  

Microsoft Academic Search

Host defence peptides (HDPs) are considered to be excellent candidates for the development of novel therapeutic agents. Recently, it was demonstrated that the peptide C1-15, an N-terminal segment of chicken HDP cathelicidin-2, exhibits potent antibacterial activity while lacking cytotoxicity towards eukaryotic cells. In the present study, we report that C1-15 is active against bacteria such as Bacillus anthracis and Yersinia

E. Margo Molhoek; Albert van Dijk; Edwin J. A. Veldhuizen; Helma Dijk-Knijnenburg; Roos H. Mars-Groenendijk; Linda C. L. Boele; Wendy E. Kaman-van Zanten; Henk P. Haagsman; Floris J. Bikker

2010-01-01

147

Immunomodulatory effects of Toll-like receptor-7 activation on chronic lymphocytic leukemia cells.  

PubMed

Weak immunogenicity of chronic lymphocytic leukemia (CLL) cells may contribute to disease progression and inhibit effective immunotherapy. Accordingly, agents that enhance the immunogenicity of CLL cells may be useful in immunotherapeutic approaches to this disease. Since Toll-like receptors (TLRs) are major regulators of innate immunity and initiation of adaptive immunity, we studied the effects of viral pathogen associated molecular pattern agonists (that are recognized by TLRs) on the costimulatory phenotype and function of CLL cells. CLL cells (especially those with high endogenous expression of CD38) responded to TLR7-activating imidazoquinolines and guanosine analogs by increasing costimulatory molecule expression, producing inflammatory cytokines, and becoming more sensitive to killing by cytotoxic effectors. Additional activation of protein kinase C pathways increased the ability to stimulate T-cell proliferation, blocked phosphorylation of the transcription factor, signal transducer and activator of transcription (STAT)3, and resulted in the acquisition of a dendritic cell surface phenotype by TLR7-activated CLL cells. Normal B cells also responded to TLR7 activation by increasing costimulatory molecule expression and cytokine production. These findings suggest a potential role for TLR7 agonists in CLL immunotherapy. PMID:16341037

Spaner, D E; Shi, Y; White, D; Mena, J; Hammond, C; Tomic, J; He, L; Tomai, M A; Miller, R L; Booth, J; Radvanyi, L

2006-02-01

148

Immunomodulatory Activity of Lactococcus lactis A17 from Taiwan Fermented Cabbage in OVA-Sensitized BALB/c Mice  

PubMed Central

From fermented Taiwan foods, we have isolated numerous lactic acid bacteria (LAB) of plant origin and investigated their biological activities. This study aimed to investigate the immunomodulatory effect and mechanism of Lactococcus lactis A17 (A17), isolated from Taiwan fermented cabbage, on ovalbumin (OVA)-sensitized mice. Human peripheral blood mononuclear cells were used to verify immune responses of A17 by IFN-? production. Live (A17-A) and heat-killed A17 (A17-H) were orally administered to OVA-sensitized BALB/c mice to investigate their effects on immunoglobulin (Ig) and cytokine production. The mRNA expression of Toll-like receptors (TLR) and nucleotide binding oligomerization domain (NOD)-like protein receptors in spleen cells was analyzed by real-time RT-PCR. Both live and heat-killed A17 modulate OVA-induced allergic effects. B-cell response was modulated by diminishing IgE production and raising OVA-specific IgG2a production, while T-cell response was modulated by increasing IFN-? production and decreasing IL-4 production. The mRNA expression of NOD-1, NOD-2, and TLR-4 was down-regulated by A17 as well. This is the first report to describe a naďve Lactococcus lactis A17 strain as a promising candidate for prophylactic and therapeutic treatments of allergic diseases via oral administration. Our results suggest the ameliorative effects of A17 may be caused by modulating NOD-1 NOD-2, and TLR-4 expression. PMID:23401710

Mei, Hui-Ching; Liu, Yen-Wenn; Chiang, Yi-Chin; Chao, Shiou-Huei; Mei, Nai-Wen; Liu, Yu-Wen; Tsai, Ying-Chieh

2013-01-01

149

Phenotypic Diversity and Emerging New Tools to Study Macrophage Activation in Bacterial Infectious Diseases  

PubMed Central

Macrophage polarization is a concept that has been useful to describe the different features of macrophage activation related to specific functions. Macrophage polarization is responsible for a dichotomic approach (killing vs. repair) of the host response to bacteria; M1-type conditions are protective, whereas M2-type conditions are associated with bacterial persistence. The use of the polarization concept to classify the features of macrophage activation in infected patients using transcriptional and/or molecular data and to provide biomarkers for diagnosis and prognosis has most often been unsuccessful. The confrontation of polarization with different clinical situations in which monocytes/macrophages encounter bacteria obliged us to reappraise this concept. With the exception of M2-type infectious diseases, such as leprosy and Whipple’s disease, most acute (sepsis) or chronic (Q fever, tuberculosis) infectious diseases do not exhibit polarized monocytes/macrophages. This is also the case for commensals that shape the immune response and for probiotics that alter the immune response independent of macrophage polarization. We propose that the type of myeloid cells (monocytes vs. macrophages) and the kinetics of the immune response (early vs. late responses) are critical variables for understanding macrophage activation in human infectious diseases. Explorating the role of these new markers will provide important tools to better understand complex macrophage physiology. PMID:25346736

Ka, Mignane B.; Daumas, Aurélie; Textoris, Julien; Mege, Jean-Louis

2014-01-01

150

Phenotypic diversity and emerging new tools to study macrophage activation in bacterial infectious diseases.  

PubMed

Macrophage polarization is a concept that has been useful to describe the different features of macrophage activation related to specific functions. Macrophage polarization is responsible for a dichotomic approach (killing vs. repair) of the host response to bacteria; M1-type conditions are protective, whereas M2-type conditions are associated with bacterial persistence. The use of the polarization concept to classify the features of macrophage activation in infected patients using transcriptional and/or molecular data and to provide biomarkers for diagnosis and prognosis has most often been unsuccessful. The confrontation of polarization with different clinical situations in which monocytes/macrophages encounter bacteria obliged us to reappraise this concept. With the exception of M2-type infectious diseases, such as leprosy and Whipple's disease, most acute (sepsis) or chronic (Q fever, tuberculosis) infectious diseases do not exhibit polarized monocytes/macrophages. This is also the case for commensals that shape the immune response and for probiotics that alter the immune response independent of macrophage polarization. We propose that the type of myeloid cells (monocytes vs. macrophages) and the kinetics of the immune response (early vs. late responses) are critical variables for understanding macrophage activation in human infectious diseases. Explorating the role of these new markers will provide important tools to better understand complex macrophage physiology. PMID:25346736

Ka, Mignane B; Daumas, Aurélie; Textoris, Julien; Mege, Jean-Louis

2014-01-01

151

Macrophage-oriented cytotoxic activity of novel triterpene saponins extracted from roots of Securidaca inappendiculata.  

PubMed

It is recognized that macrophages in peripheral tissues often proliferate under pathological conditions such as tumors, inflammation and atherosclerosis. Because the growth state of macrophages is believed to be a factor regulating the pathological process of the diseases, substances that regulate macrophage growth or survival may be useful for disease control. In this paper, we identified the activity inhibiting macrophage growth in a hot water extract of roots of Securidaca inappendiculata. The extract markedly inhibited macrophage colony-stimulating factor (M-CSF/CSF-1)-induced growth of macrophages, whereas it exerted a less potent effect on growth of Concanavalin A (Con A)-stimulated thymocytes or M-CSF-stimulated bone marrow cells. The inhibition of macrophage growth was caused by a cytotoxic effect rather than a cytostatic effect. Cell death was due to the induction of apoptosis, as judged by staining with terminal deoxynucleotidyl transferase-mediated d-UTP nick end labelling (TUNEL). The cytotoxic activity seemed to be specific to peripheral macrophages; it showed a weak effect on the growth and survival of tumor cell lines including a macrophage-like cell line, J-774.1. Moreover, the saponin fraction induced apoptotic cell death of macrophages only when they were stimulated by M-CSF; it did not affect the viability of macrophages cultured without M-CSF or with granulocyte/macrophage-CSF. We determined the structures of the two active triterpene saponin compounds in the fraction, named securioside A and securioside B having a 3,4-dimethoxycinnamic group which is essential for the cell death-inducing activity. They are believed to be the primary compounds of new drugs for the treatment of pathological states in which macrophage proliferation occurs. PMID:11606030

Yui, S; Ubukata, K; Hodono, K; Kitahara, M; Mimaki, Y; Kuroda, M; Sashida, Y; Yamazaki, M

2001-10-01

152

Cytosolic phospholipase a2 activation by Candida albicans in alveolar macrophages: role of dectin-1.  

PubMed

Candida albicans is an increasingly important pulmonary fungal pathogen. Resident alveolar macrophages are important in host defense against opportunistic fungal infections. Activation of Group IVA cytosolic phospholipase A(2)alpha (cPLA(2)alpha) in macrophages initiates arachidonic acid (AA) release for production of eicosanoids, which regulate inflammation and immune responses. We investigated the ability of C. albicans to activate cPLA(2)alpha in unprimed alveolar macrophages and after priming with granulocyte macrophage colony-stimulating factor (GM-CSF), which regulates alveolar macrophage maturation. AA was released within minutes by GM-CSF-primed but not unprimed alveolar macrophages in response to C. albicans, and was blocked by soluble glucan phosphate (S-GP). The expression of the beta-glucan receptor dectin-1 was increased in GM-CSF-primed macrophages, and AA release from GM-CSF-primed dectin-1(-/-) alveolar macrophages was reduced to basal levels. The enhanced activation of extracellular signal-regulated kinases and phosphorylation of cPLA(2)alpha on Ser-505 that occurred in GM-CSF-primed macrophages were reduced by MEK1 and Syk inhibitors, which also suppressed AA release. At later times after C. albicans infection (6 h), unprimed and GM-CSF-primed macrophages released similar levels of AA. The expression of cyclooxygenase 2 and prostanoid production at 6 hours was higher in GM-CSF-primed macrophages, but the responses were not dependent on dectin-1. However, dectin-1 contributed to the C. albicans-stimulated increase in TNF-alpha production that occurred in GM-CSF-primed macrophages. The results demonstrate that dectin-1 mediates the acute activation of cPLA(2)alpha in GM-CSF-primed alveolar macrophages, but not in the more delayed phase of AA release and GM-CSF-dependent prostanoid production. PMID:19502385

Parti, Rajinder P; Loper, Robyn; Brown, Gordon D; Gordon, Siamon; Taylor, Philip R; Bonventre, Joseph V; Murphy, Robert C; Williams, David L; Leslie, Christina C

2010-04-01

153

Sericins exhibit ROS-scavenging, anti-tyrosinase, anti-elastase, and in vitro immunomodulatory activities.  

PubMed

Some biological properties of Bombyx mori sericins from twenty strains were investigated, fourteen fed with artificial diet, two with fresh mulberry leaves and four with both diets. Sericin exhibited ROS-scavenging, anti-tyrosinase and anti-elastase properties, the strain significantly influenced these properties, while diet only influenced the anti-tyrosinase activity. Sericins were clustered into 5 groups and one sericin from each group was further studied: sericins showed anti-proliferative activity on in vitro stimulated peripheral blood mononuclear cells; some strains decreased in vitro secretion of IFN?, while no effects were observed on TNF? and IL10 release. Therefore, a mixture of sericins extracted from the most promising strains may be useful for dermatological and cosmetic use. PMID:23541552

Chlapanidas, Theodora; Faragň, Silvio; Lucconi, Giulia; Perteghella, Sara; Galuzzi, Marta; Mantelli, Melissa; Avanzini, Maria Antonietta; Tosca, Marta Cecilia; Marazzi, Mario; Vigo, Daniele; Torre, Maria Luisa; Faustini, Massimo

2013-07-01

154

Putting on the Brakes: Cyclic AMP as a Multipronged Controller of Macrophage Function  

NSDL National Science Digital Library

Macrophages orchestrate innate immune responses in tissues by activating various proinflammatory signaling programs. A key mechanism for preventing inflammatory disease states that result from excessive activation of such programs is the generation of the second messenger cyclic adenosine monophosphate (cAMP) by ligation of certain guanine nucleotide–binding protein (G protein)–coupled receptors (GPCRs). The pleiotropic actions of this cyclic nucleotide on various inflammatory functions of macrophages are mediated by diverse molecular mechanisms, including the assembly of distinct multiprotein complexes. A better understanding of crosstalk between cAMP signaling and proinflammatory pathways in macrophages may provide a basis for improved immunomodulatory strategies.

Marc Peters-Golden (Ann Arbor;University of Michigan Medical School REV)

2009-06-16

155

A20 promotes Brucella intracellular growth via inhibition of macrophage cell death and activation.  

PubMed

The zinc-finger protein A20 has crucial physiological functions as a dual inhibitor of macrophage activation and apoptosis in tumor necrosis factor receptor1 (TNFR1) signaling pathway. Brucella infection can induce A20 expression in macrophages. Here, we hypothesize that A20 promotes Brucella intracellular growth via inhibition of activation and apoptosis of macrophages. To test this hypothesis, we stably incorporated mouse A20-shRNA into the RAW264.7 cells by lentiviral gene transfer to successfully knockdown A20. A20-deficient RAW264.7 cells were subsequently challenged with Brucella abortus and colony formation units (CFUs) of bacteria, TNF? production, NF-kB activation, macrophages apoptosis and cell death were evaluated. The A20 knockdown was shown to effectively promote B. abortus-stimulated TNF? release, NF-kB activation and macrophage cell death, which suppressed B. abortus intracellular replication. Unexpectedly, deficiency of A20 failed to lead to B. abortus-induced macrophage apoptosis. A20 deficiency coupled NF-kB inhibition promoted caspase-8 dependent B. abortus-induced macrophage apoptosis. These findings provide a novel mechanism by which Brucella intracellular growth within macrophages occurs through up-regulation of A20 thereby limiting activation and macrophages cell death. PMID:25433453

Wei, Pan; Cui, Guimei; Lu, Qiang; Yang, Li; Guan, Zhenhong; Sun, Wanchun; Zhao, Yuxi; Wang, Shuangxi; Peng, Qisheng

2015-01-30

156

Induction of heat shock proteins and their possible roles in macrophages during activation by macrophage colony-stimulating factor.  

PubMed Central

(1) Treatment of resident peritoneal macrophages for 8 h with macrophage colony-stimulating factor (M-CSF) increased release of superoxide anion (O2-) stimulated by phorbol 12-myristate 13-acetate. Gel electrophoresis of pulse-labelled proteins with L-[35S]methionine showed that a number of proteins were induced during activation by M-CSF. Immunoblot analysis with antibody against heat shock protein (HSP) 90, HSP70, or HSP60 demonstrated that M-CSF induced these stress-inducible HSPs; the timing of induction and level of each HSP correlated with the increase in O2- production. The activated macrophages acquired resistance to H2O2-induced damage. M-CSF also stimulated the synthesis of a heat shock cognate protein (HSC70); however, the induction occurred at 1 h, when O2- production was not yet augmented, but at which time L-[35S]methionine incorporation into cell proteins was already enhanced. (2) Gel mobility shift assay with oligonucleotide coding for the heat shock element showed that M-CSF activated the heat shock factor within 15 min, and the activation continued for at least 8 h. Northern-blot analysis with a cDNA probe for human HSP70 or HSC70 showed that accumulations of HSP70 and HSC70 mRNAs coincided with the inductions of the respective proteins. (3) These results suggest that M-CSF may induce the transcriptional activation of heat shock genes, and that the stress-inducible HSPs as well as HSC70 may play an important role in the activation of macrophages by functioning as molecular chaperones and by protecting the macrophage against the auto-oxidative damage associated with the respiratory burst. PMID:8615820

Teshima, S; Rokutan, K; Takahashi, M; Nikawa, T; Kishi, K

1996-01-01

157

A transient reversal of miRNA-mediated repression controls macrophage activation  

PubMed Central

In mammalian macrophages, the expression of a number of cytokines is regulated by miRNAs. Upon macrophage activation, proinflammatory cytokine mRNAs are translated, although the expression of miRNAs targeting these mRNAs remains largely unaltered. We show that there is a transient reversal of miRNA-mediated repression during the early phase of the inflammatory response in macrophages, which leads to the protection of cytokine mRNAs from miRNA-mediated repression. This derepression occurs through Ago2 phosphorylation, which results in its impaired binding to miRNAs and to the corresponding target mRNAs. Macrophages expressing a mutant, non-phosphorylatable AGO2—which remains bound to miRNAs during macrophage activation—have a weakened inflammatory response and fail to prevent parasite invasion. These findings highlight the relevance of the transient relief of miRNA repression for macrophage function. PMID:24030283

Mazumder, Anup; Bose, Mainak; Chakraborty, Abhijit; Chakrabarti, Saikat; Bhattacharyya, Suvendra N

2013-01-01

158

CD47-dependent immunomodulatory and angiogenic activities of extracellular vesicles produced by T cells.  

PubMed

Intercellular communication is critical for integrating complex signals in multicellular eukaryotes. Vascular endothelial cells and T lymphocytes closely interact during the recirculation and trans-endothelial migration of T cells. In addition to direct cell-cell contact, we show that T cell derived extracellular vesicles can interact with endothelial cells and modulate their cellular functions. Thrombospondin-1 and its receptor CD47 are expressed on exosomes/ectosomes derived from T cells, and these extracellular vesicles are internalized and modulate signaling in both T cells and endothelial cells. Extracellular vesicles released from cells expressing or lacking CD47 differentially regulate activation of T cells induced by engaging the T cell receptor. Similarly, T cell-derived extracellular vesicles modulate endothelial cell responses to vascular endothelial growth factor and tube formation in a CD47-dependent manner. Uptake of T cell derived extracellular vesicles by recipient endothelial cells globally alters gene expression in a CD47-dependent manner. CD47 also regulates the mRNA content of extracellular vesicles in a manner consistent with some of the resulting alterations in target endothelial cell gene expression. Therefore, the thrombospondin-1 receptor CD47 directly or indirectly regulates intercellular communication mediated by the transfer of extracellular vesicles between vascular cells. PMID:24887393

Kaur, Sukhbir; Singh, Satya P; Elkahloun, Abdel G; Wu, Weiwei; Abu-Asab, Mones S; Roberts, David D

2014-07-01

159

Liver X Receptor (LXR) activation negatively regulates visfatin expression in macrophages  

SciTech Connect

Research highlights: {yields} Synthetic LXR ligands decreased visfatin expression in human macrophages. {yields} LXR activation leads to a modest and transient decrease of NAD{sup +} concentration. {yields} LXR activation decreased PPAR{gamma}-induced visfatin in human macrophages. -- Abstract: Adipose tissue macrophages (ATM) are the major source of visfatin, a visceral fat adipokine upregulated during obesity. Also known to play a role in B cell differentiation (pre-B cell colony-enhancing factor (PBEF)) and NAD biosynthesis (nicotinamide phosphoribosyl transferase (NAMPT)), visfatin has been suggested to play a role in inflammation. Liver X Receptor (LXR) and Peroxisome Proliferator-Activated Receptor (PPAR){gamma} are nuclear receptors expressed in macrophages controlling the inflammatory response. Recently, we reported visfatin as a PPAR{gamma} target gene in human macrophages. In this study, we examined whether LXR regulates macrophage visfatin expression. Synthetic LXR ligands decreased visfatin gene expression in a LXR-dependent manner in human and murine macrophages. The decrease of visfatin mRNA was paralleled by a decrease of protein secretion. Consequently, a modest and transient decrease of NAD{sup +} concentration was observed. Interestingly, LXR activation decreased the PPAR{gamma}-induced visfatin gene and protein secretion in human macrophages. Our results identify visfatin as a gene oppositely regulated by the LXR and PPAR{gamma} pathways in human macrophages.

Mayi, Therese Hervee; Rigamonti, Elena [Univ Lille Nord de France, F-59000 Lille (France) [Univ Lille Nord de France, F-59000 Lille (France); INSERM UR1011, F-59000 Lille (France) [France; UDSL, F-59000 Lille (France) [France; Institut Pasteur de Lille, F-59019 Lille (France); Pattou, Francois [Univ Lille Nord de France, F-59000 Lille (France) [Univ Lille Nord de France, F-59000 Lille (France); Department of Endocrine Surgery, University Hospital, Lille (France); U859 Biotherapies for Diabetes, INSERM, Lille (France); Staels, Bart, E-mail: bart.staels@pasteur-lille.fr [Univ Lille Nord de France, F-59000 Lille (France) [Univ Lille Nord de France, F-59000 Lille (France); INSERM UR1011, F-59000 Lille (France) [France; UDSL, F-59000 Lille (France) [France; Institut Pasteur de Lille, F-59019 Lille (France); Chinetti-Gbaguidi, Giulia [Univ Lille Nord de France, F-59000 Lille (France) [Univ Lille Nord de France, F-59000 Lille (France); INSERM UR1011, F-59000 Lille (France) [France; UDSL, F-59000 Lille (France) [France; Institut Pasteur de Lille, F-59019 Lille (France)

2011-01-07

160

Secretion of monocyte chemotactic activity by alveolar macrophages.  

PubMed Central

The purpose of this study was to determine if alveolar macrophages (AMs) are a source of monocyte chemoattractants and the role bleomycin interaction with AMs may play in the recruitment of monocytes to the lung in a rodent model of bleomycin-induced pulmonary fibrosis. AMs isolated from rats with bleomycin-induced fibrosis secreted significantly greater amounts of monocyte chemoattractants than those isolated from normal rats. When AMs from normal rats were stimulated with bleomycin in vitro, monocyte chemotactic activity was secreted into the medium. Chemotactic activity secretion by AM stimulated with 0.01 to 0.1 micrograms/ml bleomycin was significantly higher than that of cells incubated in medium alone. This activity was truly chemotactic for monocytes, but caused only minimal migration of normal AMs. Bleomycin itself at concentrations of 1 pg/ml to 10 micrograms/ml had no monocyte chemoattractant activity. Characterization of the chemotactic activity in conditioned media (CM) from bleomycin-stimulated AM demonstrated that the major portion of the activity bound to gelatin, was heterogeneous, with estimated molecular weights of 20 to 60 kd, and was inactivated by specific antifibronectin antibody. These findings suggest that fibronectin fragments are primarily responsible for the monocyte chemotactic activity secreted by AMs. Through increased secretion of such chemotactic substances, AMs could play a key role in the recruitment of peripheral blood monocytes into the lung in inflammatory lung disease and fibrosis. PMID:2476935

Denholm, E. M.; Wolber, F. M.; Phan, S. H.

1989-01-01

161

Activation of Olfactory Receptors on Mouse Pulmonary Macrophages Promotes Monocyte Chemotactic Protein-1 Production  

PubMed Central

Background Emerging evidence suggests that non-olfactory tissues and cells can express olfactory receptors (ORs), however, the exact function of ectopic OR expression remains unknown. We have previously shown in mouse models that a unique cooperation between interferon-? (IFN-?) and lipopolysaccharide (LPS) drives the activation of pulmonary macrophages and leads to the induction of pathogenic responses in the respiratory tract. Further, through gene array studies, we have shown that activation of macrophages by these molecules results in the selective expression of a number of ORs. In this study, we validated the expression of these ORs in mouse airway and pulmonary macrophages in response to IFN-? and LPS (?/LPS) stimulation, and further explored the effect of odorant stimulation on macrophage function. Methodology/Principal Findings OR expression in airway and pulmonary macrophages in response to IFN-?, LPS or ?/LPS treatments was assessed by microarray and validated by q-PCR. OR expression (e.g. OR622) on macrophages was confirmed by visualization in immunofluoresence assays. Functional responses to odorants were assessed by quantifying inflammatory cytokine and chemokine expression using q-PCR and cell migration was assessed by a modified Boyden chamber migration assay. Our results demonstrate that eight ORs are expressed at basal levels in both airway and pulmonary macrophages, and that ?/LPS stimulation cooperatively increased this expression. Pulmonary macrophages exposed to the combined treatment of ?/LPS+octanal (an odorant) exhibited a 3-fold increase in MCP-1 protein production, compared to cells treated with ?/LPS alone. Supernatants from ?/LPS+octanal exposed macrophages also increased macrophage migration in vitro. Conclusions/Significance Eight different ORs are expressed at basal levels in pulmonary macrophages and expression is upregulated by the synergistic action of ?/LPS. Octanal stimulation further increased MCP-1 production and the motility of macrophages. Our results suggest that ORs may mediate macrophage function by regulating MCP-1 production and cell migration. PMID:24278251

Li, Jing Jing; Tay, Hock L.; Plank, Maximilian; Essilfie, Ama-Tawiah; Hansbro, Philip M.; Foster, Paul S.; Yang, Ming

2013-01-01

162

Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone attenuates postincisional pain by regulating macrophage polarization  

SciTech Connect

Highlights: Black-Right-Pointing-Pointer Rosiglitazone attenuated postincisional pain. Black-Right-Pointing-Pointer Rosiglitazone alters macrophage polarization to F4/80{sup +}CD206{sup +} M2 macrophages at the incisional sites. Black-Right-Pointing-Pointer Transplantation of rosiglitazone-treated macrophages produced analgesic effects. -- Abstract: Acute inflammation triggered by macrophage infiltration to injured tissue promotes wound repair and may induce pain hypersensitivity. Peroxisome proliferator-activated receptor {gamma} (PPAR){gamma} signaling is known to regulate heterogeneity of macrophages, which are often referred to as classically activated (M1) and alternatively activated (M2) macrophages. M1 macrophages have considerable antimicrobial activity and produce a wide variety of proinflammatory cytokines. In contrast, M2 macrophages are involved in anti-inflammatory and homeostatic functions linked to wound healing and tissue repair. Although it has been suggested that PPAR{gamma} agonists attenuate pain hypersensitivity, the molecular mechanism of macrophage-mediated effects of PPAR{gamma} signaling on pain development has not been explored. In this study, we investigated the link between the phenotype switching of macrophage polarization induced by PPAR{gamma} signaling and the development of acute pain hypersensitivity. Local administration of rosiglitazone significantly ameliorated hypersensitivity to heat and mechanical stimuli, and paw swelling. Consistent with the down-regulation of nuclear factor {kappa}B (NF{kappa}B) phosphorylation by rosiglitazone at the incisional sites, the number of F4/80{sup +}iNOS{sup +} M1 macrophages was decreased whereas numbers of F4/80{sup +}CD206{sup +} M2 macrophages were increased in rosiglitazone-treated incisional sites 24 h after the procedure. In addition, gene induction of anti-inflammatory M2-macrophage-associated markers such as arginase1, FIZZ1 and interleukin (IL)-10 were significantly increased, whereas M1-macrophage-related molecules such as integrin {alpha}X, IL-1{beta}, MIP2{alpha} and leptin were decreased at rosiglitazone-treated incisional sites. Moreover, transplantation of rosiglitazone-treated peritoneal macrophages into the incisional sites significantly attenuated hyperalgesia. We speculate that local administration of rosiglitazone significantly alleviated the development of postincisional pain, possibly through regulating macrophage polarity at the inflamed site. PPAR{gamma} signaling in macrophages may be a potential therapeutic target for the treatment of acute pain development.

Hasegawa-Moriyama, Maiko, E-mail: hase-mai@m3.kufm.kagoshima-u.ac.jp [Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan)] [Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Ohnou, Tetsuya; Godai, Kohei; Kurimoto, Tae; Nakama, Mayo; Kanmura, Yuichi [Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan)] [Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan)

2012-09-14

163

[Effect of lymphocytes on macrophage phagocytic activity in delayed hypersensitivity to Staphylococcus].  

PubMed

The direct contact of macrophages with lymphocytes enhanced the functional activity of macrophages: the phagocytosis rate increased from 53.5% to 92.7%, the phagocytosis index increased from 8.7 to 15.7. Splenic lymphocytes obtained from mice with delayed hypersensitivity to staphylococci, when stimulated with staphylococcal corpuscular antigen in vitro, released lymphokines into the culture fluid. These lymphokines enhanced the capacity of macrophages and lymphocytes for mutual contacts. PMID:7102184

Vikhot', N E

1982-05-01

164

Antiviral, Immunomodulatory, and Free Radical Scavenging Activities of a Protein-Enriched Fraction from the Larvae of the Housefly, Musca domestica  

PubMed Central

In our previous study, protein-enriched fraction (PEF) that was isolated from the larvae of the housefly, Musca domestica L. (Diptera: Muscidae), showed excellent hepatoprotective activity as well as the potential for clinical application in therapy for liver diseases. In this study, antiviral, immunomodulatory, and free radical scavenging activities of PEF were evaluated. The antiviral results demonstrated that PEF inhibited the infection of avian influenza virus H9N2 and had a virucidal effect against the multicapsid nucleopolyhedrovirus of the alfalfa looper, Autographa californica Speyer (Lepidoptera: Noctuidae) in vitro. The mortality of silkworm larve in a PEF treatment group decreased significantly compared with a negative control. PEF showed excellent scavenging activity for 1,1-diphenyl-2-picrylhydrazyl and superoxide anion radicals, which were similar to those of ascorbic acid. The imunomodulatory results suggested that PEF could effectively improve immune function in experimental mice. Our results indicated that PEF could possibly be used for the prophylaxis and treatment of diseases caused by avian influenza virus infection. In addition, PEF with virucidal activity against insect viruses might provide useful for the development of antimicrobial breeding technology for economically important insects. As a natural product from insects, PEF could be a potential source for the discovery of potent antioxidant and immunomodulatory agents. PMID:24735244

Ai, Hui; Wang, Furong; Zhang, Na; Zhang, Lingyao; Lei, Chaoliang

2013-01-01

165

Macrophage Activation in Acute Exacerbation of Idiopathic Pulmonary Fibrosis  

PubMed Central

Background Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) is a common cause of disease acceleration in IPF and has a major impact on mortality. The role of macrophage activation in AE of IPF has never been addressed before. Methods We evaluated BAL cell cytokine profiles and BAL differential cell counts in 71 IPF patients w/wo AE and in 20 healthy volunteers. Twelve patients suffered from AE at initial diagnosis while sixteen patients developed AE in the 24 months of follow-up. The levels of IL-1ra, CCL2, CCL17, CCL18, CCL22, TNF-?, IL-1?, CXCL1 and IL-8 spontaneously produced by BAL-cells were analysed by ELISA. Results In patients with AE, the percentage of BAL neutrophils was significantly increased compared to stable patients. We found an increase in the production rate of the pro-inflammatory cytokines CXCL1 and IL-8 combined with an increase in all tested M2 cytokines by BAL-cells. An increase in CCL18 levels and neutrophil counts during AE was observed in BAL cells from patients from whom serial lavages were obtained. Furthermore, high baseline levels of CCL18 production by BAL cells were significantly predictive for the development of future AE. Conclusions BAL cell cytokine production levels at acute exacerbation show up-regulation of pro-inflammatory as well as anti-inflammatory/ M2 cytokines. Our data suggest that AE in IPF is not an incidental event but rather driven by cellular mechanisms including M2 macrophage activation. PMID:25590613

Schupp, Jonas Christian; Binder, Harald; Jäger, Benedikt; Cillis, Giuseppe; Zissel, Gernot; Müller-Quernheim, Joachim; Prasse, Antje

2015-01-01

166

Macrophages Contribute to the Cyclic Activation of Adult Hair Follicle Stem Cells  

PubMed Central

Skin epithelial stem cells operate within a complex signaling milieu that orchestrates their lifetime regenerative properties. The question of whether and how immune cells impact on these stem cells within their niche is not well understood. Here we show that skin-resident macrophages decrease in number because of apoptosis before the onset of epithelial hair follicle stem cell activation during the murine hair cycle. This process is linked to distinct gene expression, including Wnt transcription. Interestingly, by mimicking this event through the selective induction of macrophage apoptosis in early telogen, we identify a novel involvement of macrophages in stem cell activation in vivo. Importantly, the macrophage-specific pharmacological inhibition of Wnt production delays hair follicle growth. Thus, perifollicular macrophages contribute to the activation of skin epithelial stem cells as a novel, additional cue that regulates their regenerative activity. This finding may have translational implications for skin repair, inflammatory skin diseases and cancer. PMID:25536657

Castellana, Donatello; Paus, Ralf; Perez-Moreno, Mirna

2014-01-01

167

Histochemical studies relating the activation of macrophages to the intracellular destruction of tubercle bacilli.  

PubMed Central

Dermal tuberculous lesions, both primary and those of reinfection, were produced in rabbits with 14C-labeled BCG and biopsied once at various times. Macrophage activation was evaluated by the indolyl histochemical test for beta-galatosidase, the number of bacilli in macrophages by acid-fast staining, and the breakdown of bacilli by autoradiography. After the rabbits became tuberculin positive, the stongly activated macrophage population contained a) fewer parasitized cell, b) fewer bacilli in each parasitized cell, and c) more "free" 14C-label (not associated with intact bacilli) than the weakly activated macrophage population. These results suggest that the more highly activated macrophages had destroyed many of the bacilli that they once contained and that their power to do so was enhanced by immunologic mechanisms. PMID:320876

Ando, M.; Dannenberg, A. M.; Sugimoto, M.; Tepper, B. S.

1977-01-01

168

The intestinal anti-inflammatory effect of minocycline in experimental colitis involves both its immunomodulatory and antimicrobial properties.  

PubMed

Some antibiotics, including minocycline, have recently been reported to display immunomodulatory properties in addition to their antimicrobial activity. The use of a compound with both immunomodulatory and antibacterial properties could be very interesting in the treatment of inflammatory bowel disease (IBD), so the aim of our study was to evaluate the anti-inflammatory effect of minocycline in several experimental models of IBD. Firstly, the immunomodulatory activity of the antibiotic was tested in vitro using Caco-2 intestinal epithelial cells and RAW 264.7 macrophages; minocycline was able to inhibit IL-8 and nitrite production, respectively. In vivo studies were performed in trinitrobenzenesulfonic acid (TNBS)-induced rat colitis and dextran sodium sulfate (DSS)-induced mouse colitis. The results revealed that minocycline exerted an intestinal anti-inflammatory effect when administered as a curative treatment in the TNBS model, modulating both immune and microbiological parameters, being confirmed in the DSS model; whereas none of the other antibiotics tested (tetracycline and metronidazole) showed anti-inflammatory effect. However, minocycline administration before the colitis induction was not able to prevent the development of the intestinal inflammation, thus showing that only its antimicrobial activity is not enough for the anti-inflammatory effect. In conclusion, minocycline displays an anti-inflammatory effect on different models of rodent colitis which could be attributed to the association of its antibacterial and immunomodulatory properties. PMID:21193045

Garrido-Mesa, Natividad; Camuesco, Desirée; Arribas, Belén; Comalada, Mňnica; Bailón, Elvira; Cueto-Sola, Margarita; Utrilla, Pilar; Nieto, Ana; Zarzuelo, Antonio; Rodríguez-Cabezas, María Elena; Gálvez, Julio

2011-04-01

169

IL-33 Priming Enhances Peritoneal Macrophage Activity in Response to Candida albicans.  

PubMed

IL-33 is a member of the IL-1 cytokine family and plays a role in the host defense against bacteria, viruses, and fungi. In this study, we investigated the function of IL-33 and its receptor in in vitro macrophage responses to Candida albicans. Our results demonstrate that pre-sensitization of isolated peritoneal macrophages with IL-33 enhanced their pro-inflammatory cytokine production and phagocytic activity in response to C. albicans. These macrophage activities were entirely dependent on the ST2-MyD88 signaling pathway. In addition, pre-sensitization with IL-33 also increased ROS production and the subsequent killing ability of macrophages following C. albicans challenge. These results indicate that IL-33 may increase anti-fungal activity against Candida through macrophage-mediated resistance mechanisms. PMID:25177252

Tran, Vuvi G; Cho, Hong R; Kwon, Byungsuk

2014-08-01

170

The macrophage chemotactic activity of Streptococcus agalactiae and Streptococcus iniae extracellular products (ECP).  

PubMed

The ability of Streptococcus agalactiae and Streptococcus iniae to attract macrophages of Nile tilapia (Oreochromis niloticus) was investigated. The extracellular products (ECP) from S. agalactiae and S. iniae were tested in vitro for macrophage chemotaxis using blind-well chambers. The macrophages were obtained from the peritoneal cavity 4-5 days after intraperitoneal injection of squalene. Both macrophage chemotactic and chemokinetic activities were demonstrated using the S. agalactiae ECP. However, only chemotactic activity was shown for S. iniae ECP. High-pressure liquid chromatography fractionation revealed that semi-purified S. agalactiae and S. iniae ECPs had estimated molecular weights of 7.54 and 19.2kDa, respectively. The prominent chemotactic activities of ECP from S. agalactiae and S. iniae are likely to be involved in the proinflammatory responses of macrophages to S. agalactiae and S. iniae infections. PMID:17212985

Klesius, Phillip H; Evans, Joyce J; Shoemaker, Craig A

2007-05-01

171

IL-33 Priming Enhances Peritoneal Macrophage Activity in Response to Candida albicans  

PubMed Central

IL-33 is a member of the IL-1 cytokine family and plays a role in the host defense against bacteria, viruses, and fungi. In this study, we investigated the function of IL-33 and its receptor in in vitro macrophage responses to Candida albicans. Our results demonstrate that pre-sensitization of isolated peritoneal macrophages with IL-33 enhanced their pro-inflammatory cytokine production and phagocytic activity in response to C. albicans. These macrophage activities were entirely dependent on the ST2-MyD88 signaling pathway. In addition, pre-sensitization with IL-33 also increased ROS production and the subsequent killing ability of macrophages following C. albicans challenge. These results indicate that IL-33 may increase anti-fungal activity against Candida through macrophage-mediated resistance mechanisms. PMID:25177252

Tran, Vuvi G.

2014-01-01

172

Alginates from wound dressings activate human macrophages to secrete tumour necrosis factor- ?  

Microsoft Academic Search

Alginates are used to manufacture a number of wound dressings. Clinical observations indicate that they may initiate or accelerate healing of chronic wounds after treatment of underlying pathology. Wound granulation tissue contains large numbers of macrophages and they are thought to regulate the healing process. As purified alginates have been demonstrated to activate macrophages this study was initiated to determine

A Thomas; K. G Harding; K Moore

2000-01-01

173

Bone resorbing activity released from zymosan-activated mouse peritoneal macrophages - the role of prostanoids and interleukin-1  

Microsoft Academic Search

Objective: To study the effect of zymosan on the release of osteoclast stimulating activity from macrophages.¶Materials: Calvarial bones from neonatal mice and peritoneal macrophages were incubated in the absence and presence of zymosan for 72 h and supernatants harvested for subsequent analysis of bone resorbing activities and prostaglandin concentration.¶Methods: Bone resorption was assessed in vitro by analysing the release of

A. Ohlin; U. Sjögren; U. H. Lerner

1999-01-01

174

Macrophage activation by factors released from acetaminophen-injured hepatocytes: Potential role of HMGB1  

SciTech Connect

Toxic doses of acetaminophen (AA) cause hepatocellular necrosis. Evidence suggests that activated macrophages contribute to the pathogenic process; however, the factors that activate these cells are unknown. In these studies, we assessed the role of mediators released from AA-injured hepatocytes in macrophage activation. Treatment of macrophages with conditioned medium (CM) collected 24 hr after treatment of mouse hepatocytes with 5 mM AA (CM-AA) resulted in increased production of reactive oxygen species (ROS). Macrophage expression of heme oxygenase-1 (HO-1) and catalase mRNA was also upregulated by CM-AA, as well as cyclooxygenase (COX)-2 and 12/15-lipoxygenase (LOX). CM-AA also upregulated expression of the proinflammatory chemokines, MIP-1{alpha} and MIP-2. The effects of CM-AA on expression of COX-2, MIP-1{alpha} and MIP-2 were inhibited by blockade of p44/42 MAP kinase, suggesting a biochemical mechanism mediating macrophage activation. Hepatocytes injured by AA were found to release HMGB1, a potent macrophage activator. This was inhibited by pretreatment of hepatocytes with ethyl pyruvate (EP), which blocks HMGB1 release. EP also blocked CM-AA induced ROS production and antioxidant expression, and reduced expression of COX-2, but not MIP-1{alpha} or MIP-2. These findings suggest that HMGB1 released by AA-injured hepatocytes contributes to macrophage activation. This is supported by our observation that expression of the HMGB1 receptor RAGE is upregulated in macrophages in response to CM-AA. These data indicate that AA-injured hepatocytes contribute to the inflammatory environment in the liver through the release of mediators such as HMGB1. Blocking HMGB1/RAGE may be a useful approach to limiting classical macrophage activation and AA-induced hepatotoxicity. - Research Highlights: > These studies analyze macrophage activation by mediators released from acetaminophen-damaged hepatocytes. > Factors released from acetaminophen-injured hepatocytes induce macrophage ROS production and expression of COX-2, chemokines, and RAGE. > Hepatocyte-mediated macrophage activation involves p44/42 MAP kinase signaling. > HMGB1 is released from acetaminophen-injured hepatocytes and contributes to macrophage activation.

Dragomir, Ana-Cristina [Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, NJ 08854 (United States); Laskin, Jeffrey D. [Department of Environmental and Occupational Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ 08854 (United States); Laskin, Debra L., E-mail: laskin@eohsi.rutgers.edu [Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, NJ 08854 (United States)

2011-06-15

175

Macrophage expression of active MMP-9 induces acute plaque disruption in apoE-deficient mice  

PubMed Central

The majority of acute clinical manifestations of atherosclerosis are due to the physical rupture of advanced atherosclerotic plaques. It has been hypothesized that macrophages play a key role in inducing plaque rupture by secreting proteases that destroy the extracellular matrix that provides physical strength to the fibrous cap. Despite reports detailing the expression of multiple proteases by macrophages in rupture-prone regions, there is no direct proof that macrophage-mediated matrix degradation can induce plaque rupture. We aimed to test this hypothesis by retrovirally overexpressing the candidate enzyme MMP-9 in macrophages of advanced atherosclerotic lesions of apoE–/– mice. Despite a greater than 10-fold increase in the expression of MMP-9 by macrophages, there was only a minor increase in the incidence of plaque fissuring. Subsequent analysis revealed that macrophages secrete MMP-9 predominantly as a proform, and this form is unable to degrade the matrix component elastin. Expression of an autoactivating form of MMP-9 in macrophages in vitro greatly enhances elastin degradation and induces significant plaque disruption when overexpressed by macrophages in advanced atherosclerotic lesions of apoE–/– mice in vivo. These data show that enhanced macrophage proteolytic activity can induce acute plaque disruption and highlight MMP-9 as a potential therapeutic target for stabilizing rupture-prone plaques. PMID:16374516

Gough, Peter J.; Gomez, Ivan G.; Wille, Paul T.; Raines, Elaine W.

2006-01-01

176

The active enhancer network operated by liganded RXR supports angiogenic activity in macrophages  

PubMed Central

RXR signaling is predicted to have a major impact in macrophages, but neither the biological consequence nor the genomic basis of its ligand activation is known. Comprehensive genome-wide studies were carried out to map liganded RXR-mediated transcriptional changes, active binding sites, and cistromic interactions in the context of the macrophage genome architecture. The macrophage RXR cistrome has 5200 genomic binding sites, which are not impacted by ligand. Active enhancers are characterized by PU.1 binding, an increase of enhancer RNA, and P300 recruitment. Using these features, 387 liganded RXR-bound enhancers were linked to 226 genes, which predominantly reside in CTCF/cohesin-limited functional domains. These findings were molecularly validated using chromosome conformation capture (3C) and 3C combined with sequencing (3C-seq), and we show that selected long-range enhancers communicate with promoters via stable or RXR-induced loops and that some of the enhancers interact with each other, forming an interchromosomal network. A set of angiogenic genes, including Vegfa, has liganded RXR-controlled enhancers and provides the macrophage with a novel inducible program. PMID:25030696

Daniel, Bence; Hah, Nasun; Horvath, Attila; Czimmerer, Zsolt; Poliska, Szilard; Gyuris, Tibor; Keirsse, Jiri; Gysemans, Conny; Van Ginderachter, Jo A.; Balint, Balint L.; Evans, Ronald M.; Barta, Endre; Nagy, Laszlo

2014-01-01

177

The active enhancer network operated by liganded RXR supports angiogenic activity in macrophages.  

PubMed

RXR signaling is predicted to have a major impact in macrophages, but neither the biological consequence nor the genomic basis of its ligand activation is known. Comprehensive genome-wide studies were carried out to map liganded RXR-mediated transcriptional changes, active binding sites, and cistromic interactions in the context of the macrophage genome architecture. The macrophage RXR cistrome has 5200 genomic binding sites, which are not impacted by ligand. Active enhancers are characterized by PU.1 binding, an increase of enhancer RNA, and P300 recruitment. Using these features, 387 liganded RXR-bound enhancers were linked to 226 genes, which predominantly reside in CTCF/cohesin-limited functional domains. These findings were molecularly validated using chromosome conformation capture (3C) and 3C combined with sequencing (3C-seq), and we show that selected long-range enhancers communicate with promoters via stable or RXR-induced loops and that some of the enhancers interact with each other, forming an interchromosomal network. A set of angiogenic genes, including Vegfa, has liganded RXR-controlled enhancers and provides the macrophage with a novel inducible program. PMID:25030696

Daniel, Bence; Nagy, Gergely; Hah, Nasun; Horvath, Attila; Czimmerer, Zsolt; Poliska, Szilard; Gyuris, Tibor; Keirsse, Jiri; Gysemans, Conny; Van Ginderachter, Jo A; Balint, Balint L; Evans, Ronald M; Barta, Endre; Nagy, Laszlo

2014-07-15

178

Francisella tularensis LVS induces Macrophage Alternative Activation As a Survival Mechanism1  

PubMed Central

Francisella tularensis(Ft), the causative agent of tularemia, elicits a potent inflammatory response early in infection, yet persists within host macrophages and can be lethal if left unchecked. We report herein that Ft live vaccine strain (LVS) infection of murine macrophages induced TLR2-dependent expression of “alternative activation” markers that followed the appearance of “classically activated” markers. Intraperitoneal infection with Ft LVS also resulted in induction of alternatively activated macrophages (AA-M?). Induction of AA-M? by treatment of cells with rIL-4 or by infection with Ft LVS promoted replication of intracellular Ft, in contrast to classically activated (IFN-? + LPS) macrophages that promoted intracellular killing of Ft LVS. Ft LVS failed to induce alternative activation in IL-4R??/? or STAT6?/? macrophages and prolonged the classical inflammatory response in these cells, resulting in intracellular killing of Ft. Treatment of macrophages with anti-IL-4 and anti-IL-13 antibody blunted Ft-induced AA-M? differentiation and resulted in increased expression of IL-12 p70 and decreased bacterial replication. In vivo, Ft-infected IL-4R??/? mice exhibited increased survival compared to WT mice. Thus, redirection of macrophage differentiation by Ft LVS from a classical to an alternative activation state enables the organism to survive at the expense of the host. PMID:18768873

Shirey, Kari Ann; Cole, Leah E.; Keegan, Achsah D.; Vogel, Stefanie N.

2008-01-01

179

MicroRNAs Control Macrophage Formation and Activation: The Inflammatory Link between Obesity and Cardiovascular Diseases  

PubMed Central

Activation and recruitment of resident macrophages in tissues in response to physiological stress are crucial regulatory processes in promoting the development of obesity-associated metabolic disorders and cardiovascular diseases. Recent studies have provided compelling evidence that microRNAs play important roles in modulating monocyte formation, macrophage maturation, infiltration into tissues and activation. Macrophage-dependent systemic physiological and tissue-specific responses also involve cell-cell interactions between macrophages and host tissue niche cell components, including other tissue-resident immune cell lineages, adipocytes, vascular smooth muscle and others. In this review, we highlight the roles of microRNAs in regulating the development and function of macrophages in the context of obesity, which could provide insights into the pathogenesis of obesity-related metabolic syndrome and cardiovascular diseases. PMID:25014161

Chang, Richard Cheng-An; Ying, Wei; Bazer, Fuller W.; Zhou, Beiyan

2014-01-01

180

Stromal down-regulation of macrophage CD4/CCR5 expression and NF-?B activation mediates HIV-1 non-permissiveness in intestinal macrophages.  

PubMed

Tissue macrophages are derived exclusively from blood monocytes, which as monocyte-derived macrophages support HIV-1 replication. However, among human tissue macrophages only intestinal macrophages are non-permissive to HIV-1, suggesting that the unique microenvironment in human intestinal mucosa renders lamina propria macrophages non-permissive to HIV-1. We investigated this hypothesis using blood monocytes and intestinal extracellular matrix (stroma)-conditioned media (S-CM) to model the exposure of newly recruited monocytes and resident macrophages to lamina propria stroma, where the cells take up residence in the intestinal mucosa. Exposure of monocytes to S-CM blocked up-regulation of CD4 and CCR5 expression during monocyte differentiation into macrophages and inhibited productive HIV-1 infection in differentiated macrophages. Importantly, exposure of monocyte-derived macrophages simultaneously to S-CM and HIV-1 also inhibited viral replication, and sorted CD4+ intestinal macrophages, a proportion of which expressed CCR5+, did not support HIV-1 replication, indicating that the non-permissiveness to HIV-1 was not due to reduced receptor expression alone. Consistent with this conclusion, S-CM also potently inhibited replication of HIV-1 pseudotyped with vesicular stomatitis virus glycoprotein, which provides CD4/CCR5-independent entry. Neutralization of TGF-? in S-CM and recombinant TGF-? studies showed that stromal TGF-? inhibited macrophage nuclear translocation of NF-?B and HIV-1 replication. Thus, the profound inability of intestinal macrophages to support productive HIV-1 infection is likely the consequence of microenvironmental down-regulation of macrophage HIV-1 receptor/coreceptor expression and NF-?B activation. PMID:21637819

Shen, Ruizhong; Meng, Gang; Ochsenbauer, Christina; Clapham, Paul R; Grams, Jayleen; Novak, Lea; Kappes, John C; Smythies, Lesley E; Smith, Phillip D

2011-05-01

181

Detection of tumor necrosis factor activity in the supernatants of feline macrophages and lymphocytes.  

PubMed

Using tumor necrosis factor (TNF)-sensitive L929 cells, TNF-like activity was assayed in the supernatants of feline macrophage and lymphocyte cultures. Macrophages were separated from thioglycollate-elicited peritoneal cells. Lymphocytes were purified from peripheral blood and were then stimulated with calcium ionophore A23187 and phorbol myristate acetate. Lymphocyte stimulators alone did not have cytotoxicity against L929 cells. Based on the facts that cytotoxicity decreased with increasing dilutions of supernatant and that this cytotoxic activity could be blocked by antibody to human TNF, the activity detected in the supernatants of the feline macrophages and lymphocytes was likely due to feline TNF-alpha or -beta. PMID:8440090

Lin, D S; Bowman, D D

1993-01-01

182

Macrophage reporter cell assay for screening immunopharmacological activity of cell wall-active antifungals.  

PubMed

Antifungal exposure can elicit immunological effects that contribute to activity in vivo, but this activity is rarely screened in vitro in a fashion analogous to MIC testing. We used RAW 264.7 murine macrophages that express a secreted embryonic alkaline phosphatase (SEAP) gene induced by transcriptional activation of NF-?B and activator protein 1 (AP-1) to develop a screen for immunopharmacological activity of cell wall-active antifungal agents. Isolates of Candida albicans and Aspergillus fumigatus that conditionally express genes involved in cell wall synthesis were also tested with the reporter macrophages. We found that growth of fungi in subinhibitory concentrations of glucan synthesis inhibitors (caspofungin and enfumafungin A) or repression of the ?-glucan catalytic subunit of glucan synthase, FKS1, increased macrophage NF-?B/AP-1 activation in a dectin-1-dependent manner. This pattern of activation was also transiently observed with repression of chitin synthesis in C. albicans or when yeast cells were incubated in low concentrations of the chitin synthesis inhibitor nikkomycin Z. PMID:24395226

Lewis, Russell E; Liao, Guangling; Young, Katherine; Douglas, Cameron; Kontoyiannis, Dimitrios P

2014-01-01

183

Decursin Inhibits Induction of Inflammatory Mediators by Blocking Nuclear Factor-B Activation in MacrophagesS  

E-print Network

inhibitors of matrix metalloproteinase (MMP)-9 induction in macrophages, we isolated decursin, a coumarin cap through overexpression of active matrix metalloproteinases (MMPs) renders this structure weak, and ex- tracellular matrix (ECM) degradation. Macrophages play par- ticularly important roles

Lee, Won-Ha

184

Critical role of p38 MAPK in IL-4-induced alternative activation of peritoneal macrophages.  

PubMed

Alternative activation of macrophages plays an important role in a range of physiological and pathological processes. This alternative phenotype, also known as M2 macrophages, is induced by type 2 cytokines such as IL-4. The binding of IL-4 to its receptor leads to activation of two major signaling pathways: STAT-6 and PI3K. However, recent studies have described that p38 MAPK might play a role in IL-4-dependent signaling in some cells, although its role in macrophages is still controversial. In this study, we investigated whether p38 MAPK plays a role in the polarization of macrophages in mice. Our results reveal that IL-4 induces phosphorylation of p38 MAPK in thioglycollate-elicited murine peritoneal macrophages, in addition to STAT-6 and PI3K activation. Furthermore, p38 MAPK inactivation, by gene silencing or pharmacological inhibition, suppressed IL-4-induced typical M2 markers, indicating the involvement of p38 MAPK in the signaling of IL-4 leading to M2-macrophage polarization. Moreover, p38 MAPK inhibition blocked phosphorylation of STAT-6 and Akt, suggesting that p38 MAPK is upstream of these signaling pathways. Finally, we show that in an in vivo model of chitin-induced M2 polarization, p38 MAPK inhibition also diminished activation of M2 markers. Taken together, our data establish a new role for p38 MAPK during IL-4-induced alternative activation of macrophages. PMID:25328047

Jiménez-Garcia, Lidia; Herránz, Sandra; Luque, Alfonso; Hortelano, Sonsoles

2015-01-01

185

Rapid host defense against Aspergillus fumigatus involves alveolar macrophages with a predominance of alternatively activated phenotype.  

PubMed

The ubiquitous fungus Aspergillus fumigatus is associated with chronic diseases such as invasive pulmonary aspergillosis in immunosuppressed patients and allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis or severe asthma. Because of constant exposure to this fungus, it is critical for the host to exercise an immediate and decisive immune response to clear fungal spores to ward off disease. In this study, we observed that rapidly after infection by A. fumigatus, alveolar macrophages predominantly express Arginase 1 (Arg1), a key marker of alternatively activated macrophages (AAMs). The macrophages were also found to express Ym1 and CD206 that are also expressed by AAMs but not NOS2, which is expressed by classically activated macrophages. The expression of Arg1 was reduced in the absence of the known signaling axis, IL-4R?/STAT6, for AAM development. While both Dectin-1 and TLR expressed on the cell surface have been shown to sense A. fumigatus, fungus-induced Arg1 expression in CD11c(+) alveolar macrophages was not dependent on either Dectin-1 or the adaptor MyD88 that mediates intracellular signaling by most TLRs. Alveolar macrophages from WT mice efficiently phagocytosed fungal conidia, but those from mice deficient in Dectin-1 showed impaired fungal uptake. Depletion of macrophages with clodronate-filled liposomes increased fungal burden in infected mice. Collectively, our studies suggest that alveolar macrophages, which predominantly acquire an AAM phenotype following A. fumigatus infection, have a protective role in defense against this fungus. PMID:21246055

Bhatia, Shikha; Fei, Mingjian; Yarlagadda, Manohar; Qi, Zengbiao; Akira, Shizuo; Saijo, Shinobu; Iwakura, Yoichiro; van Rooijen, Nico; Gibson, Gregory A; St Croix, Claudette M; Ray, Anuradha; Ray, Prabir

2011-01-01

186

Liposomal Cholesterol Delivery Activates the Macrophage Innate Immune Arm To Facilitate Intracellular Leishmania donovani Killing  

PubMed Central

Leishmania donovani causes visceral leishmaniasis (VL) by infecting the monocyte/macrophage lineage and residing inside specialized structures known as parasitophorous vacuoles. The protozoan parasite has adopted several means of escaping the host immune response, with one of the major methods being deactivation of host macrophages. Previous reports highlight dampened macrophage signaling, defective antigen presentation due to increased membrane fluidity, and the downregulation of several genes associated with L. donovani infection. We have reported previously that the defective antigen presentation in infected hamsters could be corrected by a single injection of a cholesterol-containing liposome. Here we show that cholesterol in the form of a liposomal formulation can stimulate the innate immune arm and reactivate macrophage function. Augmented levels of reactive oxygen species (ROS) and reactive nitrogen intermediates (RNI), along with proinflammatory cytokines such as tumor necrosis factor alpha (TNF-?) and interleukin 6 (IL-6), corroborate intracellular parasite killing. Cholesterol incorporation kinetics is favored in infected macrophages more than in normal macrophages. Such an enhanced cholesterol uptake is associated with preferential apoptosis of infected macrophages in an endoplasmic reticulum (ER) stress-dependent manner. All these events are coupled with mitogen-activated protein (MAP) kinase activation, while inhibition of such pathways resulted in increased parasite loads. Hence, liposomal cholesterol is a potential facilitator of the macrophage effector function in favor of the host, independently of the T-cell arm. PMID:24478076

Ghosh, June; Guha, Rajan; Das, Shantanabha

2014-01-01

187

Liposomal cholesterol delivery activates the macrophage innate immune arm to facilitate intracellular Leishmania donovani killing.  

PubMed

Leishmania donovani causes visceral leishmaniasis (VL) by infecting the monocyte/macrophage lineage and residing inside specialized structures known as parasitophorous vacuoles. The protozoan parasite has adopted several means of escaping the host immune response, with one of the major methods being deactivation of host macrophages. Previous reports highlight dampened macrophage signaling, defective antigen presentation due to increased membrane fluidity, and the downregulation of several genes associated with L. donovani infection. We have reported previously that the defective antigen presentation in infected hamsters could be corrected by a single injection of a cholesterol-containing liposome. Here we show that cholesterol in the form of a liposomal formulation can stimulate the innate immune arm and reactivate macrophage function. Augmented levels of reactive oxygen species (ROS) and reactive nitrogen intermediates (RNI), along with proinflammatory cytokines such as tumor necrosis factor alpha (TNF-?) and interleukin 6 (IL-6), corroborate intracellular parasite killing. Cholesterol incorporation kinetics is favored in infected macrophages more than in normal macrophages. Such an enhanced cholesterol uptake is associated with preferential apoptosis of infected macrophages in an endoplasmic reticulum (ER) stress-dependent manner. All these events are coupled with mitogen-activated protein (MAP) kinase activation, while inhibition of such pathways resulted in increased parasite loads. Hence, liposomal cholesterol is a potential facilitator of the macrophage effector function in favor of the host, independently of the T-cell arm. PMID:24478076

Ghosh, June; Guha, Rajan; Das, Shantanabha; Roy, Syamal

2014-02-01

188

Immunomodulatory Activity and Protective Effects of Polysaccharide from Eupatorium adenophorum Leaf Extract on Highly Pathogenic H5N1 Influenza Infection  

PubMed Central

The development of novel broad-spectrum, antiviral agents against H5N1 infection is urgently needed. In this study, we evaluated the immunomodulatory activities and protective effect of Eupatorium adenophorum polysaccharide (EAP) against the highly pathogenic H5N1 subtype influenza virus. EAP treatment significantly increased the production of IL-6, TNF-?, and IFN-? both in vivo and in vitro as measured by qPCR and ELISA. In a mouse infection model, intranasal administration of EAP at a dose of 25?mg/kg body weight prior to H5N1 viral challenge efficiently inhibited viral replication, decreased lung lesions, and increased survival rate. We further evaluated the innate immune recognition of EAP, as this process is regulated primarily Dectin-1 and mannose receptor (MR). These results indicate that EAP may have immunomodulatory properties and a potential prophylactic effect against H5N1 influenza infection. Our investigation suggests an alternative strategy for the development of novel antiinfluenza agents and benefits of E. adenophorum products. PMID:24159339

Hou, Lingyu

2013-01-01

189

Macrophage-lymphocyte interactions mediate anti- Burkholderia pseudomallei activity  

Microsoft Academic Search

The mechanisms involved in the pathogenesis of melioidosis, caused by the intracellular bacterium Burkholderia pseudomallei, are unclear. C57BL\\/6 mice are resistant to infection, while BALB\\/c mice are highly susceptible. Previous studies have demonstrated that peritoneal exudate cell preparations enriched for macrophages are capable of effectively eliminating intracellular pathogens. In this study we present evidence showing that interaction of macrophages with

Glen C Ulett; Natkunam Ketheesan; Robert G Hirst

1998-01-01

190

Non-targeted metabolite profiling in activated macrophage secretion  

Microsoft Academic Search

Periodontal diseases are inflammatory infectious diseases that affect the periodontal tissue. Macrophages play a central role\\u000a in inflammatory conditions, leading to the destruction of tissues. Identifying the signaling molecules secreted by macrophages\\u000a would be valuable to the study of these diseases. Here, we present non-targeted analysis using capillary electrophoresis time-of-flight\\u000a mass spectrometry (CE-TOFMS) for the profiling of extracellular metabolites released

Masahiro SugimotoHiroshi; Hiroshi Sakagami; Yoshiko Yokote; Hiromi Onuma; Miku Kaneko; Masayo Mori; Yasuko Sakaguchi; Tomoyoshi Soga; Masaru Tomita

191

Macrophage activation syndrome: why and what should a gastroenterologist know.  

PubMed

We recently treated a patient with adult-onset Still's disease who developed macrophage activation syndrome (MAS) secondary to disseminated histoplasmosis while being treated with adalimumab. The gastroenterology service was consulted early, before diagnosis, as the patient presented with elevated liver enzymes and disseminated intravascular coagulation. MAS is an exaggerated immune response that can develop as a primary condition or secondary to infections, drugs and various diseases, resulting in liver dysfunction, encephalopathy, pancytopenia and disseminated intravascular coagulation. The development of MAS has also been reported in patients with inflammatory bowel disease and post-liver transplantation and has been triggered by medications used by gastroenterologists, particularly sulfasalazine and anti-tumor necrosis factor biologic modifiers. Therefore, we present a review on etiology, pathogenesis, clinical and laboratory features, and treatment of MAS with a focus on gastrointestinal aspects and presentations. MAS is a life threatening condition with a high mortality rate if untreated. Therefore it is important to recognize this condition early. As these patients may occasionally present to gastroenterologists we hope this review will increase awareness of this rare, but serious syndrome. PMID:20921900

Jayakar, Bijal A; Hashkes, Philip J

2011-03-01

192

Polyclonal activation of B lymphocytes by lipopolysaccharide requires macrophage-derived interleukin-1.  

PubMed Central

Lipopolysaccharide (LPS) is a potent murine polyclonal B-cell activator which induces cellular proliferation and IgM secretion. The precise role of activated macrophages in the induction of LPS-dependent, B-cell responses has been unclear. Although early reports concluded that the LPS effect occurs independently of other cell types, other studies have suggested that adherent macrophages exert either potentiating or inhibitory effects. In the present study, B-cell mitogenesis and IgM production were measured in primary spleen cell cultures after removing adherent cells by a variety of experimental procedures. B-cell activation by LPS was found to be strictly dependent on the presence of adherent macrophages. Antibody neutralization and cytokine reconstitution studies demonstrated that macrophage-derived interleukin- (IL-1) is a necessary co-factor for LPS-induced polyclonal activation. PMID:1493918

Bucala, R

1992-01-01

193

Immunomodulatory activity of dietary fiber: arabinoxylan and mixed-linked beta-glucan isolated from barley show modest activities in vitro.  

PubMed

High intake of dietary fiber is claimed to protect against development of colorectal cancer. Barley is a rich source of dietary fiber, and possible immunomodulatory effects of barley polysaccharides might explain a potential protective effect. Dietary fiber was isolated by extraction and enzyme treatment. A mixed-linked ?-glucan (WSM-TPX, 96.5% ?-glucan, Mw 886 kDa), an arabinoxylan (WUM-BS-LA, 96.4% arabinoxylan, Mw 156 kDa), a mixed-linked ?-glucan rich fraction containing 10% arabinoxylan (WSM-TP) and an arabinoxylan rich fraction containing 30% mixed-linked ?-glucan (WUM-BS) showed no significant effect on IL-8 secretion and proliferation of two intestinal epithelial cell lines, Caco-2 and HT-29, and had no significant effect on the NF-?B activity in the monocytic cell line U937-3?B-LUC. Further enriched arabinoxylan fractions (WUM-BS-LA) from different barley varieties (Tyra, NK96300, SB94897 and CDCGainer) were less active than the mixed-linked ?-glucan rich fractions (WSM-TP and WSM-TPX) in the complement-fixing test. The mixed-linked ?-glucan rich fraction from NK96300 and CDCGainer showed similar activities as the positive control while mixed-linked ?-glucan rich fractions from Tyra and SB94897 were less active. From these results it is concluded that the isolated high molecular weight mixed-linked ?-glucans and arabinoxylans from barley show low immunological responses in selected in vitro test systems and thus possible anti-colon cancer effects of barley dietary fiber cannot be explained by our observations. PMID:21340001

Samuelsen, Anne Berit; Rieder, Anne; Grimmer, Stine; Michaelsen, Terje E; Knutsen, Svein H

2011-01-01

194

GADD34 inhibits activation-induced apoptosis of macrophages through enhancement of autophagy  

PubMed Central

Autophagy is a common physiological function in all eukaryotes. The process is induced by depletion of nutrients including amino acids. GADD34 is expressed following DNA damage, ER stresses and amino acid deprivation. Here, we investigated the effects of GADD34 on autophagy and cell activation in macrophages. The deprivation of tyrosine and cysteine markedly induced the expression of GADD34 in macrophages. LPS stimulation combined with tyrosine/cysteine-deprivation initially activated macrophages, but then shifted to cell death in late phase of stimulation. When LPS stimulation was combined with tyrosine/cysteine-deprivation, a deficiency of GADD34 enhanced cell activation signaling such as Src-family, Erk1/2, p38 MAPK and Akt. In the late phase of stimulation, a deficiency of GADD34 increased apoptosis more than that in wild-type macrophages. Further we found that mTOR-S6K signaling was highly enhanced in GADD34-deficient macrophages compared with wild-type cells when cells were treated by LPS combined with tyrosine/cysteine-deprivation. LC3-II was increased by LPS stimulation combined with tyrosine/cysteine-deprivation. Defective GADD34 reduced LC3-II and autophagosome formation induced by LPS-stimulation and tyrosine/cysteine-deprivation compared with that seen in wild-type macrophages. These results indicates that GADD34 enhances autophagy and suppresses apoptosis stimulated by LPS combined with amino acid deprivation through regulation of mTOR signaling pathway in macrophages. PMID:25659802

Ito, Sachiko; Tanaka, Yuriko; Oshino, Reina; Aiba, Keiko; Thanasegaran, Suganya; Nishio, Naomi; Isobe, Ken-ichi

2015-01-01

195

Activation of TNF-a transcription utilizes distinct MAP kinase pathways in different macrophage populations  

Microsoft Academic Search

Stimulation of macrophages by lipopoly- saccharide (LPS) leads to the rapid activation of MAP kinases (MAPK) and the subsequent induction of cytokine gene expression. We sought to deter- mine whether LPS-inducible cytokine genes were differentially regulated in macrophages derived from different tissues. Our studies revealed that PD98059, an inhibitor of the extracellular-regu- lated kinase (ERK) pathway, blocked LPS-induced activation of

Terry K. Means; Ryan P. Pavlovich; Dominic Roca; Mary W. Vermeulen; Matthew J. Fenton

2000-01-01

196

Transcellular regulation of cell respiration by nitric oxide generated by activated macrophages  

Microsoft Academic Search

A macrophage cell line (J774), activated with interferon-? and endotoxin to express the inducible form of NO synthase (iNOS), immediately inhibited the cellular respiration of co-incubated L-929 fibroblasts or non-activated J774 macrophages. The inhibition was potent, rapid and reversible when the NO was removed by adding oxyhaemoglobin or by inhibiting iNOS. Exogenously added NO also rapidly and reversibly inhibited cellular

Guy C Brown; Neale Foxwell; Salvador Moncada

1998-01-01

197

Translational Regulation of Specific mRNAs Controls Feedback Inhibition and Survival during Macrophage Activation  

PubMed Central

For a rapid induction and efficient resolution of the inflammatory response, gene expression in cells of the immune system is tightly regulated at the transcriptional and post-transcriptional level. The control of mRNA translation has emerged as an important determinant of protein levels, yet its role in macrophage activation is not well understood. We systematically analyzed the contribution of translational regulation to the early phase of the macrophage response by polysome fractionation from mouse macrophages stimulated with lipopolysaccharide (LPS). Individual mRNAs whose translation is specifically regulated during macrophage activation were identified by microarray analysis. Stimulation with LPS for 1 h caused translational activation of many feedback inhibitors of the inflammatory response including NF-?B inhibitors (Nfkbid, Nfkbiz, Nr4a1, Ier3), a p38 MAPK antagonist (Dusp1) and post-transcriptional suppressors of cytokine expression (Zfp36 and Zc3h12a). Our analysis showed that their translation is repressed in resting and de-repressed in activated macrophages. Quantification of mRNA levels at a high temporal resolution by RNASeq allowed us to define groups with different expression patterns. Thereby, we were able to distinguish mRNAs whose translation is actively regulated from mRNAs whose polysomal shifts are due to changes in mRNA levels. Active up-regulation of translation was associated with a higher content in AU-rich elements (AREs). For one example, Ier3 mRNA, we show that repression in resting cells as well as de-repression after stimulation depends on the ARE. Bone-marrow derived macrophages from Ier3 knockout mice showed reduced survival upon activation, indicating that IER3 induction protects macrophages from LPS-induced cell death. Taken together, our analysis reveals that translational control during macrophage activation is important for cellular survival as well as the expression of anti-inflammatory feedback inhibitors that promote the resolution of inflammation. PMID:24945926

Schott, Johanna; Reitter, Sonja; Philipp, Janine; Haneke, Katharina; Schäfer, Heiner; Stoecklin, Georg

2014-01-01

198

Macrophage activation syndrome in a newborn infant born to a mother with autoimmune disease.  

PubMed

Macrophage activation syndrome (MAS) is a complication of rheumatic disorders characterized by cytopenia, multiple organ dysfunction and coagulopathy associated with an inappropriate activation of macrophage. In neonatal lupus erythematosus, MAS is rare but fatal, requiring early diagnosis and treatment for optimal outcome. We report a case of MAS in a neonate born to a mother with autoimmune disease, improved by treatment with steroid, intravenous immunoglobulin and cyclosporine. PMID:25627282

Park, J H; Kim, S H; Kim, H J; Lee, S J; Jeong, D C; Kim, S Y

2015-02-01

199

Metabolic Characterization of Leishmania major Infection in Activated and Nonactivated Macrophages.  

PubMed Central

Infection with Leishmania spp. can lead to a range of symptoms in the affected individual, depending on underlying immune-metabolic processes. The macrophage activation state hereby plays a key role. Whereas the l-arginine pathway has been described in detail as the main biochemical process responsible for either nitric oxide mediated parasite killing (classical activation) or amplification of parasite replication (alternative activation), we were interested in a wider characterization of metabolic events in vitro. We therefore assessed cell growth medium, parasite extract, and intra- and extracellular metabolome of activated and nonactivated macrophages, in presence and absence of Leishmania major. A metabolic profiling approach was applied combining 1H NMR spectroscopy with multi- and univariate data treatment. Metabolic changes were observed along both conditional axes, that is, infection state and macrophage activation, whereby significantly higher levels of potential parasite end products were found in parasite exposed samples including succinate, acetate, and alanine, compared to uninfected macrophages. The different macrophage activation states were mainly discriminated by varying glucose consumption. The presented profiling approach allowed us to obtain a metabolic snapshot of the individual biological compartments in the assessed macrophage culture experiments and represents a valuable read out system for further multiple compartment in vitro studies. PMID:22724526

2012-01-01

200

Metabolic characterization of Leishmania major infection in activated and nonactivated macrophages.  

PubMed

Infection with Leishmania spp. can lead to a range of symptoms in the affected individual, depending on underlying immune-metabolic processes. The macrophage activation state hereby plays a key role. Whereas the l-arginine pathway has been described in detail as the main biochemical process responsible for either nitric oxide mediated parasite killing (classical activation) or amplification of parasite replication (alternative activation), we were interested in a wider characterization of metabolic events in vitro. We therefore assessed cell growth medium, parasite extract, and intra- and extracellular metabolome of activated and nonactivated macrophages, in presence and absence of Leishmania major. A metabolic profiling approach was applied combining 1H NMR spectroscopy with multi- and univariate data treatment. Metabolic changes were observed along both conditional axes, that is, infection state and macrophage activation, whereby significantly higher levels of potential parasite end products were found in parasite exposed samples including succinate, acetate, and alanine, compared to uninfected macrophages. The different macrophage activation states were mainly discriminated by varying glucose consumption. The presented profiling approach allowed us to obtain a metabolic snapshot of the individual biological compartments in the assessed macrophage culture experiments and represents a valuable read out system for further multiple compartment in vitro studies. PMID:22724526

Lamour, Sabrina D; Choi, Beak-San; Keun, Hector C; Müller, Ingrid; Saric, Jasmina

2012-08-01

201

Chitohexaose Activates Macrophages by Alternate Pathway through TLR4 and Blocks Endotoxemia  

PubMed Central

Sepsis is a consequence of systemic bacterial infections leading to hyper activation of immune cells by bacterial products resulting in enhanced release of mediators of inflammation. Endotoxin (LPS) is a major component of the outer membrane of Gram negative bacteria and a critical factor in pathogenesis of sepsis. Development of antagonists that inhibit the storm of inflammatory molecules by blocking Toll like receptors (TLR) has been the main stay of research efforts. We report here that a filarial glycoprotein binds to murine macrophages and human monocytes through TLR4 and activates them through alternate pathway and in the process inhibits LPS mediated classical activation which leads to inflammation associated with endotoxemia. The active component of the nematode glycoprotein mediating alternate activation of macrophages was found to be a carbohydrate residue, Chitohexaose. Murine macrophages and human monocytes up regulated Arginase-1 and released high levels of IL-10 when incubated with chitohexaose. Macrophages of C3H/HeJ mice (non-responsive to LPS) failed to get activated by chitohexaose suggesting that a functional TLR4 is critical for alternate activation of macrophages also. Chitohexaose inhibited LPS induced production of inflammatory molecules TNF-?, IL-1? and IL-6 by macropahges in vitro and in vivo in mice. Intraperitoneal injection of chitohexaose completely protected mice against endotoxemia when challenged with a lethal dose of LPS. Furthermore, Chitohexaose was found to reverse LPS induced endotoxemia in mice even 6/24/48 hrs after its onset. Monocytes of subjects with active filarial infection displayed characteristic alternate activation markers and were refractory to LPS mediated inflammatory activation suggesting an interesting possibility of subjects with filarial infections being less prone to develop of endotoxemia. These observations that innate activation of alternate pathway of macrophages by chtx through TLR4 has offered novel opportunities to cell biologists to study two mutually exclusive activation pathways of macrophages being mediated through a single receptor. PMID:22654663

Panda, Santosh K.; Kumar, Sunil; Tupperwar, Nitin C.; Vaidya, Tushar; George, Anna; Rath, Satyajit; Bal, Vineeta; Ravindran, Balachandran

2012-01-01

202

Human activated macrophages and hypoxia: a comprehensive review of the literature  

PubMed Central

Macrophages accumulate in poorly vascularised and hypoxic sites including solid tumours, wounds and sites of infection and inflammation where they can be exposed to low levels of oxygen for long periods. Up to date, different studies have shown that a number of transcription factors are activated by hypoxia which in turn activate a broad array of mitogenic, pro-invasive, pro-angiogenic, and pro-metastatic genes. On the other hand, macrophages respond to hypoxia by up-regulating several genes which are chief factors in angiogenesis and tumorigenesis. Therefore, in this review article we focus mainly on the role of macrophages during inflammation and discuss their response to hypoxia by regulating a diverse array of transcription factors. We also review the existing literatures on hypoxia and its cellular and molecular mechanism which mediates macrophages activation. PMID:25691922

Sotoodehnejadnematalahi, Fattah; Burke, Bernard

2014-01-01

203

Molecular imaging of macrophage protease activity in cardiovascular inflammation in vivo  

PubMed Central

Summary Macrophages contribute pivotally to cardiovascular diseases (CVD), notably to atherosclerosis. Imaging of macrophages in vivo could furnish new tools to advance evaluation of disease and therapies. Proteolytic enzymes serve as key effectors of many macrophage contributions to CVD. Therefore, intravital imaging of protease activity could aid evaluation of the progress and outcome of atherosclerosis, aortic aneurysm formation, or rejection of cardiac allografts. Among the large families of proteases, matrix metalloproteinases (MMPs) and cysteinyl cathepsins have garnered the most interest because of their participation in extracellular matrix remodeling. These considerations have spurred the development of dedicated imaging agents for protease activity detection. Activatable fluorescent probes, radiolabeled inhibitors, and nanoparticles are currently under exploration for this purpose. While some agents and technologies may soon see clinical use, others will require further refinement. Imaging of macrophages and protease activity should provide an important adjunct to understanding pathophysiology in vivo, evaluating the effects of interventions, and ultimately aiding clinical care. PMID:21225096

Quillard, Thibaut; Croce, Kevin; Jaffer, Farouc A.; Weissleder, Ralph; Libby, Peter

2011-01-01

204

The timing of TNF and IFN-? signaling affects macrophage activation strategies during Mycobacterium tuberculosis infection  

PubMed Central

During most infections, the population of immune cells known as macrophages are key to taking up and killing bacteria as an integral part of the immune response. However, during infection with Mycobacterium tuberculosis (Mtb), host macrophages serve as the preferred environment for mycobacterial growth. Further, killing of Mtb by macrophages is impaired unless they become activated. Activation is induced by stimulation from bacterial antigens and inflammatory cytokines derived from helper T cells. The key macrophage-activating cytokines in Mtb infection are tumor necrosis factor-? (TNF) and interferon (IFN)-?. Due to differences in cellular sources and secretion pathways for TNF and IFN- ?, the possibility of heterogeneous cytokine distributions exists, suggesting that the timing of macrophage activation from these signals may affect activation kinetics and thus impact the outcome of Mtb infection. Here we use a mathematical model to show that negative feedback from production of nitric oxide (the key mediator of mycobacterial killing) that typically optimizes macrophage responses to activating stimuli may reduce effective killing of Mtb. Statistical sensitivity analysis predicts that if TNF and IFN-? signals precede infection, the level of negative feedback may have a strong effect on how effectively macrophages kill Mtb. However, this effect is relaxed when IFN-? or TNF + IFN-? signals are received coincident with infection. Under these conditions, the model suggests that negative feedback induces fast responses and an initial overshoot of nitric oxide production for given doses of TNF and IFN-?, favoring killing of Mtb. Together, our results suggest that direct entry of macrophages into a granuloma site (and not distal to it) from lung vascular sources represents a preferred host strategy for mycobacterial control. We examine implications of these results in establishment of latent Mtb infection. PMID:18321531

Ray, J. Christian J.; Wang, Jian; Chan, John; Kirschnera, Denise E.

2008-01-01

205

Hyper-Inflammation and Skin Destruction Mediated by Rosiglitazone Activation of Macrophages in IL-6 Deficiency  

PubMed Central

Injury initiates recruitment of macrophages to support tissue repair; however, excessive macrophage activity may exacerbate tissue damage causing further destruction and subsequent delay in wound repair. Here we show that the peroxisome proliferation–activated receptor-? agonist, rosiglitazone (Rosi), a medication recently reintroduced as a drug to treat diabetes and with known anti-inflammatory properties, paradoxically generates pro-inflammatory macrophages. This is observed in both IL-6-deficient mice and control wild-type mice experimentally induced to produce high titers of auto-antibodies against IL-6, mimicking IL-6 deficiency in human diseases. IL-6 deficiency when combined with Rosi-mediated upregulation of suppressor of cytokine signaling 3 leads to an altered ratio of nuclear signal transducer and activator of transcription 3/NF-?B that allows hyper-induction of inducible nitric oxide synthase (iNOS). Macrophages activated in this manner cause de novo tissue destruction, recapitulating human chronic wounds, and can be reversed in vivo by recombinant IL-6, blocking macrophage infiltration, or neutralizing iNOS. This study provides insight into an unanticipated paradoxical role of Rosi in mediating hyper-inflammatory macrophage activation significant for diseases associated with IL-6 deficiency. PMID:25184961

Das, Lopa M; Rosenjack, Julie; Au, Liemin; Galle, Pia S; Hansen, Morten B; Cathcart, Martha K; McCormick, Thomas S; Cooper, Kevin D; Silverstein, Roy L; Lu, Kurt Q

2015-01-01

206

The Contributions of Reactive Oxygen Intermediates and Reactive Nitrogen Intermediates to Listericidal Mechanisms Differ in Macrophages Activated Pre- and Postinfection  

PubMed Central

The contribution of reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI) to the killing of Listeria monocytogenes by macrophages activated by addition of spleen cells from listeria-immune mice plus specific antigen was examined. When macrophages were infected with L. monocytogenes and then spleen cells were added, there was not as big a difference in listericidal activity between macrophages cultured with normal spleen cells and those cultured with immune spleen cells as expected. In this culture system, RNI was mainly involved in the macrophage intracellular killing. In macrophages first activated and then infected, a significant level of enhanced killing was observed. Blockade of ROI production drastically affected the enhanced killing ability, while inhibition of RNI production had a negligible effect. Thus, the contributions of ROI and RNI to listericidal mechanisms of macrophages were different between macrophages activated at pre- and postinfection stages. PMID:9712745

Ohya, Satoshi; Tanabe, Yoshinari; Makino, Masato; Nomura, Takamasa; Xiong, Huabao; Arakawa, Masaaki; Mitsuyama, Masao

1998-01-01

207

Adoptive transfer of experimental allergic encephalomyelitis after in vitro treatment with recombinant murine interleukin-12. Preferential expansion of interferon-gamma-producing cells and increased expression of macrophage-associated inducible nitric oxide synthase as immunomodulatory mechanisms.  

PubMed Central

In an adoptive transfer model of experimental allergic encephalomyelitis, stimulation of lymph node cells with proteolipid protein and recombinant murine interleukin (rmIL)-12 before cell transfer accelerated the onset and exacerbates clinical disease. In vitro stimulation with proteolipid protein in the presence of rmIL-12 was associated with an increase in interferon-gamma-producing cells and a decrease in IL-4-producing cells, indicating a preferential expansion of Th1 effector cells. This was supported by the finding that severe disease with rapid onset could be transferred with as few as 10 x 10(6) rmIL-12-stimulated lymph node cells. Immunohistochemical analysis confirmed that the accelerated onset of disease after in vitro stimulation with rmIL-12 coincided with an acute inflammatory response in the central nervous system. At peak disease, both control and rmIL-12 treatment groups exhibited extensive cellular infiltration with characteristic perivascular cuffing. No notable differences in either the cellular composition or cytokine expression within the lesions were seen between groups. However, the frequency of macrophages that stained positively for inducible nitric oxide synthase was increased in animals challenged with rmIL-12-treated lymph node cells. The results suggest that, in addition to promoting the preferential expansion of interferon-gamma-producing cells by rmIL-12 in vitro, secondary in vivo effects leading to macrophage activation and inducible nitric oxide synthase expression may contribute to the severe and protracted course of central nervous system inflammation in this model. Images Figure 2 PMID:8579100

Waldburger, K. E.; Hastings, R. C.; Schaub, R. G.; Goldman, S. J.; Leonard, J. P.

1996-01-01

208

Effect of cinnamon water extract on monocyte-to-macrophage differentiation and scavenger receptor activity  

PubMed Central

Background Water soluble cinnamon extract has been shown to increase insulin sensitivity and modulate macrophage activation, a desirable trait for the management of obesity or atherosclerosis. Our present study investigated whether cinnamon water extract (CWE) may influence the differentiation of monocytes into macrophages and the activity of macrophage scavenger receptors, commonly observed in atherosclerotic lesions. Methods We investigated the effect of CWE on the expression of various surface markers and the uptake of acetylated low density lipoprotein (LDL) in phorbol-12-myristate-13-acetate (PMA)-stimulated THP-1 cells. The protein levels of PMA or macrophage-colony stimulating factor (M-CSF)-stimulated type 1 macrophage scavenger receptor (SRA) were analyzed. Finally, the role of extracellar signal-related kinase (ERK) 1/2 in SRA synthesis and the effect of CWE on PMA-stimulated ERK1/2 were determined. Results CWE inhibited the differentiation of monocyte by decreasing the expression of CD11b, CD36 and SRA and the uptake of acetyl LDL. CWE suppressed the upregulation of SRA by M-CSF and modulated ERK1/2 activity, which was required for PMA-induced SRA synthesis. Conclusions Our results demonstrate that CWE was able to interfere with monocyte differentiation and macrophage scavenger activity, indicating its potential in preventing the development of atherosclerotic lesions. PMID:24602512

2014-01-01

209

Hydroxysafflor yellow A attenuates ischemia/reperfusion-induced liver injury by suppressing macrophage activation.  

PubMed

Hydroxysafflor yellow A (HSYA), a major constituent in the hydrophilic fraction of the safflower plant, can retard the progress of hepatic fibrosis. However, the anti-inflammatory properties and the underlying mechanisms of HSYA on I/R-induced acute liver injury are unknown. Inhibiting macrophage activation is a potential strategy to treat liver ischemia/reperfusion (I/R) injury. In this study, we investigated the therapeutic effect of HSYA on liver I/R injury and the direct effect of HSYA on macrophage activation following inflammatory conditions. The therapeutic effects of HSYA on I/R injury were tested in vivo using a mouse model of segmental (70%) hepatic ischemia. The mechanisms of HSYA were examined in vitro by evaluating migration and the cytokine expression profile of the macrophage cell line RAW264.7 exposed to acute hypoxia and reoxygenation (H/R). Results showed that mice pretreated with HSYA had reduced serum transaminase levels, attenuated inflammation and necrosis, reduced expression of inflammatory cytokines, and less macrophage recruitment following segmental hepatic ischemia. In vitro HSYA pretreated RAW264.7 macrophages displayed reduced migratory response and produced less inflammatory cytokines. In addition, HSYA pretreatment down-regulated the expression of matrix matalloproteinase-9 and reactive oxygen species, and inhibited NF-?B activation and P38 phosphorylation in RAW264.7 cells. Thus, these data suggest that HSYA can reduce I/R-induced acute liver injury by directly attenuating macrophage activation under inflammatory conditions. PMID:24966974

Jiang, Shujun; Shi, Zhen; Li, Changyong; Ma, Chunlei; Bai, Xianyong; Wang, Chaoyun

2014-01-01

210

Functional Activity of Monocytes and Macrophages in HTLV-1 Infected Subjects.  

PubMed

The Human T lymphotropic virus type-1 (HTLV-1) infects predominantly T cells, inducing proliferation and lymphocyte activation. Additionally, HTLV-1 infected subjects are more susceptible to other infections caused by other intracellular agents. Monocytes/macrophages are important cells in the defense against intracellular pathogens. Our aims were to determine the frequency of monocytes subsets, expression of co-stimulatory molecules in these cells and to evaluate microbicidal ability and cytokine and chemokine production by macrophages from HTLV-1 infected subjects. Participants were 23 HTLV-1 carriers (HC), 22 HAM/TSP patients and 22 healthy subjects (HS) not infected with HTLV-1. The frequencies of monocyte subsets and expression of co-stimulatory molecules were determined by flow cytometry. Macrophages were infected with L. braziliensis or stimulated with LPS. Microbicidal activity of macrophages was determined by optic microscopy. Cytokines/chemokines from macrophage supernatants were measured by ELISA. HAM/TSP patients showed an increase frequency of intermediate monocytes, but expression of co-stimulatory molecules was similar between the groups. Macrophages from HTLV-1 infected individuals were infected with L. braziliensis at the same ratio than macrophages from HS, and all the groups had the same ability to kill Leishmania parasites. However, macrophages from HTLV-1 infected subjects produced more CXCL9 and CCL5, and less IL-10 than cells from HS. While there was no correlation between IFN-? and cytokine/chemokine production by macrophages, there was a correlation between proviral load and TNF and CXCL10. These data showed a dissociation between the inflammatory response and microbicidal ability of macrophages from HTLV-1 infected subjects. While macrophages ability to kill an intracellular pathogen did not differ among HTLV-1 infected subjects, these cells secreted high amount of chemokines even in unstimulated cultures. Moreover the increasing inflammatory activity of macrophages was similar in HAM/TSP patients and HC and it was related to HTLV-1 proviral load rather than the high IFN-? production observed in these subjects. PMID:25521499

Amorim, Camila F; Souza, Anselmo S; Diniz, Angela G; Carvalho, Natália B; Santos, Silvane B; Carvalho, Edgar M

2014-12-01

211

Functional Activity of Monocytes and Macrophages in HTLV-1 Infected Subjects  

PubMed Central

The Human T lymphotropic virus type-1 (HTLV-1) infects predominantly T cells, inducing proliferation and lymphocyte activation. Additionally, HTLV-1 infected subjects are more susceptible to other infections caused by other intracellular agents. Monocytes/macrophages are important cells in the defense against intracellular pathogens. Our aims were to determine the frequency of monocytes subsets, expression of co-stimulatory molecules in these cells and to evaluate microbicidal ability and cytokine and chemokine production by macrophages from HTLV-1 infected subjects. Participants were 23 HTLV-1 carriers (HC), 22 HAM/TSP patients and 22 healthy subjects (HS) not infected with HTLV-1. The frequencies of monocyte subsets and expression of co-stimulatory molecules were determined by flow cytometry. Macrophages were infected with L. braziliensis or stimulated with LPS. Microbicidal activity of macrophages was determined by optic microscopy. Cytokines/chemokines from macrophage supernatants were measured by ELISA. HAM/TSP patients showed an increase frequency of intermediate monocytes, but expression of co-stimulatory molecules was similar between the groups. Macrophages from HTLV-1 infected individuals were infected with L. braziliensis at the same ratio than macrophages from HS, and all the groups had the same ability to kill Leishmania parasites. However, macrophages from HTLV-1 infected subjects produced more CXCL9 and CCL5, and less IL-10 than cells from HS. While there was no correlation between IFN-? and cytokine/chemokine production by macrophages, there was a correlation between proviral load and TNF and CXCL10. These data showed a dissociation between the inflammatory response and microbicidal ability of macrophages from HTLV-1 infected subjects. While macrophages ability to kill an intracellular pathogen did not differ among HTLV-1 infected subjects, these cells secreted high amount of chemokines even in unstimulated cultures. Moreover the increasing inflammatory activity of macrophages was similar in HAM/TSP patients and HC and it was related to HTLV-1 proviral load rather than the high IFN-? production observed in these subjects. PMID:25521499

Amorim, Camila F.; Souza, Anselmo S.; Diniz, Angela G.; Carvalho, Natália B.; Santos, Silvane B.; Carvalho, Edgar M.

2014-01-01

212

Activation of caprine arthritis-encephalitis virus expression during maturation of monocytes to macrophages.  

PubMed

Lentiviruses, which cause arthritis-encephalitis and maedi-visna in goats and sheep, respectively, cause persistent infections in these animals. The viruses replicate productively at low levels in macrophages in diseased organs such as the "maedi lung" and nonproductively in other cell types such as leukocytes in peripheral blood. Nonproductive infections become productive during in vitro cultivation of the cells. This study showed that monocytes were the only cells in the peripheral blood leukocytes of an infected animal in which virus was detected and that virus activation occurred only when these cells matured into macrophages. Only a minute fraction of cultured monocytes matured into macrophages, and viral infectivity was associated exclusively with this fraction. Antiglobulin-coated glass wool fragments were lethal for monocyte macrophages because of toxic phagocytosis, but had no effect on B or T lymphocytes. The simultaneous addition of the glass fragments and leukocytes to culture dishes resulted in no macrophage maturation and no virus production. The addition of the fragments to virus-producing macrophages caused the death of the cells and a decline in virus production. Virus production in less avidly phagocytic cells was unaffected by the glass. Thus, although macrophages may be permissive for virus replication, one mechanism for restricted virus expression in vivo may be physiological factors controlling the maturation of these cells. PMID:6862634

Narayan, O; Kennedy-Stoskopf, S; Sheffer, D; Griffin, D E; Clements, J E

1983-07-01

213

Macrophage Derived Platelet Activating Factor Implicated in the Resolution Phase of Gouty Inflammation  

PubMed Central

Human blood derived in vitro differentiated monocytes or macrophages are a population of cells which have been investigated over the years to determine the role these cells play in the resolution phase of gout. Macrophages are able to phagocytose monosodium urate monohydrate (MSU) crystals without releasing inflammatory factors. This study analysed macrophage platelet activating factor secretion and its possible role in the pathway of gout resolution. Analysis of sunatants from in vitro differentiated macrophages stimulated with MSU crystals revealed the secretion of platelet activating factor (PAF)??1.54 ± 0.10 mean ± SEM;?ng/mL per 106 cells. This secretion was absent in immature monocytes treated similarly. When these monocytes were pretreated with recombinant human PAF-acetylhydrolase (rhuPAF-AH) and MSU crystals resulted in TNF? suppression. Addition of WEB2086, a platelet activating factor (PAF) antagonist, to differentiated macrophages with MSU crystals unmasked TNF? secretion 0.7 ± 0.06 mean ± SEM;?ng/mL per 106 cells. This study identifies a role for PAF and the PAF receptor antagonist in the pathway by which macrophages ingest MSU crystals and resolve the concomitant inflammation. PMID:25328755

2014-01-01

214

Allergens as immunomodulatory proteins: the cat dander protein Fel d 1 enhances TLR activation by lipid ligands.  

PubMed

Allergic responses can be triggered by structurally diverse allergens. Most allergens are proteins, yet extensive research has not revealed how they initiate the allergic response and why the myriad of other inhaled proteins do not. Among these allergens, the cat secretoglobulin protein Fel d 1 is a major allergen and is responsible for severe allergic responses. In this study, we show that similar to the mite dust allergen Der p 2, Fel d 1 substantially enhances signaling through the innate receptors TLR4 and TLR2. In contrast to Der p 2, however, Fel d 1 does not act by mimicking the TLR4 coreceptor MD2 and is not able to bind stably to the TLR4/MD2 complex in vitro. Fel d 1 does, however, bind to the TLR4 agonist LPS, suggesting that a lipid transfer mechanism may be involved in the Fel d 1 enhancement of TLR signaling. We also show that the dog allergen Can f 6, a member of a distinct class of lipocalin allergens, has very similar properties to Fel d 1. We propose that Fel d 1 and Can f 6 belong to a group of allergen immunomodulatory proteins that enhance innate immune signaling and promote airway hypersensitivity reactions in diseases such as asthma. PMID:23878318

Herre, Jurgen; Grönlund, Hans; Brooks, Heather; Hopkins, Lee; Waggoner, Lisa; Murton, Ben; Gangloff, Monique; Opaleye, Olaniyi; Chilvers, Edwin R; Fitzgerald, Kate; Gay, Nick; Monie, Tom; Bryant, Clare

2013-08-15

215

M2 Macrophages Activate WNT Signaling Pathway in Epithelial Cells: Relevance in Ulcerative Colitis  

PubMed Central

Macrophages, which exhibit great plasticity, are important components of the inflamed tissue and constitute an essential element of regenerative responses. Epithelial Wnt signalling is involved in mechanisms of proliferation and differentiation and expression of Wnt ligands by macrophages has been reported. We aim to determine whether the macrophage phenotype determines the expression of Wnt ligands, the influence of the macrophage phenotype in epithelial activation of Wnt signalling and the relevance of this pathway in ulcerative colitis. Human monocyte-derived macrophages and U937-derived macrophages were polarized towards M1 or M2 phenotypes and the expression of Wnt1 and Wnt3a was analyzed by qPCR. The effects of macrophages and the role of Wnt1 were analyzed on the expression of ?-catenin, Tcf-4, c-Myc and markers of cell differentiation in a co-culture system with Caco-2 cells. Immunohistochemical staining of CD68, CD206, CD86, Wnt1, ?-catenin and c-Myc were evaluated in the damaged and non-damaged mucosa of patients with UC. We also determined the mRNA expression of Lgr5 and c-Myc by qPCR and protein levels of ?-catenin by western blot. Results show that M2, and no M1, activated the Wnt signaling pathway in co-culture epithelial cells through Wnt1 which impaired enterocyte differentiation. A significant increase in the number of CD206+ macrophages was observed in the damaged mucosa of chronic vs newly diagnosed patients. CD206 immunostaining co-localized with Wnt1 in the mucosa and these cells were associated with activation of canonical Wnt signalling pathway in epithelial cells and diminution of alkaline phosphatase activity. Our results show that M2 macrophages, and not M1, activate Wnt signalling pathways and decrease enterocyte differentiation in co-cultured epithelial cells. In the mucosa of UC patients, M2 macrophages increase with chronicity and are associated with activation of epithelial Wnt signalling and diminution in enterocyte differentiation. PMID:24167598

Cosín-Roger, Jesús; Ortiz-Masiá, Dolores; Calatayud, Sara; Hernández, Carlos; Álvarez, Angeles; Hinojosa, Joaquin; Esplugues, Juan V.; Barrachina, Maria D.

2013-01-01

216

Guinea pig neutrophils infected with Mycobacterium tuberculosis produce cytokines which activate alveolar macrophages in noncontact cultures.  

PubMed

The early influx of neutrophils to the site of infection may be an important step in host resistance against Mycobacterium tuberculosis. In this study, we investigated the effect of M. tuberculosis infection on the ability of guinea pig neutrophils to produce interleukin-8 (IL-8; CXCL8) and tumor necrosis factor alpha (TNF-alpha) and to activate alveolar macrophages. Neutrophils and alveolar macrophages were isolated from naďve guinea pigs, cultured together or alone, and infected with virulent M. tuberculosis for 3, 12, and 24 h. IL-8 protein production in cocultures, as measured by using an enzyme-linked immunosorbent assay, was found to be additive at 24 h and significantly greater in M. tuberculosis-infected cocultures than in uninfected cocultures and in cultures of the infected neutrophils or macrophages alone. The IL-8 mRNA levels, determined by real-time reverse transcription-PCR, were elevated at 24 h in infected cocultures and infected cells cultured alone. In order to elucidate the contributions of neutrophils and their soluble mediators to the activation of alveolar macrophages, neutrophils and alveolar macrophages were cultured in a contact-independent manner by using a Transwell insert system. Neutrophils were infected with virulent M. tuberculosis in the upper wells, and alveolar macrophages were cultured in the lower wells. The release of hydrogen peroxide from alveolar macrophages exposed to soluble products from infected neutrophils was significantly increased compared to that from unexposed alveolar macrophages. Significant up-regulation of IL-1beta and TNF-alpha mRNA levels in alveolar macrophages was observed at 24 and 30 h, respectively, compared to those in cells not exposed to soluble neutrophil products. Treatment with anti-guinea pig TNF-alpha polyclonal antibody completely abolished the response of alveolar macrophages to neutrophil products. This finding suggests that TNF-alpha produced by infected neutrophils may be involved in the activation of alveolar macrophages and hence may contribute to the containment of M. tuberculosis infection during the early period of infection. PMID:17283104

Sawant, Kirti V; McMurray, David N

2007-04-01

217

ORIGINAL ARTICLE Activation of the stress response in macrophages alters the M1/M2  

E-print Network

ORIGINAL ARTICLE Activation of the stress response in macrophages alters the M1/M2 balance phenotypes along a spectrum between two opposite stages (M1/M2) during activation. In the present study, we uncharacterized M activation state formed in response to stress, associated with secretion of large quantities

Nizet, Victor

218

Adipose tissue macrophages in insulin-resistant subjects are associated with collagen VI and fibrosis and demonstrate alternative activation  

PubMed Central

Adipose tissue macrophages are associated with insulin resistance and are linked to changes in the extracellular matrix. To better characterize adipose macrophages, the extracellular matrix, and adipocyte-macrophage interactions, gene expression from adipose tissue and the stromal vascular fraction was assessed for markers of inflammation and fibrosis, and macrophages from obese and lean subjects were counted and characterized immunohistochemically. Coculture experiments examined the effects of adipocyte-macrophage interaction. Collagen VI gene expression was associated with insulin sensitivity and CD68 (r = ?0.56 and 0.60, P < 0.0001) and with other markers of inflammation and fibrosis. Compared with adipose tissue from lean subjects, adipose tissue from obese subjects contained increased areas of fibrosis, which correlated inversely with insulin sensitivity (r = ?0.58, P < 0.02) and positively with macrophage number (r = 0.70, P < 0.01). Although macrophages in crownlike structures (CLS) were more abundant in obese adipose tissue, the majority of macrophages were associated with fibrosis and were not organized in CLS. Macrophages in CLS were predominantly M1, but most other macrophages, particularly those in fibrotic areas, were M2 and also expressed CD150, a marker of M2c macrophages. Coculture of THP-1 macrophages with adipocytes promoted the M2 phenotype, with a lower level of IL-1 expression and a higher ratio of IL-10 to IL-12. Transforming growth factor-? (TGF-?) was more abundant in M2 macrophages and was further increased by coculture with adipocytes. Downstream effectors of TGF-?, such as plasminogen activator inhibitor-1, collagen VI, and phosphorylated Smad, were increased in macrophages and adipocytes. Thus adipose tissue of insulin-resistant humans demonstrated increased fibrosis, M2 macrophage abundance, and TGF-? activity. PMID:20841504

Spencer, Michael; Yao-Borengasser, Aiwei; Unal, Resat; Rasouli, Neda; Gurley, Catherine M.; Zhu, Beibei; Peterson, Charlotte A.

2010-01-01

219

Immunocytochemical localization of latent transforming growth factor-beta1 activation by stimulated macrophages  

NASA Technical Reports Server (NTRS)

Transforming growth factor-beta1 (TGF-beta) is secreted in a latent form consisting of mature TGF-beta noncovalently associated with its amino-terminal propeptide, which is called latency associated peptide (LAP). Biological activity depends upon the release of TGF-beta from the latent complex following extracellular activation, which appears to be the key regulatory mechanism controlling TGF-beta action. We have identified two events associated with latent TGF-beta (LTGF-beta) activation in vivo: increased immunoreactivity of certain antibodies that specifically detect TGF-beta concomitant with decreased immunoreactivity of antibodies to LAP. Macrophages stimulated in vitro with interferon-gamma and lipopolysaccharide reportedly activate LTGF-beta via cell membrane-bound protease activity. We show through dual immunostaining of paraformaldehyde-fixed macrophages that such physiological TGF-beta activation is accompanied by a loss of LAP immunoreactivity with concomitant revelation of TGF-beta epitopes. The induction of TGF-beta immunoreactivity colocalized with immunoreactive betaglycan/RIII in activated macrophages, suggesting that LTGF-beta activation occurs on the cell surface. Confocal microscopy of metabolically active macrophages incubated with antibodies to TGF-beta and betaglycan/RIII prior to fixation supported the localization of activation to the cell surface. The ability to specifically detect and localize LTGF-beta activation provides an important tool for studies of its regulation.

Chong, H.; Vodovotz, Y.; Cox, G. W.; Barcellos-Hoff, M. H.; Chatterjee, A. (Principal Investigator)

1999-01-01

220

Immunocytochemical Localization of Latent Transforming Growth Factor-B1 Activation by Stimulated Macrophages  

SciTech Connect

Transforming growth factor-{beta}1 (TGF-{beta}) is secreted in a latent form consisting of mature TGF-{beta} noncovalently associated with its amino-terminal propeptide, which is called latency associated peptide (LAP). Biological activity depends upon the release of TGF-{beta} from the latent complex following extracellular activation, which appears to be the key regulatory mechanism controlling TGF-{beta} action. We have identified two events associated with latent TGF-{beta} (LTGF-{beta}) activation in vivo: increased immunoreactivity of certain antibodies that specifically detect TGF-{beta} concomitant with decreased immunoreactivity of antibodies to LAP. Macrophages stimulated in vitro with interferon-{gamma} and lipopolysaccharide reportedly activate LTGF-{beta} via cell membrane-bound protease activity. We show through dual immunostaining of paraformaldehyde-fixed macrophages that such physiological TGF-{beta} activation is accompanied by a loss of LAP immunoreactivity with concomitant revelation of TGF-{beta} epitopes. The induction of TGF-{beta} immunoreactivity colocalized with immunoreactive betaglycan/RIII in activated macrophages, suggesting that LTGF-{beta} activation occurs on the cell surface. Confocal microscopy of metabolically active macrophages incubated with antibodies to TGF-{beta} and betaglycan/RIII prior to fixation supported the localization of activation to the cell surface. The ability to specifically detect and localize LTGF-{beta} activation provides an important tool for studies of its regulation.

Chong, Hyonkyong; Vodovotz, Yoram; Cox, G.W.; Barcellos-Hoff, M.H.

1998-09-22

221

MyD88 Primes Macrophages for Full-Scale Activation by Interferon-? yet Mediates Few Responses to Mycobacterium tuberculosis  

PubMed Central

Macrophages are activated from a resting state by a combination of cytokines and microbial products. Microbes are often sensed through Toll-like receptors signaling through MyD88. We used large-scale microarrays in multiple replicate experiments followed by stringent statistical analysis to compare gene expression in wild-type (WT) and MyD88?/? macrophages. We confirmed key results by quantitative reverse transcription polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assay. Surprisingly, many genes, such as inducible nitric oxide synthase, IRG-1, IP-10, MIG, RANTES, and interleukin 6 were induced by interferon (IFN)-? from 5- to 100-fold less extensively in MyD88?/? macrophages than in WT macrophages. Thus, widespread, full-scale activation of macrophages by IFN-? requires MyD88. Analysis of the mechanism revealed that MyD88 mediates a process of self-priming by which resting macrophages produce a low level of tumor necrosis factor. This and other factors lead to basal activation of nuclear factor ?B, which synergizes with IFN-? for gene induction. In contrast, infection by live, virulent Mycobacterium tuberculosis (Mtb) activated macrophages largely through MyD88-independent pathways, and macrophages did not need MyD88 to kill Mtb in vitro. Thus, MyD88 plays a dynamic role in resting macrophages that supports IFN-?–dependent activation, whereas macrophages can respond to a complex microbial stimulus, the tubercle bacillus, chiefly by other routes. PMID:14517275

Shi, Shuangping; Nathan, Carl; Schnappinger, Dirk; Drenkow, Jörg; Fuortes, Michele; Block, Ellen; Ding, Aihao; Gingeras, Thomas R.; Schoolnik, Gary; Akira, Shizuo; Takeda, Kiyoshi; Ehrt, Sabine

2003-01-01

222

IRAK-M Promotes Alternative Macrophage Activation and Fibroproliferation in Bleomycin-Induced Lung Injury.  

PubMed

Idiopathic pulmonary fibrosis is a devastating lung disease characterized by inflammation and the development of excessive extracellular matrix deposition. Currently, there are only limited therapeutic intervenes to offer patients diagnosed with pulmonary fibrosis. Although previous studies focused on structural cells in promoting fibrosis, our study assessed the contribution of macrophages. Recently, TLR signaling has been identified as a regulator of pulmonary fibrosis. IL-1R-associated kinase-M (IRAK-M), a MyD88-dependent inhibitor of TLR signaling, suppresses deleterious inflammation, but may paradoxically promote fibrogenesis. Mice deficient in IRAK-M (IRAK-M(-/-)) were protected against bleomycin-induced fibrosis and displayed diminished collagen deposition in association with reduced production of IL-13 compared with wild-type (WT) control mice. Bone marrow chimera experiments indicated that IRAK-M expression by bone marrow-derived cells, rather than structural cells, promoted fibrosis. After bleomycin, WT macrophages displayed an alternatively activated phenotype, whereas IRAK-M(-/-) macrophages displayed higher expression of classically activated macrophage markers. Using an in vitro coculture system, macrophages isolated from in vivo bleomycin-challenged WT, but not IRAK-M(-/-), mice promoted increased collagen and ?-smooth muscle actin expression from lung fibroblasts in an IL-13-dependent fashion. Finally, IRAK-M expression is upregulated in peripheral blood cells from idiopathic pulmonary fibrosis patients and correlated with markers of alternative macrophage activation. These data indicate expression of IRAK-M skews lung macrophages toward an alternatively activated profibrotic phenotype, which promotes collagen production, leading to the progression of experimental pulmonary fibrosis. PMID:25595781

Ballinger, Megan N; Newstead, Michael W; Zeng, Xianying; Bhan, Urvashi; Mo, Xiaokui M; Kunkel, Steven L; Moore, Bethany B; Flavell, Richard; Christman, John W; Standiford, Theodore J

2015-02-15

223

Polyoxygenated Cholesterol Ester Hydroperoxide Activates TLR4 and SYK Dependent Signaling in Macrophages  

PubMed Central

Oxidation of low-density lipoprotein (LDL) is one of the major causative mechanisms in the development of atherosclerosis. In previous studies, we showed that minimally oxidized LDL (mmLDL) induced inflammatory responses in macrophages, macropinocytosis and intracellular lipid accumulation and that oxidized cholesterol esters (OxCEs) were biologically active components of mmLDL. Here we identified a specific OxCE molecule responsible for the biological activity of mmLDL and characterized signaling pathways in macrophages in response to this OxCE. Using liquid chromatography – tandem mass spectrometry and biological assays, we identified an oxidized cholesteryl arachidonate with bicyclic endoperoxide and hydroperoxide groups (BEP-CE) as a specific OxCE that activates macrophages in a TLR4/MD-2-dependent manner. BEP-CE induced TLR4/MD-2 binding and TLR4 dimerization, phosphorylation of SYK, ERK1/2, JNK and c-Jun, cell spreading and uptake of dextran and native LDL by macrophages. The enhanced macropinocytosis resulted in intracellular lipid accumulation and macrophage foam cell formation. Bone marrow-derived macrophages isolated from TLR4 and SYK knockout mice did not respond to BEP-CE. The presence of BEP-CE was demonstrated in human plasma and in the human plaque material captured in distal protection devices during percutaneous intervention. Our results suggest that BEP-CE is an endogenous ligand that activates the TLR4/SYK signaling pathway. Because BEP-CE is present in human plasma and human atherosclerotic lesions, BEP-CE-induced and TLR4/SYK-mediated macrophage responses may contribute to chronic inflammation in human atherosclerosis. PMID:24376657

Choi, Soo-Ho; Yin, Huiyong; Ravandi, Amir; Armando, Aaron; Dumlao, Darren; Kim, Jungsu; Almazan, Felicidad; Taylor, Angela M.; McNamara, Coleen A.; Tsimikas, Sotirios; Dennis, Edward A.; Witztum, Joseph L.; Miller, Yury I.

2013-01-01

224

Another barrier to regeneration in the CNS: activated macrophages induce extensive retraction of dystrophic axons through direct physical interactions.  

PubMed

Injured axons of the adult CNS undergo lengthy retraction from the initial site of axotomy after spinal cord injury. Macrophage infiltration correlates spatiotemporally with this deleterious phenomenon, but the direct involvement of these inflammatory cells has not been demonstrated. In the present study, we examined the role of macrophages in axonal retraction within the dorsal columns after spinal cord injury in vivo and found that retraction occurred between days 2 and 28 after lesion and that the ends of injured axons were associated with ED-1+ cells. Clodronate liposome-mediated depletion of infiltrating macrophages resulted in a significant reduction in axonal retraction; however, we saw no evidence of regeneration. We used time-lapse imaging of adult dorsal root ganglion neurons in an in vitro model of the glial scar to examine macrophage-axon interactions and observed that adhesive contacts and considerable physical interplay between macrophages and dystrophic axons led to extensive axonal retraction. The induction of retraction was dependent on both the growth state of the axon and the activation state of the macrophage. Only dystrophic adult axons were susceptible to macrophage "attack." Unlike intrinsically active cell line macrophages, both primary macrophages and microglia required activation to induce axonal retraction. Contact with astrocytes had no deleterious effect on adult dystrophic axons, suggesting that the induction of extensive retraction was specific to phagocytic cells. Our data are the first to indicate a direct role of activated macrophages in axonal retraction by physical cell-cell interactions with injured axons. PMID:18799667

Horn, Kevin P; Busch, Sarah A; Hawthorne, Alicia L; van Rooijen, Nico; Silver, Jerry

2008-09-17

225

Aging Enhances Production of Reactive Oxygen Species and Bactericidal Activity in Peritoneal Macrophages by Up-Regulating Classical Activation Pathways  

PubMed Central

Maintenance of macrophages in their basal state and their rapid activation in response to pathogen detection is central to the innate immune system, acting to limit nonspecific oxidative damage and promote pathogen killing following infection. To identify possible age-related alterations in macrophage function, we have assayed the function of peritoneal macrophages from young (3–4 mo) and aged (14–15 mo) Balb/c mice. In agreement with prior suggestions, we observe age-dependent increases in macrophage recruitment into the peritoneum, as well as ex vivo functional changes involving enhanced nitric oxide production under resting conditions that contribute to a reduction in the time needed for full activation of senescent macrophages following exposure to LPS. Further, we observe enhanced bactericidal activity following Salmonella uptake by macrophages isolated from aged Balb/c mice in comparison with those isolated from young animals. Pathways responsible for observed phenotypic changes were interrogated using tandem mass spectrometry, which identified age-dependent increases in proteins linked to immune cell pathways under both basal conditions and following LPS activation. Immune pathways up-regulated in macrophages isolated from aged mice include proteins critical to formation of the immunoproteasome. Detection of these latter proteins are dramatically enhanced following LPS exposure for macrophages isolated from aged animals; in comparison, the identification of immunoproteasome subunits is insensitive to LPS exposure for macrophages isolated from young animals. Consistent with observed global changes in the proteome, quantitative proteomic measurements indicate that there are age-dependent abundance changes involving specific proteins linked to immune cell function under basal conditions. LPS exposure selectively increases many proteins involved in immune cell function in aged Balb/c mice. Collectively these results indicate that macrophages isolated from old mice are in a pre-activated state that enhances their sensitivities of LPS exposure. The hyper-responsive activation of macrophages in aged animals may act to minimize infection to general bacterial threats that arise due to age-dependent declines in adaptive immunity. However, this hypersensitivity and the associated increase in the formation of reactive oxygen species is likely to contribute to observed age-dependent increases in oxidative damage that underlie many diseases of the elderly. PMID:21981794

Smallwood, Heather S.; López-Ferrer, Daniel; Squier, Thomas C.

2011-01-01

226

Immunostimulatory activity of polysaccharides isolated from Caulerpa lentillifera on macrophage cells.  

PubMed

Polysaccharides were extracted from Caulerpa lentillifera by treating with water and then purified by size-exclusion chromatography. The purified polysaccharides, termed SP1, were found to be sulfated xylogalactans with a molecular mass of more than 100 kDa. Adding SP1 to murine macrophage RAW 264.7 cells increased the production of nitric oxide (NO) in a dose-dependent manner. NO was found by immunoblotting and RT-PCR analyses to be synthesized by an inducible NO synthase. SP1 caused the degradation of I?B-? and the nuclear translocation of nuclear factor (NF)-?B subunit p65 in macrophage cells. SP1 also increased the phosphorylation of p38 mitogen-activated protein kinase (MAPK). These results demonstrate that SP1 activated macrophage cells via both the NF-?B and p38 MAPK signaling pathways. Moreover, SP1 increased the expression of various genes encoding cytokines, and the phagocytic activity of macrophage cells. These combined results show that SP1 immunostimulated the activity of macrophage cells. PMID:22451391

Maeda, Reiko; Ida, Tomoaki; Ihara, Hideshi; Sakamoto, Tatsuji

2012-01-01

227

Folate receptor-? in activated macrophages: ligand binding and receptor recycling kinetics.  

PubMed

Activated macrophages overexpress a receptor for the vitamin folic acid termed the folate receptor ? (FR-?). Because conjugation of folate to low molecular weight drugs, genes, liposomes, nanoparticles, and imaging agents has minor effects on FR binding, the vitamin can be exploited to target both therapeutic and imaging agents to activated macrophages without promoting their uptake by other healthy cells. In this paper, we characterize the binding, internalization, and recycling kinetics of FR-? on activated macrophages in inflamed tissues of rats with adjuvant-induced arthritis. Our results demonstrate that saturation of macrophage FR is achieved at injection doses of ?150-300 nmol/kg, with more rapidly perfused tissues saturating at lower doses than inflamed appendages. After binding, FR-? internalizes and recycles back to the cell surface every ?10-20 min, providing empty receptors for additional folate conjugate uptake. Because the half-life of low molecular weight folate conjugates in the vasculature is usually <1 h, these data suggest that targeting of folate conjugates to activated macrophages in vivo can be maximized by frequent dosing at conjugate concentrations that barely saturate FR (?150 nmol/kg), thereby minimizing nonspecific binding to receptor-negative tissues and maximizing the probability that unoccupied cell surface receptors will be exposed to folate-drug conjugate. PMID:25166491

Varghese, Bindu; Vlashi, Erina; Xia, Wei; Ayala Lopez, Wilfredo; Paulos, Chrystal M; Reddy, Joseph; Xu, Le-Cun; Low, Philip S

2014-10-01

228

Plant nitrate reductase gene fragments enhance nitrite production in activated murine macrophage cell lines.  

PubMed

Nitrate reductase (NR) gene fragments (1.1 kb and 800 bp) from the barley plant were incorporated into pSV2neo and transfected by electroporation into a variety of cell lines of different functionality. Only transfected murine macrophage cell lines demonstrated appreciably enhanced NO2- production (i.e., NR activity) both in the presence and absence of exogenous nitrate (NO3-). Addition of NO3- caused the greatest increase in NO2- production when macrophages were primed with interferon-gamma (INF-gamma) and lipopolysaccharide (LPS). Transfection of RAW 264.7 murine macrophages led to isolation of several novel neomycin-resistant subpopulations designated NR10(1), NR10(2) (both containing the 1.1 kb NR fragment) and NR800(5) (containing the 800 bp NR fragment). Similarly transfected nonleukocytic and leukocytic stem cell lines showed no significant NO2- production. Outside of the macrophage cell lines, only the murine T cell line EL-4 showed evidence of mild nitrite production enhancement. The mechanism of enhanced NO2- formation in NR transfected murine macrophages is unknown. However, study of these novel cells may lead to greater understanding of the expression of a plant NR in mammalian cells and highly controlled production of a cytotoxic molecule (NO2-) in macrophages. PMID:8198585

Bruno, J G; Parker, J E; Kiel, J L

1994-05-30

229

Nonspecific hemolytic effector of activated macrophages as activation marker of allograft rejection.  

PubMed

The aim was to assess a nonspecific hemolytic effector of activated monocytes/macrophages, designated spontaneous plaque-forming cell (SPFC), as an activation marker in allograft rejection. An in vitro study on the immunologic characteristics of SPFC monocytes in man and an in vivo study in Lewis rats as to the monitoring of SPFC generation of allograft infiltrating cells with or without immunosuppression were conducted. Hemolysis of SPFC was mediated by CR3 adhesion molecules, detected by Mo-1 and OKM10 monoclonal antibodies. Hemolysis of SPFC was nonspecific, and nonrosette-forming T cells with autologous erythrocytes (non-ARFC-T) acted as suppressor T cells inhibiting SPFC-hemolysis against autologous erythrocytes. A 6-day course of immunosuppression with a daily dose of cyclosporin A (CyA) 10 mg/kg and of FK506 1 mg/kg suppressed the SPFC generation to the level of syngeneic control. In contrast, peak SPFC generation coincided with rejection, and the degree of SPFC generation reflected the grade of histoincompatibility. The present findings suggested that SPFC-activated monocytes/macrophages may be one of the activation markers in allograft rejection and lead to a new concept of graft rejection and self or nonself discrimination mediated by nonspecific, hemolytic SPFC effectors and suppressor T cells inhibiting autoreactivity. PMID:14621804

Ishibashi, M; Moutabarrik, A; Kameoka, H; Takano, Y; Jiang, H; Kokado, Y; Takahara, S

1992-01-01

230

Synthetic cationic peptide IDR-1018 modulates human macrophage differentiation.  

PubMed

Macrophages play a critical role in the innate immune response. To respond in a rapid and efficient manner to challenges in the micro-environment, macrophages are able to differentiate towards classically (M1) or alternatively (M2) activated phenotypes. Synthetic, innate defense regulators (IDR) peptides, designed based on natural host defence peptides, have enhanced immunomodulatory activities and reduced toxicity leading to protection in infection and inflammation models that is dependent on innate immune cells like monocytes/macrophages. Here we tested the effect of IDR-1018 on macrophage differentiation, a process essential to macrophage function and the immune response. Using transcriptional, protein and systems biology analysis, we observed that differentiation in the presence of IDR-1018 induced a unique signature of immune responses including the production of specific pro and anti-inflammatory mediators, expression of wound healing associated genes, and increased phagocytosis of apoptotic cells. Transcription factor IRF4 appeared to play an important role in promoting this IDR-1018-induced phenotype. The data suggests that IDR-1018 drives macrophage differentiation towards an intermediate M1-M2 state, enhancing anti-inflammatory functions while maintaining certain pro-inflammatory activities important to the resolution of infection. Synthetic peptides like IDR-1018, which act by modulating the immune system, could represent a powerful new class of therapeutics capable of treating the rising number of multidrug resistant infections as well as disorders associated with dysregulated immune responses. PMID:23308112

Pena, Olga M; Afacan, Nicole; Pistolic, Jelena; Chen, Carol; Madera, Laurence; Falsafi, Reza; Fjell, Christopher D; Hancock, Robert E W

2013-01-01

231

CD14 influences host immune responses and alternative activation of macrophages during Schistosoma mansoni infection.  

PubMed

Antigen-presenting cell (APC) plasticity is critical for controlling inflammation in metabolic diseases and infections. The roles that pattern recognition receptors (PRRs) play in regulating APC phenotypes are just now being defined. We evaluated the expression of PRRs on APCs in mice infected with the helminth parasite Schistosoma mansoni and observed an upregulation of CD14 expression on macrophages. Schistosome-infected Cd14(-/-) mice showed significantly increased alternative activation of (M2) macrophages in the livers compared to infected wild-type (wt) mice. In addition, splenocytes from infected Cd14(-/-) mice exhibited increased production of CD4(+)-specific interleukin-4 (IL-4), IL-5, and IL-13 and CD4(+)Foxp3(+)IL-10(+) regulatory T cells compared to cells from infected wt mice. S. mansoni-infected Cd14(-/-) mice also presented with smaller liver egg granulomas associated with increased collagen deposition compared to granulomas in infected wt mice. The highest expression of CD14 was found on liver macrophages in infected mice. To determine if the Cd14(-/-) phenotype was in part due to increased M2 macrophages, we adoptively transferred wt macrophages into Cd14(-/-) mice and normalized the M2 and CD4(+) Th cell balance close to that observed in infected wt mice. Finally, we demonstrated that CD14 regulates STAT6 activation, as Cd14(-/-) mice had increased STAT6 activation in vivo, suggesting that lack of CD14 impacts the IL-4R?-STAT6 pathway, altering macrophage polarization during parasite infection. Collectively, these data identify a previously unrecognized role for CD14 in regulating macrophage plasticity and CD4(+) T cell biasing during helminth infection. PMID:24866794

Tundup, Smanla; Srivastava, Leena; Nagy, Tamas; Harn, Donald

2014-08-01

232

Contribution of macrophages to proteolysis and plasmin activity in ewe bulk milk.  

PubMed

A total of 225 bulk sheep milk samples were collected from 5 intensively managed flocks during early, mid, and late lactation to assess the contribution of macrophages to the regulation of the plasmin-plasminogen system. Samples were analyzed for composition, somatic cell counts, milk renneting characteristics, and for plasmin (PL), plasminogen (PG), and plasminogen activators (PA) activities. Isolation of macrophages from milk was performed using a magnetic positive separation and mouse antiovine macrophage antibody; separated cells were lysed by several freeze-thaw cycles, and activity of urokinase PA (u-PA) was determined. Plasmin activity decreased during lactation (42.06 +/- 0.66, early; 31.29 +/- 0.66, mid; 28.19 +/- 0.66 U/mL, late). The reduction in PL activity recorded in the mid and late lactation milk matched the increase in PG:PL ratio. The activity of PA increased throughout lactation; the highest value being recorded in the late lactation milk (260.20 +/- 8.66 U/mL). Counts of isolated and concentrated macrophages were higher in early and mid lactation milk (3.89 +/- 0.08 and 3.98 +/- 0.08 log10 cells/mL, respectively) than in late lactation milk (3.42 +/- 0.08 log10 cells/mL). Stage of lactation did not influence the activity of u-PA detected in isolated macrophages. The activity of u-PA associated with isolated milk macrophages only minimally contributed to total PA activity detected in milk. Proteolytic enzymes, associated with isolated macrophages, act on alpha-casein hydrolysis, as shown by urea-PAGE electrophoresis analysis. Somatic cell counts did not exceed 600,000 cells/mL, and this threshold can be considered a good index of health status of the flock and of the ability of milk to being processed. Our results lend support to the hypothesis that macrophages in ewe bulk milk from healthy flocks only slightly contribute to the activation of the PL-PG system. PMID:17517716

Caroprese, M; Marzano, A; Schena, L; Marino, R; Santillo, A; Albenzio, M

2007-06-01

233

INTERLEUKIN-4- AND INTERLEUKIN-13-MEDIATED ALTERNATIVELY ACTIVATED MACROPHAGES: ROLES IN HOMEOSTASIS AND DISEASE  

PubMed Central

The macrophage, a versatile cell type prominently involved in host defense and immunity, assumes a distinct state of alternative activation in the context of polarized type 2 immune responses such as allergic inflammation and helminth infection. This alternatively activated phenotype is induced by the canonical type 2 cytokines interleukin (IL)-4 and IL-13, which mediate expression of several characteristic markers along with a dramatic shift in macrophage metabolic pathways that influence surrounding cells and tissues. We discuss recent advances in the understanding of IL-4- and IL-13-mediated alternatively activated macrophages and type 2 immune responses; such advances have led to an expanded appreciation for functions of these cells beyond immunity, including maintenance of physiologic homeostasis and tissue repair. PMID:23298208

Van Dyken, Steven J.; Locksley, Richard M.

2013-01-01

234

Aging Enhances the Production of Reactive Oxygen Species and Bactericidal Activity in Peritoneal Macrophages by Upregulating Classical Activation Pathways  

SciTech Connect

Maintenance of macrophages in their basal state and their rapid activation in response to pathogen detection are central to the innate immune system, acting to limit nonspecific oxidative damage and promote pathogen killing following infection. To identify possible age-related alterations in macrophage function, we have assayed the function of peritoneal macrophages from young (3?4 months) and aged (14?15 months) Balb/c mice. In agreement with prior suggestions, we observe age-dependent increases in the extent of recruitment of macrophages into the peritoneum, as well as ex vivo functional changes involving enhanced nitric oxide production under resting conditions that contribute to a reduction in the time needed for full activation of senescent macrophages following exposure to lipopolysaccharides (LPS). Further, we observe enhanced bactericidal activity following Salmonella uptake by macrophages isolated from aged Balb/c mice in comparison with those isolated from young animals. Pathways responsible for observed phenotypic changes were interrogated using tandem mass spectrometry, which identified age-dependent increases in levels of proteins linked to immune cell pathways under basal conditions and following LPS activation. Immune pathways upregulated in macrophages isolated from aged mice include proteins critical to the formation of the immunoproteasome. Detection of these latter proteins is dramatically enhanced following LPS exposure for macrophages isolated from aged animals; in comparison, the identification of immunoproteasome subunits is insensitive to LPS exposure for macrophages isolated from young animals. Consistent with observed global changes in the proteome, quantitative proteomic measurements indicate that there are age-dependent abundance changes involving specific proteins linked to immune cell function under basal conditions. LPS exposure selectively increases the levels of many proteins involved in immune cell function in aged Balb/c mice. Collectively, these results indicate that macrophages isolated from old mice are in a preactivated state that enhances their sensitivities to LPS exposure. The hyper-responsive activation of macrophages in aged animals may act to minimize infection by general bacterial threats that arise due to age-dependent declines in adaptive immunity. However, this hypersensitivity and the associated increase in the level of formation of reactive oxygen species are likely to contribute to observed age-dependent increases in the level of oxidative damage that underlie many diseases of the elderly.

Smallwood, Heather S.; Lopez-Ferrer, Daniel; Squier, Thomas C.

2011-10-07

235

Immunomodulatory Effect of Mangiferin in Experimental Animals with Benzo(a)Pyrene-induced Lung Carcinogenesis  

PubMed Central

The immunomodulatory activity of mangiferin was studied in various groups of animals. For this study, adult Swiss albino male mice were treated with benzo(a)pyrene, abbreviated as B(a)P, at 50 mg/kg body weight orally twice a week for 4 weeks; and mangiferin was also given orally (pre- and post-initiation of carcinoma) at 100 mg/kg body weight. Immunocompetence and immune complexes as measured by phagocyte index, avidity index, and soluble immune complex (SIC) levels (p<0.001), as well as NBT reduction, were decreased in the B(a)P-treated animals;whereas increased levels of immunocompetence were noted in the mangiferin-treated animals given B(a)P (p<0.001, p<0.05). The levels of immunoglobulins such as IgG and IgM were decreased considerably (p<0.001) in the B(a)P-treated animals compared with their levels in the control animals; whereas the IgA level was increased (p<0.001). In the mangiferin-treated experimental animals given B(a)P, the levels of IgG and IgM were significantly (p<0.001, p<0.05) increased whereas the IgA level was decreased compared with those for the B(a)P-treated mice. Oxidative changes in lymphocytes, neutrophils, and macrophages were also measured. The enhanced lipid peroxidation and decreased catalase and superoxide dismutase activities found in the lymphocytes, polymorphonuclear cells (PMN), and macrophages from B(a)P-treated mice were significantly reduced and increased, respectively, by the mangiferin treatment. This study confirms the immunomodulatory effect of mangiferin and shows an immunoprotective role arbitrated through a reduction in the reactive intermediate-induced oxidative stress in lymphocytes, neutrophils, and macrophages. PMID:23847456

Rajendran, Peramaiyan; Jayakumar, Thangavel; Nishigaki, Ikuo; Ekambaram, Ganapathy; Nishigaki, Yutaka; Vetriselvi, Jayabal; Sakthisekaran, Dhanapal

2013-01-01

236

Paeoniflorin attenuates schistosomiasis japonica-associated liver fibrosis through inhibiting alternative activation of macrophages.  

PubMed

Interleukin (IL)-13 and alternatively activated macrophages (AAMs) play an important role in liver granuloma and fibrosis of schistosomiasis. Paeoniflorin (PAE, C23H28O11) has been reported to have an anti-hepatic fibrosis effect in schistosomiasis; however, the mechanism has not been fully elucidated. In this study, we measured serum hyaluronic acid (HA) concentrations, liver granuloma diameter and volume density, fibrosis degree and expressions of IL-13, arginase-1 (ARG-1), nitric oxide synthase-2 (NOS-2), and phosphorylated signal transducer and activator of transcription 6 (p-STAT6) in mice liver of schistosomiasis. Then we detected expressions of specific biomarkers of AAMs and activity of Arg-1 in Kupffer cells (KCs) from infected and PAE-treated mice, or in KCs from uninfected mice, but exposed to rIL-13 in vitro. Finally, we observed expression of IL-13 signalling molecules in KCs and secretion of IL-13 from lymphocytes of infected and PAE-treated mice. Our results showed that during schistosomiasis, IL-13 expression and secretion increased with liver macrophages activated alternatively. PAE not only directly inhibited alternative activation of macrophages via reducing the phosphorylations of janus-activated kinase 2 (JAK2) and/or STAT6, leading to reduction of AAMs-related markers and Arg-1 activity, but also indirectly suppressed alternative activation of macrophages through decreasing secretion of IL-13. PAE might be a promising prophylactic agent for hepatic granuloma and fibrosis of schistosomiasis japonica. PMID:21810309

Chu, Deyong; Du, Mingzhan; Hu, Xiangyang; Wu, Qiang; Shen, Jilong

2011-09-01

237

Activation of alveolar macrophages in lung injury associated with experimental acute pancreatitis is mediated by the liver.  

PubMed Central

OBJECTIVE: To evaluate (1) whether alveolar macrophages are activated as a consequence of acute pancreatitis (AP), (2) the implication of inflammatory factors released by these macrophages in the process of neutrophil migration into the lungs observed in lung injury induced by AP, and (3) the role of the liver in the activation of alveolar macrophages. SUMMARY BACKGROUND DATA: Acute lung injury is the extrapancreatic complication most frequently associated with death and complications in severe AP. Neutrophil infiltration into the lungs seems to be related to the release of systemic and local mediators. The liver and alveolar macrophages are sources of mediators that have been suggested to participate in the lung damage associated with AP. METHODS: Pancreatitis was induced in rats by intraductal administration of 5% sodium taurocholate. The inflammatory process in the lung and the activation of alveolar macrophages were investigated in animals with and without portocaval shunting 3 hours after AP induction. Alveolar macrophages were obtained by bronchoalveolar lavage. The generation of nitric oxide, leukotriene B4, tumor necrosis factor-alpha, and MIP-2 by alveolar macrophages and the chemotactic activity of supernatants of cultured macrophages were evaluated. RESULTS: Pancreatitis was associated with increased infiltration of neutrophils into the lungs 3 hours after induction. This effect was prevented by the portocaval shunt. Alveolar macrophages obtained after induction of pancreatitis generated increased levels of nitric oxide, tumor necrosis factor-alpha, and MIP-2, but not leukotriene B4. In addition, supernatants of these macrophages exhibited a chemotactic activity for neutrophils when instilled into the lungs of unmanipulated animals. All these effects were abolished when portocaval shunting was carried out before induction of pancreatitis. CONCLUSION: Lung damage induced by experimental AP is associated with alveolar macrophage activation. The liver mediates the alveolar macrophage activation in this experimental model. Images Figure 3. PMID:10024105

Closa, D; Sabater, L; Fernández-Cruz, L; Prats, N; Gelpí, E; Roselló-Catafau, J

1999-01-01

238

Macrophage stimulating protein: purification, partial amino acid sequence, and cellular activity  

PubMed Central

Macrophage stimulating protein (MSP) was purified to homogeneity from human blood plasma by selection of biologically active fractions obtained by sequential immunoaffinity and high pressure liquid ion exchange chromatography. By sodium dodecyl sulfate-polyacrylamide gel electrophoresis the molecular mass of MSP was 70 kilodaltons (kD); under reducing conditions two gel bands were seen, at 47 and 22 kD. The disulfide-linked two-chain structure of MSP was confirmed by separation of reduced and alkylated MSP chains. A computer search comparison of six partial sequences of MSP digests showed that MSP has not been recorded in data banks of protein sequences. Two MSP fragments had greater than 80% identity in overlaps of 12-16 residues to sequences in the protein family that includes human prothrombin, plasminogen, and hepatocyte growth factor. The concentration of purified MSP required for half-maximal biological activity was the order of 10(-10) M. In addition to making mouse resident peritoneal macrophages responses to chemoattractants, MSP caused the appearance of long cytoplasmic processes and pinocytic vesicles in freshly plated macrophages. MSP also caused phagocytosis via the C3b receptor, CR1. Whereas resident peritoneal macrophages bind but do not ingest sheep erythrocytes opsonized with IgM anti-Forssman antibody and mouse C3b, addition of MSP caused ingestion. Thus, MSP causes direct or indirect activation of two receptors of the mouse resident peritoneal macrophage, CR1 and the C5a receptor. PMID:1827141

1991-01-01

239

Reduced inflammatory activity of RAW 264.7 macrophages on titania nanotube modified Ti surface.  

PubMed

Macrophages play a pivotal role in the hosts response to biomaterials being considered as an essential cell type during both optimal tissue-implant integration and pathologic process of implant failure. Hence, understanding of their cellular activity on biomaterials is important for improving evaluation and design of biomaterials for biomedical applications. In the present study, we have comparatively investigated the interactions of titania nanotubes (78 nm diameter) and commercial pure Ti with RAW 264.7 macrophages in both standard and pro-inflammatory (stimulation with lipopolysaccharide, LPS) culture conditions. In vitro tests showed that TiO2 nanotubes exhibited significantly decreased inflammatory activity of macrophages with respect to cytokine and chemokine gene expression/protein secretion, induction of foreign body giant cells (FBGCs) and nitric oxide (NO) release thereby mitigating the inflammatory response induced by LPS as compared to flat Ti surface. Therefore, our results suggest a novel role of TiO2 nanotubes in modulating macrophage response in biomaterial-associated bacterial infections. Overall, the current study provides new insight into how TiO2 nanotubes can be involved in macrophage activation and supports the great promise of such surface modifications for biomedical applications. PMID:25220343

Neacsu, Patricia; Mazare, Anca; Cimpean, Anisoara; Park, Jung; Costache, Marieta; Schmuki, Patrik; Demetrescu, Ioana

2014-10-01

240

Anti-inflammatory Activity and Mechanism of Surfactin in Lipopolysaccharide-Activated Macrophages.  

PubMed

Surfactin is primarily produced by Bacillus natto TK-1 and is one of the most powerful biosurfactants. It consists of a heptapeptide interlinked with a ?-hydroxy fatty acid. Because of its special structure, surfactin shows broad biological effects, including anti-tumour, anti-microbial and anti-mycoplasma activities. It also has potential anti-inflammatory activity; however, the anti-inflammatory mechanism of surfactin has not been explored. In this study, we investigated the anti-inflammatory mechanism of surfactin in lipopolysaccharide (LPS)-stimulated macrophages. Surfactin exhibited an anti-inflammatory effect without cytotoxicity at certain concentrations, and the lipopolysaccharide (LPS)-stimulated cells appeared normal after surfactin treatment. Surfactin significantly inhibited the increased expression of IFN-?, IL-6, iNOS and nitric oxide (NO). TLR4 is the critical receptor for LPS; therefore, the TLR4 signal transduction pathway is the primary pathway that mediates LPS-induced inflammation. The results show that surfactin downregulated the LPS-induced TLR4 protein expression of macrophages and indicated that the surfactin-mediated signal pathway was involved in with TLR4. The subsequent studies demonstrated that surfactin exhibited anti-inflammatory effects by attenuating the activation of nuclear factor-?B (NF-?B), which is involved in the nuclear factor-?B (NF-?B) cell signalling pathways. These results suggest that surfactin may be a new therapeutic agent for inflammation. PMID:25331175

Zhang, Yuanyuan; Liu, Chuan; Dong, Bin; Ma, Xiaolei; Hou, Lihua; Cao, Xiaohong; Wang, Chunling

2014-10-21

241

Activation of the Stem Cell-Derived Tyrosine Kinase\\/RON Receptor Tyrosine Kinase by Macrophage-Stimulating Protein Results in the Induction of Arginase Activity in Murine Peritoneal Macrophages1  

Microsoft Academic Search

Regulation of macrophage activities in response to inflammatory stimuli must be finely tuned to promote an effective immune response while, at the same time, preventing damage to the host. Our lab and others have previously shown that macrophage- stimulating protein (MSP), through activation of its receptor RON, negatively regulates NO production in response to IFN- and LPS by inhibiting the

Amy C. Morrison; Pamela H. Correll

242

Mesenchymal stem cells ameliorate rhabdomyolysis-induced acute kidney injury via the activation of M2 macrophages  

PubMed Central

Introduction The mortality of rhabdomyolysis-induced acute kidney injury (AKI) is still high, as there is no effective therapy. It has been shown that bone marrow-derived mesenchymal stem cells (MSCs) can induce M2 macrophages, which mediate MSC protection in other experimental inflammation-related organ injury. This study was designed to investigate the protective effects of macrophage activation in MSC therapy of rhabdomyolysis-induced AKI. Methods MSCs were injected into glycerol-induced rhabdomyolysis mice. Renal injury was evaluated using the serum creatinine, urea nitrogen, renal pathology and acute tubular necrosis score. The distribution of MSCs was detected using two-photon fluorescence confocal imaging. Immunofluorescence of anti-F4/80 and anti-CD206 was performed to determine macrophages and M2 macrophages in the tissues of the kidney, and M2 macrophage infiltration was also evaluated using western blotting analyses. After depletion of macrophages using clodronate liposomes at the phase of kidney repair, renal injury was re-evaluated. RAW 264.7 macrophages were incubated with lipopolysaccharide and co-cultured with MSCs and subsequently visualised using immunofluorescence staining and flow cytometry analysis. Finally, disparate phenotype macrophages, including normal macrophages (M0), lipopolysaccharide-stimulated macrophages (M1), and MSC-co-cultured macrophages (M2), were infused into mice with AKI, which were pre-treated with liposomal clodronate. Results In vivo infusion of MSCs protected AKI mice from renal function impairment and severe tubular injury, which was accompanied by a time-dependent increase in CD206-positive M2 macrophage infiltration. In addition, depleting macrophages with clodronate delayed restoration of AKI. In vitro, macrophages co-cultured with MSCs acquired an anti-inflammatory M2 phenotype, which was characterised by an increased expression of CD206 and the secretory cytokine interleukin (IL)-10. The concentrations of IL-10, IL-6 and tumor necrosis factor ? were evaluated using enzyme-linked immunosorbent assay. Furthermore, macrophage-depleted mice with intramuscular injection of glycerol were subjected to a single injection of different types of RAW 264.7 macrophages. Mice infused with M0 and M1 macrophages suffered a more severe histological and functional injury, while mice transfused with MSC-educated M2 macrophages showed reduced kidney injury. Conclusions Our findings suggested that MSCs can ameliorate rhabdomyolysis-induced AKI via the activation of macrophages to a trophic M2 phenotype, which supports the transition from tubule injury to tubule repair. PMID:24961539

2014-01-01

243

Muscle cells challenged with saturated fatty acids mount an autonomous inflammatory response that activates macrophages.  

PubMed

Obesity is associated with chronic low-grade inflammation. Within adipose tissue of mice fed a high fat diet, resident and infiltrating macrophages assume a pro-inflammatory phenotype characterized by the production of cytokines which in turn impact on the surrounding tissue. However, inflammation is not restricted to adipose tissue and high fat-feeding is responsible for a significant increase in pro-inflammatory cytokine expression in muscle. Although skeletal muscle is the major disposer of dietary glucose and a major determinant of glycemia, the origin and consequence of muscle inflammation in the development of insulin resistance are poorly understood.We used a cell culture approach to investigate the vectorial crosstalk between muscle cells and macrophages upon exposure to physiological, low levels of saturated and unsaturated fatty acids. Inflammatory pathway activation and cytokine expression were analyzed in L6 muscle cells expressing myc-tagged GLUT4 (L6GLUT4myc) exposed to 0.2 mM palmitate or palmitoleate. Conditioned media thereof, free of fatty acids, were then tested for their ability to activate RAW264.7 macrophages.Palmitate -but not palmitoleate- induced IL-6, TNF? and CCL2 expression in muscle cells, through activation of the NF-?B pathway. Palmitate (0.2 mM) alone did not induce insulin resistance in muscle cells, yet conditioned media from palmitate-challenged muscle cells selectively activated macrophages towards a pro-inflammatory phenotype.These results demonstrate that low concentrations of palmitate activate autonomous inflammation in muscle cells to release factors that turn macrophages pro-inflammatory. We hypothesize that saturated fat-induced, low-grade muscle cell inflammation may trigger resident skeletal muscle macrophage polarization, possibly contributing to insulin resistance in vivo. PMID:23078640

Pillon, Nicolas J; Arane, Karen; Bilan, Philip J; Chiu, Tim T; Klip, Amira

2012-01-01

244

Immunomodulatory Effects of Triphala and its Individual Constituents: A Review  

PubMed Central

The role of plant extracts and Ayurvedic polyherbal preparations in treating various ailments has been acknowledged since time immemorial. Studies based on the effect of these extracts in treatment of different diseases have also been well documented. Indian medicinal literature also emphasizes the synergistic effect of polyherbal drugs in restoring and rejuvenating immune system. This review focuses on the immunomodulatory potential of the polyherbal preparation, Triphala and its three constituents, Terminalia bellerica, Terminalia chebula and Emblica officinalis. The role of Triphala and its extract has been emphasized in stimulating neutrophil function. Under stress condition such as noise, Triphala significantly prevents elevation of IL-4 levels as well as corrects decreased IL-2 and IFN-? levels. Under the condition of inflammatory stress its immunosuppressive activity is attributed to its inhibitory action on complement system, humoral immunity, cell mediated immunity and mitogen-induced T-lymphocyte proliferation. The aqueous and alcoholic extracts of the individual constituents reportedly enhance especially the macrophage activation due to their free radical scavenging activity and the ability to neutralize reactive oxygen species. This study thus concludes the use of Triphala and its three individual constituents as potential immunostimulants and/or immunosuppressants further suggests them to be a better alternative for allopathic immunomodulators.

Belapurkar, Pranoti; Goyal, Pragya; Tiwari-Barua, Preeti

2014-01-01

245

Effects of drying methods on physicochemical and immunomodulatory properties of polysaccharide-protein complexes from litchi pulp.  

PubMed

Dried litchi pulp has been used in traditional remedies in China for many years to treat various diseases, and the therapeutic activity has been, at least partly, attributed to the presence of bioactive polysaccharides. Polysaccharide-protein complexes from vacuum freeze-(VF), vacuum microwave-(VM) and heat pump (HP) dried litchi pulp, which were coded as LP-VF, LP-VM and LP-HP, were comparatively studied on the physicochemical and immunomodulatory properties. LP-HP had a predominance of galactose, while glucose was the major sugar component in LP-VF and LP-VM. Compared with LP-VF and LP-VM, LP-HP contained more aspartate and glutamic in binding protein. LP-HP also exhibited a stronger stimulatory effect on splenocyte proliferation at 200 ?g/mL and triggered higher NO, TNF-? and IL-6 secretion from RAW264.7 macrophages. Different drying methods caused the difference in physicochemical properties of polysaccharide-protein complexes from dried litchi pulp, which resulted in significantly different immunomodulatory activity. HP drying appears to be the best method for preparing litchi pulp to improve its immunomodulatory properties. PMID:25140451

Huang, Fei; Guo, Yajuan; Zhang, Ruifen; Yi, Yang; Deng, Yuanyuan; Su, Dongxiao; Zhang, Mingwei

2014-01-01

246

Signaling events during macrophage activation with Betula pendula roth pectic polysaccharides.  

PubMed

We studied the effect of two pectic polysaccharides PS-B1-AG and PS-B2-RG that were contained in total polysaccharides extracted from Betula pendula leaves on NO production by mouse macrophages and the contribution of signaling molecules to macrophage activation by the test substances. Unlike the total sample, pectins produced a NO-stimulating effect on macrophages. The effect of PS-B2-RG (10 ?g/ml) did not differ from the effect of LPS, while PS-B1-AG produced this effect only in a concentration of 20 ?g/ml, which was probably due to differences in the chemical structure of the test substances. The studied pectin polysaccharides activated transcription factor NF-?B, kinases p38 and PI3, and cAMP as a negative regulator. These results indicate that Betula pendula polysaccharides are promising substances for creation of immunomodulating drugs. PMID:24771428

Ligacheva, A A; Danilets, M G; Trofimova, E S; Belsky, Y P; Belska, N V; Zyuz'kov, G N; Zhdanov, V V; Ivanova, A N; Guriev, A M; Belousov, M V; Yusubov, M S; Dygai, A M

2014-02-01

247

Vessel-associated myogenic precursors control macrophage activation and clearance of apoptotic cells.  

PubMed

Swift and regulated clearance of apoptotic cells prevents the accumulation of cell remnants in injured tissues and contributes to the shift of macrophages towards alternatively activated reparatory cells that sustain wound healing. Environmental signals, most of which are unknown, in turn control the efficiency of the clearance of apoptotic cells and as such determine whether tissues eventually heal. In this study we show that vessel-associated stem cells (mesoangioblasts) specifically modulate the expression of genes involved in the clearance of apoptotic cells and in macrophage alternative activation, including those of scavenger receptors and of molecules that bridge dying cells and phagocytes. Mesoangioblasts, but not immortalized myoblasts or neural precursor cells, enhance CD163 membrane expression in vitro as assessed by flow cytometry, indicating that the effect is specific. Mesoangioblasts transplanted in acutely or chronically injured skeletal muscles determine the expansion of the population of CD163(+) infiltrating macrophages and increase the extent of CD163 expression. Conversely, macrophages challenged with mesoangioblasts engulf significantly better apoptotic cells in vitro. Collectively, the data reveal a feed-forward loop between macrophages and vessel-associated stem cells, which has implications for the skeletal muscle homeostatic response to sterile injury and for diseases in which homeostasis is jeopardized, including muscle dystrophies and inflammatory myopathies. PMID:24749786

Bosurgi, L; Brunelli, S; Rigamonti, E; Monno, A; Manfredi, A A; Rovere-Querini, P

2015-01-01

248

Rat Macrophage C-Type Lectin Is an Activating Receptor Expressed by Phagocytic Cells  

PubMed Central

Macrophage C-type lectin (MCL) is a membrane surface receptor encoded by the Antigen Presenting Lectin-like gene Complex (APLEC). We generated a mouse monoclonal antibody for the study of this receptor in the rat. We demonstrate that rat MCL is expressed on blood monocytes and neutrophils, as well as on several tissue macrophage populations, including alveolar and peritoneal cavity macrophages. We also demonstrate MCL expression on a subset of resident spleen macrophages. Immunohistochemistry analysis of the spleen showed staining specifically in the marginal zone and red pulp. Exposure to pro-inflammatory mediators or to yeast cell wall extract (zymosan) increased surface MCL expression on peritoneal macrophages. We characterized a rat myeloid cell line, RMW, which expresses high levels of MCL. We found that MCL co-immunoprecipitated with the activating adaptor protein Fc?RI? in these cells. Moreover, beads coated with anti-MCL antibody increased phagocytosis in the RMW cells. Together, these observations indicate that rat MCL is a receptor that activates phagocytosis in myeloid cells under inflammatory conditions. PMID:23468983

Lobato-Pascual, Ana; Saether, Per Christian; Dahle, Maria K.; Gaustad, Peter; Dissen, Erik; Fossum, Sigbjřrn; Daws, Michael R.

2013-01-01

249

Proteome bioprofiles distinguish between M1 priming and activation states in human macrophages  

PubMed Central

Macrophage activation is a dynamic process that results in diverse functional outcomes ranging from immunoregulation to inflammation. The proinflammatory, or M1, response is a complex, bimodal progression composed of a “prime,” classically through IFN-?, and “trigger,” such as LPS. To characterize the physiological response of M1 activation, a systems biology approach was applied to determine the intracellular proteome bioprofiles of IFN-?- and LPS-treated primary human macrophages. Our goal was to develop intracellular proteomic fingerprints to serve as novel correlates of macrophage priming and/or activation to augment the existing approaches of analyzing secreted cytokines and cell-surface protein expression. The majority of the proteome, ?78%, remained stable during activation, representing the core proteome. In contrast, three distinct patterns defined response proteomes: IFN-?-specific, LPS-specific, or IFN-?- and LPS-shared or M1-specific. Although steady-state expression levels of proteins involved in energy metabolism and immune response were increased during priming and triggering, changes in protein and fatty acid metabolism, signaling, and transport pathways were most apparent. Unique proteomic fingerprints distinguish among IFN-?-specific, LPS-specific, or M1-specific activation states and provide a clear molecular, archeological profile to infer recent history of cells, as well as correlates for chronic macrophage activation in health and disease. PMID:20007246

Brown, Joseph N.; Wallet, Mark A.; Krastins, Bryan; Sarracino, David; Goodenow, Maureen M.

2010-01-01

250

Macrophage activation with multi-porous beads prepared from partially deacetylated chitin.  

PubMed

The effect of multi-porous beads prepared from 80% deacetylated chitin on the activation of mouse peritoneal macrophages was examined. Deacetylated chitin bead (DAC-bead) preparations were shown to activate macrophages for tumoricidal activity depending on the increasing concentration of acetic acid used for the pretreatment of beads. The large DAC-bead was more susceptible to treatment with acetic acid than small DAC-bead, and showed more potent capacity for the activation of macrophages under the same pretreatment conditions with acetic acid. Deacetylated bead preparations, on the other hand, showed less activities. In addition, DAC-bead pretreated with acetic acid stimulated macrophages to produce interleukin 1. The possibilities of multi-porous beads as cancer chemotherapeutic-carrier were examined by the method of column chromatography and of in vitro antitumor experiment. Forty-four percent of adriamycin adsorbed on the surface of and in bead was released within the first 60 min. of elution, and then adriamycin was released more slowly in proportion to the elution time. Antitumor activity of adriamycin-adsorbed bead was less effective than that of free adriamycin if they were compared on the basis of total content of adriamycin. PMID:3491076

Nishimura, K; Nishimura, S; Seo, H; Nishi, N; Tokura, S; Azuma, I

1986-01-01

251

Nicotine Attenuates Activation of Tissue Resident Macrophages in the Mouse Stomach through the ?2 Nicotinic Acetylcholine Receptor  

PubMed Central

Background The cholinergic anti-inflammatory pathway is an endogenous mechanism by which the autonomic nervous system attenuates macrophage activation via nicotinic acetylcholine receptors (nAChR). This concept has however not been demonstrated at a cellular level in intact tissue. To this end, we have studied the effect of nicotine on the activation of resident macrophages in a mouse stomach preparation by means of calcium imaging. Methods Calcium transients ([Ca2+]i) in resident macrophages were recorded in a mouse stomach preparation containing myenteric plexus and muscle layers by Fluo-4. Activation of macrophages was achieved by focal puff administration of ATP. The effects of nicotine on activation of macrophages were evaluated and the nAChR involved was pharmacologically characterized. The proximity of cholinergic nerves to macrophages was quantified by confocal microscopy. Expression of ?2 and ?7 nAChR was evaluated by ?2 immunohistochemistry and fluorophore-tagged ?-bungarotoxin. Results In 83% of macrophages cholinergic varicose nerve fibers were detected at distances <900nm. The ATP induced [Ca2+]i increase was significantly inhibited in 65% or 55% of macrophages by 100µM or 10µM nicotine, respectively. This inhibitory effect was reversed by the ?2 nAChR preferring antagonist dihydro-?-eryhtroidine but not by hexamethonium (non-selective nAChR-antagonist), mecamylamine (?3?4 nAChR-preferring antagonist), ?-bungarotoxin or methyllycaconitine (both ?7 nAChR-preferring antagonist). Macrophages in the stomach express ?2 but not ?7 nAChR at protein level, while those in the intestine express both receptor subunits. Conclusion This study is the first in situ demonstration of an inhibition of macrophage activation by nicotine suggesting functional signaling between cholinergic neurons and macrophages in the stomach. The data suggest that the ?2 subunit of the nAChR is critically involved in the nicotine-induced inhibition of these resident macrophages. PMID:24223920

Nemethova, Andrea; Michel, Klaus; Gomez-Pinilla, Pedro J.; Boeckxstaens, Guy E.; Schemann, Michael

2013-01-01

252

Human Immunodeficiency Virus Type 1 Infection Inhibits Granulocyte-Macrophage Colony-Stimulating Factor-Induced Activation of STAT5A in Human Monocyte-Derived Macrophages  

PubMed Central

Human immunodeficiency virus type 1 (HIV-1) infects cells of the monocyte/macrophage lineage. While infection of macrophages by HIV-1 is generally not cytopathic, it does impair macrophage function. In this study, we examined the effect of HIV-1 infection on intracellular signaling in human monocyte-derived macrophages (MDM) stimulated with the growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF is an important growth factor for cells of both the macrophage and granulocyte lineages and enhances effector functions of these cells via the heterodimeric GM-CSF receptor (GM-CSFR). A major pathway which mediates the effects of GM-CSF on macrophages involves activation of the latent transcription factor STAT5A via a Janus kinase 2 (JAK2)-dependent pathway. We demonstrate that GM-CSF-induced activation of STAT5A is inhibited in MDM after infection in vitro with the laboratory-adapted R5 strain of HIV-1, HIV-1Ba-L, but not after infection with adenovirus. HIV-1 infection of MDM did not decrease the STAT5A or JAK2 mRNA level or STAT5A protein level or result in increased constitutive activation of STAT5A. Surface expression of either the ?-chain or common ?c-chain of GM-CSFR was also unaffected. We conclude that HIV-1 inhibits GM-CSF activation of STAT5A without affecting expression of the known components of the signaling pathway. These data provide further evidence of disruption of cellular signaling pathways after HIV-1 infection, which may contribute to immune dysfunction and HIV-1 pathogenesis. PMID:14610185

Warby, Tammra J.; Crowe, Suzanne M.; Jaworowski, Anthony

2003-01-01

253

Adiponectin suppresses angiotensin II-induced inflammation and cardiac fibrosis through activation of macrophage autophagy.  

PubMed

Previous studies have indicated that adiponectin (APN) protects against cardiac remodeling, but the underlying mechanism remains unclear. The present study aimed to elucidate how APN regulates inflammatory responses and cardiac fibrosis in response to angiotensin II (Ang II). Male APN knockout (APN KO) mice and wild-type (WT) C57BL/6 littermates were sc infused with Ang II at 750 ng/kg per minute. Seven days after Ang II infusion, both APN KO and WT mice developed equally high blood pressure levels. However, APN KO mice developed more severe cardiac fibrosis and inflammation compared with WT mice. This finding was demonstrated by the up-regulation of collagen I, ?-smooth muscle actin, IL-1?, and TNF-? and increased macrophage infiltration in APN KO mice. Moreover, there were substantially fewer microtubule-associated protein 1 light chain 3-positive autophagosomes in macrophages in the hearts of Ang II-infused APN KO mice. Additional in vitro studies also revealed that globular APN treatment induced autophagy, inhibited Ang II-induced nuclear factor-?B activity, and enhanced the expression of antiinflammatory cytokines, including IL-10, macrophage galactose N-acetyl-galactosamine specific lectin 2, found in inflammatory zone 1, and type-1 arginase in macrophages. In contrast, APN-induced autophagy and antiinflammatory cytokine expression was diminished in Atg5-knockdown macrophages or by Compound C, an inhibitor of adenosine 5'-monophosphate-activated protein kinase. Our study indicates that APN activates macrophage autophagy through the adenosine 5'-monophosphate-activated protein kinase pathway and suppresses Ang II-induced inflammatory responses, thereby reducing the extent of cardiac fibrosis. PMID:24684303

Qi, Guan-Ming; Jia, Li-Xin; Li, Yu-Lin; Li, Hui-Hua; Du, Jie

2014-06-01

254

Legumain expression, activity and secretion are increased during monocyte-to-macrophage differentiation and inhibited by atorvastatin.  

PubMed

Abstract Macrophages express several lysosomal cysteine proteases such as cathepsins and legumain. In this study, we assessed the expression, activity and secretion of legumain in cellular models of monocytes/macrophages. Macrophages were derived from M-CSF- or GM-CSF/IFN?-stimulated human primary monocytes (M2 and M1, respectively), PMA-treated human THP-1 cells, or murine RAW264.7 macrophages. In both primary monocytes and THP-1 cells, monocyte-to-macrophage differentiation caused highly increased cellular expression and activity of legumain. Also, secretion of legumain from macrophages, but not from monocytes, was observed. Notably, M2 macrophages expressed significantly higher levels of active legumain than M1 macrophages, which are not previously reported. Legumain mRNA has been shown to be down-regulated in monocytes isolated from patients treated with the HMG-CoA reductase inhibitor atorvastatin. Interestingly, in our study, the active legumain produced by M2 macrophages was found to be inhibited by atorvastatin, which was reflected in aberrant cellular expression and processing. PMID:25205715

Solberg, Rigmor; Smith, Robert; Almlöf, Maria; Tewolde, Eyassu; Nilsen, Hilde; Johansen, Harald Thidemann

2015-01-01

255

Complement activation by the alternative pathway and macrophage enzyme secretion in the pathogenesis of chronic inflammation.  

PubMed Central

A number of stimuli known to induce acid hydrolase secretion from cultured macrophages were examined for their ability to activate C3 via the alternative pathway of the complement system. Loss of haemolytically active C3 was checked in normal and C4-deficient guinea-pig serum. For comparison the interactions of cultured macrophages with other agents well known as potent activators of the alternative pathway of the complement system have been investigated. As judged by their activity in these assays, group A streptococcal cell walls, different carrageenan preparations, dental plaque and Actinomyces viscosus were all capable of initiating the alternative pathway but differed with respect to their potency and their ability to inhibit C3 turnover at high concentrations. Zymosan, some carrageenans, polyanethol sulphonate, and Corynebacterium parvum all induce the release of hydrolytic enzymes from macrophages in culture, even in the absence of serum in the medium. The release is time- and dose-dependent and is not associated with loss of the cytoplasmic enzyme lactate dehydrogenase or any other sign of cell death. The parallelism between the capacity of several agents to activate the complement system via the alternative pathway and to induce inflammatory responses in vivo and selective lysosoma enzyme secretion from cultures of macrophages is discussed. PMID:328387

Schorlemmer, H U; Bitter-Suermann, D; Allison, A C

1977-01-01

256

Biodegradable chitosan particles induce chemokine release and negligible arginase-1 activity compared to IL-4 in murine bone marrow-derived macrophages  

E-print Network

Biodegradable chitosan particles induce chemokine release and negligible arginase-1 activity January 2011 Available online xxxx Keywords: Chitosan Bone marrow-derived macrophages Macrophage implicated in the therapeutic activity of biodegradable chitosan on wound healing, however, the mechanisms

Buschmann, Michael

257

Paeoniflorin regulates macrophage activation in dimethylnitrosamine-induced liver fibrosis in rats  

PubMed Central

Background Macrophages in other organs (e.g. kidneys, lungs, and spleen, et. al) have rarely been reported in the development of liver fibrosis. Therefore, it is important to investigate macrophage activation in the main organs in liver fibrosis. We investigated the potential antifibrogenic effects of paeoniflorin (PF) in a dimethylnitrosamine (DMN)-induced rat model with special focus on inhibiting macrophage activation in the main organs. Methods Rat hepatic fibrosis was induced by treatment with DMN three times weekly over a 4-week period. DMN rats were treated with water, PF, or gadolinium chloride (GdCl3) from the beginning of the 3rd week. The expression of CD68, marker of macrophage, was investigated using immunohistochemical, real-time PCR, and western blot analysis. Results Hepatic hydroxyproline content markedly decreased and histopathology improved in the DMN-PF rats. Expression of desmin and collagen 1 decreased notably in DMN-PF liver. CD68 expression in the liver, spleen and kidney increased markedly after 2 weeks but decreased in DMN-water rats. PF and GdCl3 decreased CD68 expression in the liver and spleen and there was no effect on kidney. CD68 expression in the lung increased gradually during the course of DMN-induced liver fibrosis, and PF inhibited CD68 expression in the lung significantly while GdCl3 increased CD68 markedly. Expression of tumor necrosis factor (TNF-?) was decreased significantly by GdCl3 in the liver, as revealed by real-time PCR analysis. However, GdCl3 could not decrease TNF-? level in the serum by enzyme linked immunosorbent assay (ELISA). Conclusions Macrophage activation was disrupted in the liver, spleen, lung and kidney during development of DMN-induced liver fibrosis. PF administration attenuated DMN-induced liver fibrosis at least in part by regulating macrophage disruption in the main organs. PMID:23237422

2012-01-01

258

Replication of Yersinia pestis in interferon ?-activated macrophages requires ripA, a gene encoded in the pigmentation locus  

PubMed Central

Yersinia pestis is a facultative intracellular bacterial pathogen that can replicate in macrophages. Little is known about the mechanism by which Y. pestis replicates in macrophages, and macrophage defense mechanisms important for limiting intracellular survival of Y. pestis have not been characterized. In this work, we investigated the ability of Y. pestis to replicate in primary murine macrophages that were activated with IFN-?. Y. pestis was able to replicate in macrophages that were activated with IFN-? after infection (postactivated). A region of chromosomal DNA known as the pigmentation (pgm) locus was required for replication in postactivated macrophages, and this replication was associated with reduced nitric oxide (NO) levels but not with reduced inducible NO synthase (iNOS) expression. Y. pestis ?pgm replicated in iNOS-/- macrophages that were postactivated with IFN-?, suggesting that killing of ?pgm Y. pestis is NO-dependent. A specific genetic locus within pgm, which shares similarity to a pathogenicity island in Salmonella, was shown to be required for replication of Y. pestis and restriction of NO levels in postactivated macrophages. These data demonstrate that intracellular Y. pestis can evade killing by macrophages that are exposed to IFN-? and identify a potential virulence gene encoded in the pgm locus that is required for this activity. PMID:16120681

Pujol, Céline; Grabenstein, Jens P.; Perry, Robert D.; Bliska, James B.

2005-01-01

259

High glucose activates Raw264.7 macrophages through RhoA kinase-mediated signaling pathway.  

PubMed

Hyperglycemia has been shown to accelerate atherogenesis, an inflammation process resulting from macrophage activation. Although high glucose (HG) was previously demonstrated to accentuate ROCK activity in macrophages and enhance their activation in vitro, the role of ROCK signaling in HG-mediated macrophage activation remains unclear. This study aimed to elucidate potential signal transduction pathways of HG-mediated ROCK upregulation and macrophage activation, including c-Jun or NF-?B pathways. A macrophage cell line, RAW264.7, was used to investigate the atherogenic effects of HG on RhoA/ROCK activity and macrophage functions. Exposure to HG significantly induced RhoA membrane translocation, RhoA-kinase activity, and phosphorylation of myosin-binding subunit, a RhoA-kinase substrate. Macrophage behaviors, including cell proliferation, adhesion, migration, and TNF-? de novo synthesis, were also increased by HG exposure. However, pharmacological ROCK inhibition by hydroxyfasudil attenuated the HG-enhanced adhesion and TNF-? production. Nuclear translocation of c-Jun and transcription factor NF-?B was simultaneously noted after HG stimulation. Pharmacological ROCK inhibition by hydroxyfasudil and siRNA-mediated ROCK1 or ROCK2 gene silencing confirmed the ROCK-dependent JNK and ERK phosphorylation, but not NF-?B activation in macrophages. In addition, both interventions effectively ameliorated the HG-mediated macrophage activation under the conditions mimicking diabetes. These findings suggest that hyperglycemia activates macrophages mainly through ROCK/JNK and ROCK/ERK pathways, which results in a more pro-inflammatory phenotype and eventually contributes to atherogenesis. In conclusion, ROCK inhibition might become a novel therapeutic strategy in atherosclerosis treatment and prevention in diabetic patients. PMID:25446262

Cheng, Cheng-I; Chen, Po-Han; Lin, Yu-Chun; Kao, Ying-Hsien

2015-02-01

260

Polymeric nanoparticle system to target activated microglia/macrophages in spinal cord injury.  

PubMed

The possibility to control the fate of the cells responsible for secondary mechanisms following spinal cord injury (SCI) is one of the most relevant challenges to reduce the post traumatic degeneration of the spinal cord. In particular, microglia/macrophages associated inflammation appears to be a self-propelling mechanism which leads to progressive neurodegeneration and development of persisting pain state. In this study we analyzed the interactions between poly(methyl methacrylate) nanoparticles (PMMA-NPs) and microglia/macrophages in vitro and in vivo, characterizing the features that influence their internalization and ability to deliver drugs. The uptake mechanisms of PMMA-NPs were in-depth investigated, together with their possible toxic effects on microglia/macrophages. In addition, the possibility to deliver a mimetic drug within microglia/macrophages was characterized in vitro and in vivo. Drug-loaded polymeric NPs resulted to be a promising tool for the selective administration of pharmacological compounds in activated microglia/macrophages and thus potentially able to counteract relevant secondary inflammatory events in SCI. PMID:24225226

Papa, Simonetta; Ferrari, Raffaele; De Paola, Massimiliano; Rossi, Filippo; Mariani, Alessandro; Caron, Ilaria; Sammali, Eliana; Peviani, Marco; Dell'Oro, Valentina; Colombo, Claudio; Morbidelli, Massimo; Forloni, Gianluigi; Perale, Giuseppe; Moscatelli, Davide; Veglianese, Pietro

2014-01-28

261

Activity and penetration of antituberculosis drugs in mouse peritoneal macrophages infected with Mycobacterium microti OV254.  

PubMed Central

The activities of some commonly used antituberculosis drugs were investigated within unstimulated peritoneal macrophages and in 7H-9 medium without Tween 80 using Mycobacterium microti OV254 as the target organism. In macrophage cultures, serial concentrations of isoniazid, rifampin, pyrazinamide, or streptomycin were added after a 2.5-h phagocytosis period. Viable counts were carried out at daily intervals for 5 or 6 days. The patterns of susceptibility to the four drugs were similar for M. microti and Mycobacterium tuberculosis. To ensure comparability with daily drug replacements in the macrophage experiments, the period of exposure to drugs in 7H-9 medium was kept to only 3 days. With in vitro culture at pH 6.4, drug penetration, measured as the ratio of MICs in macrophages to MICs in 7H-9 medium, was approximately 5 for isoniazid, 5 for rifampin, and 10 for streptomycin. With in vitro culture at pH 7.4, drug penetration was 100 for streptomycin, and at pH 5.6 it was 1 for pyrazinamide. Pyrazinamide was only bacteriostatic in macrophages but weakly bactericidal during the first day of exposure in vitro. PMID:2802553

Dhillon, J; Mitchison, D A

1989-01-01

262

Class A scavenger receptor activation inhibits endoplasmic reticulum stress-induced autophagy in macrophage.  

PubMed

Macrophage death in advanced atherosclerosis promotes plaque necrosis and destabilization. Involvement of autophagy in bulk degradation of cellular components has been recognized recently as an important mechanism for cell survival under endoplasmic reticulum (ER) stress. We previously found that the engagement of class A scavenger receptor (SR-A) triggered JNK-dependent apoptosis in ER-stressed macrophages. However, pro-apoptotic mechanisms mediated by SR-A are not fully understood. Therefore, we sought to see if SR-A mediated apoptosis was associated with autophagy in macrophages. Here, we showed that fucoidan inhibited microtubule-associated protein light chain 3-phospholipid conjugates (LC3-II) formation as well as the number of autophagosomes under ER stress. The inhibition of LC3-II formation was paralleled by the activation of the mTOR pathway, and the inhibition of mTOR allowed LC3-II induction in macrophages treated with thapsigargin plus fucoidan. Furthermore, apoptosis induced by fucoidan was prevented under ER stress by the mTOR inhibitor. We propose that fucoidan, a SR-A agonist, may contribute to macrophage apoptosis during ER stress by inhibiting autophagy. PMID:25013404

Huang, Hanpeng; Li, Xiaoyu; Zhuang, Yan; Li, Nan; Zhu, Xudong; Hu, Jin; Ben, Jingjing; Yang, Qing; Bai, Hui; Chen, Qi

2014-05-01

263

Escherichia coli and Candida albicans Induced Macrophage Extracellular Trap-Like Structures with Limited Microbicidal Activity  

PubMed Central

The formation of extracellular traps (ETs) has recently been recognized as a novel defense mechanism in several types of innate immune cells. It has been suggested that these structures are toxic to microbes and contribute significantly to killing several pathogens. However, the role of ETs formed by macrophages (METs) in defense against microbes remains little known. In this study, we demonstrated that a subset of murine J774A.1 macrophage cell line (8% to 17%) and peritoneal macrophages (8.5% to 15%) form METs-like structures (METs-LS) in response to Escherichia coli and Candida albicans challenge. We found only a portion of murine METs-LS, which are released by dying macrophages, showed detectable killing effects on trapped E. coli but not C. albicans. Fluorescence and scanning electron microscopy analyses revealed that, in vitro, both microorganisms were entrapped in J774A.1 METs-LS composed of DNA and microbicidal proteins such as histone, myeloperoxidase and lysozyme. DNA components of both nucleus and mitochondrion origins were detectable in these structures. Additionally, METs-LS formation occurred independently of ROS produced by NADPH oxidase, and this process did not result in cell lysis. In summary, our results emphasized that microbes induced METs-LS in murine macrophage cells and that the microbicidal activity of these METs-LS differs greatly. We propose the function of METs-LS is to contain invading microbes at the infection site, thereby preventing the systemic diffusion of them, rather than significantly killing them. PMID:24587206

Liao, Chengshui; Liu, Xiaolei; Du, Jing; Shi, Haining; Wang, Xuelin; Bai, Xue; Peng, Peng; Yu, Lu; Wang, Feng; Zhao, Ying; Liu, Mingyuan

2014-01-01

264

Macrophage activation state determines the response to rhinovirus infection in a mouse model of allergic asthma  

PubMed Central

Background The mechanisms by which viruses cause asthma exacerbations are not precisely known. Previously, we showed that, in ovalbumin (OVA)-sensitized and -challenged mice with allergic airway inflammation, rhinovirus (RV) infection increases type 2 cytokine production from alternatively-activated (M2) airway macrophages, enhancing eosinophilic inflammation and airways hyperresponsiveness. In this paper, we tested the hypothesis that IL-4 signaling determines the state of macrophage activation and pattern of RV-induced exacerbation in mice with allergic airways disease. Methods Eight week-old wild type or IL-4 receptor knockout (IL-4R KO) mice were sensitized and challenged with OVA and inoculated with RV1B or sham HeLa cell lysate. Results In contrast to OVA-treated wild-type mice with both neutrophilic and eosinophilic airway inflammation, OVA-treated IL-4R KO mice showed increased neutrophilic inflammation with few eosinophils in the airways. Like wild-type mice, IL-4R KO mice showed OVA-induced airway hyperreactivity which was further exacerbated by RV. There was a shift in lung cytokines from a type 2-predominant response to a type 1 response, including production of IL-12p40 and TNF-?. IL-17A was also increased. RV infection of OVA-treated IL-4R KO mice further increased neutrophilic inflammation. Bronchoalveolar macrophages showed an M1 polarization pattern and ex vivo RV infection increased macrophage production of TNF-?, IFN-? and IL-12p40. Finally, lung cells from OVA-treated IL-4R KO mice showed reduced CD206+ CD301+ M2 macrophages, decreased IL-13 and increased TNF-? and IL-17A production by F4/80+, CD11b+?macrophages. Conclusions OVA-treated IL-4R KO mice show neutrophilic airway inflammation constituting a model of allergic, type 1 cytokine-driven neutrophilic asthma. In the absence of IL-4/IL-13 signaling, RV infection of OVA-treated mice increased type 1 cytokine and IL-17A production from conventionally-activated macrophages, augmenting neutrophilic rather than eosinophilic inflammation. In mice with allergic airways inflammation, IL-4R signaling determines macrophage activation state and the response to subsequent RV infection. PMID:24907978

2014-01-01

265

Glucagon-like peptide-1 (GLP-1) induces M2 polarization of human macrophages via STAT3 activation.  

PubMed

It is known that glucagon-like peptide-1 (GLP-1) is a hormone secreted postprandially from the L-cells of the small intestine and regulates glucose homeostasis. GLP-1 is now used for the treatment of diabetes because of its beneficial role against insulin resistance. The GLP-1 receptor (GLP-1R) is expressed on many cell types, including macrophages, and GLP-1 suppresses the development of atherosclerosis by inhibiting macrophage function. However, there have so far been few studies that have investigated the significance of GLP-1/GLP-1R signaling in macrophage activation. In the present study, we examined the effect of GLP-1 and exenatide, a GLP-1R agonist, on human monocyte-derived macrophage (HMDM) activation. We found that GLP-1 induced signal transducer and activator of transcription 3 (STAT3) activation. Silencing of GLP-1R suppressed the GLP-1-induced STAT3 activation. In addition, alternatively activated (M2) macrophage-related molecules, such as IL-10, CD163, and CD204 in HMDM, were significantly upregulated by GLP-1. Furthermore, the co-culture of 3T3-L1 adipocytes with GLP-1-treated RAW 264.7 macrophages increased the secretion of adiponectin compared to co-culture of the 3T3-L1 adipocytes with untreated RAW 264.7 macrophages. Our results demonstrate that GLP-1 induces macrophage polarization toward the M2 phenotype, which may contribute to the protective effects of GLP-1 against diabetes and cardiovascular diseases. PMID:22842565

Shiraishi, Daisuke; Fujiwara, Yukio; Komohara, Yoshihiro; Mizuta, Hiroshi; Takeya, Motohiro

2012-08-24

266

Model-driven multi-omic data analysis elucidates metabolic immunomodulators of macrophage activation  

SciTech Connect

Macrophages are central players in the immune response, manifesting divergent phenotypes to control inflammation and innate immunity through the release of cytokines and other regulatory factor-dependent signaling pathways. In recent years, the focus on metabolism has been reemphasized as critical signaling and regulatory pathways of human pathophysiology, ranging from cancer to aging, often converge on metabolic responses. Here, we used genome-scale modeling and multi-omics (transcriptomics, proteomics, and metabolomics) analysis to assess metabolic features critical for macrophage functions. We constructed a genome-scale metabolic network for the RAW 264.7 cell line to determine metabolic modulators of macrophage activation. Metabolites well-known to be associated with immunoactivation (e.g., glucose and arginine) and immunosuppression (e.g., tryptophan and vitamin D3) were amongst the most critical effectors. Intracellular metabolic mechanisms linked to critical suppressive effectors were then assessed, identifying a suppressive role for de novo nucleotide synthesis. Finally, the underlying metabolic mechanisms of macrophage activation are identified by analyzing multi-omic data obtained from LPS-stimulated RAW cells in the context of our flux-based predictions. Our study demonstrates metabolism's role in regulating activation may be greater than previously anticipated and elucidates underlying metabolic connections between activation and metabolic effectors.

Bordbar, Aarash; Mo, Monica L.; Nakayasu, Ernesto S.; Rutledge, Alexandra C.; Kim, Young-Mo; Metz, Thomas O.; Jones, Marcus B.; Frank, Bryan C.; Smith, Richard D.; Peterson, Scott N.; Hyduke, Daniel R.; Adkins, Joshua N.; Palsson, Bernhard O.

2012-06-26

267

Phagocytosis by macrophages and endothelial cells inhibits procoagulant and fibrinolytic activity of acute promyelocytic leukemia cells.  

PubMed

The coagulopathy of acute promyelocytic leukemia (APL) is mainly related to procoagulant substances and fibrinolytic activators of APL blasts, but the fate of these leukemic cells is unknown. The aim of this study was to investigate the removal of APL blasts by macrophages and endothelial cells in vitro and consequent procoagulant and fibrinolytic activity of APL cells. We found that human umbilical vein endothelial cells as well as THP-1 and monocyte-derived macrophages bound, engulfed, and subsequently degraded immortalized APL cell line NB4 and primary APL cells. Lactadherin promoted phagocytosis of APL cells in a time-dependent fashion. Furthermore, factor Xa and prothrombinase activity of phosphatidylserine-exposed target APL cells was time-dependently decreased after incubation with phagocytes (THP-1-derived macrophages or HUVECs). Thrombin production on target APL cells was reduced by 40%-45% after 2 hours of coincubation with phagocytes and 80% by a combination of lactadherin and phagocytes. Moreover, plasmin generation of target APL cells was inhibited 30% by 2 hours of phagocytosis and ? 50% by lactadherin-mediated engulfment. These results suggest that engulfment by macrophages and endothelial cells reduce procoagulant and fibrinolytic activity of APL blasts. Lactadherin and phagocytosis could cooperatively ameliorate the clotting disorders in APL. PMID:22138513

Xie, Rui; Gao, Chunyan; Li, Wen; Zhu, Jiuxin; Novakovic, Valerie; Wang, Jing; Ma, Ruishuang; Zhou, Jin; Gilbert, Gary E; Shi, Jialan

2012-03-01

268

ARE MACROPHAGES ACTIVATED AND INDUCE PULMONARY INJURY BY INTRACELLULARLY BIOAVAILABLE IRON?  

EPA Science Inventory

ARE MACROPHAGES ACTIVATED AND INDUCE PULMONARY INJURY BY INTRACELLULARLY BIOAVAILABLE IRON? UP Kodavanti1, MCJ Schladweiler1, S Becker2, DL Costa1, P Mayer3, A Ziesenis3, WG Kreyling3, 1ETD, 2HSDivision, NHEERL, USEPA, Research Triangle Park, NC, USA, and 3GSF, Inhalation Biology...

269

Delayed presence of alternatively activated macrophages during a Francisella tularensis infection.  

PubMed

Francisella tularensis is an intracellular bacterium that has the ability to multiply within the macrophage. The phenotype of a macrophage can determine whether the infection is cleared or the host succumbs to disease. Previously published data has suggested that F. tularensis LVS actively induces the alternative phenotype as a survival mechanism. In these studies we demonstrate that this is not the case for the more virulent strain of F. tularensis SCHU-S4. During an intranasal mouse model of infection, immuno-histochemistry identified that iNOS positive ("classical") macrophages are present at 72 h post-infection and remain high (supported by CCL-5 release) in numbers. In contrast, arginase/FIZZ-1 positive ("alternative") cells appear later and in low numbers during the development of the disease tularemia. PMID:25284816

D'Elia, Riccardo V; Laws, Thomas R; Núńez, Alejandro; Taylor, Christopher; Clark, Graeme C

2015-01-01

270

Antitumor activity of the Korean mistletoe lectin is attributed to activation of macrophages and NK cells.  

PubMed

Inhibitory effect of the lectins (KML-C) isolated from Korean mistletoe (KM; Viscum album coloratum) on tumor metastases produced by murine tumor cells (B16-BL6 melanoma, colon 26-M3.1 carcinoma and L5178Y-ML25 lymphoma cells) was investigated in syngeneic mice. An intravenous (i.v.) administration of KML-C (20-50 ng/mouse) 2 days before tumor inoculation significantly inhibited lung metastases of both B16-BL6 and colon 26-M3.1 cells. The prophylactic effect of 50 ng/mouse of KML-C on lung metastasis was almost the same with that of 100 microg/mouse of KM. Treatment with KML-C 1 day after tumor inoculation induced a significant inhibition of not only the experimental lung metastasis induced by B16-BL6 and colon 26-M3.1 cells but also the liver and spleen metastasis of L5178Y-ML25 cells. Furthermore, multiple administration of KML-C given at 3 day-intervals after tumor inoculation led to a significant reduction of lung metastasis and suppression of the growth of B16-BL6 melanoma cells in a spontaneous metastasis model. In an assay for natural killer (NK) cell activity, i.v. administration of KML-C (50 ng/mouse) significantly augmented NK cytotoxicity against Yac-1 tumor cells 2 days after KML-C treatment. In addition, treatment with KML-C (50 ng/mouse) induced tumoricidal activity of peritoneal macrophages against B16-BL6 and 3LL cells. These results suggest that KML-C has an immunomodulating activity to enhance the host defense system against tumors, and that its prophylactic and therapeutic effect on tumor metastasis is associated with the activation of NK cells and macrophages. PMID:14609136

Yoon, Taek Joon; Yoo, Yung Choon; Kang, Tae Bong; Song, Seong Kyu; Lee, Kyung Bok; Her, Erk; Song, Kyung Sik; Kim, Jong Bae

2003-10-01

271

Involvement of absent in melanoma 2 in inflammasome activation in macrophages infected with Listeria monocytogenes.  

PubMed

Listeria monocytogenes invades the cytoplasm of macrophages and induces the activation of caspase-1 and the subsequent maturation of IL-1beta and IL-18. Although apoptosis-associated speck-like protein containing a caspase-activating and recruitment domain (ASC), an adaptor protein of nucleotide-binding oligomerization domain (Nod)-like receptors, has been shown to play an essential role in inducing this cellular response to L. monocytogenes, the mechanism has not been fully elucidated. In this study, we demonstrate the role of absent in melanoma 2 (AIM2), a recently described receptor of cytosolic DNA, in the activation of caspase-1 upon infection with L. monocytogenes. Secretion of IL-1beta and IL-18 from Nod-like receptor family, pyrin domain containing 3 (NLRP3) and Nod-like receptor family, caspase-activating and recruitment domain containing 4 (NLRC4) knockout macrophages in response to L. monocytogenes was only slightly decreased compared with the levels secreted from wild-type macrophages, whereas secretion from ASC knockout macrophages was completely impaired, suggesting that receptors other than NLRP3 and NLRC4 also take part in inflammasome activation in an ASC-dependent manner. To identify such receptors, the abilities of several receptor candidates (NLRP2, NLRP6, NLRP12, and AIM2) to induce the secretion of IL-1beta in response to L. monocytogenes were compared using the inflammasome system reconstructed in HEK293 cells. Among these receptor candidates, AIM2 conferred the highest responsiveness to the bacterium on HEK293 cells. Knockdown of AIM2 significantly decreased the secretion of IL-1beta and IL-18 from L. monocytogenes-infected macrophages. These results suggest that AIM2, in cooperation with NLRP3 and NLRC4, plays an important role in the activation of caspase-1 during L. monocytogenes infection. PMID:20566831

Tsuchiya, Kohsuke; Hara, Hideki; Kawamura, Ikuo; Nomura, Takamasa; Yamamoto, Takeshi; Daim, Sylvia; Dewamitta, Sita R; Shen, Yanna; Fang, Rendong; Mitsuyama, Masao

2010-07-15

272

GLP-1 agonists inhibit ox-LDL uptake in macrophages by activating protein kinase A.  

PubMed

Oxidized low-density lipoprotein (ox-LDL) uptake by monocytes/macrophages plays a pivotal role in atherogenesis. This study was designed to examine the effect of glucagon-like peptide-1 (GLP-1) agonists on ox-LDL uptake in macrophages. Human primary monocytes/macrophages were incubated with native GLP-1 (nGLP-1) or GLP-1 agonist liraglutide to evaluate their effect on ox-LDL uptake and the expression of scavenger receptors (SRs), such as SR-A, CD36, and lectin-like ox-LDL SR-1, in this process. Our study showed a decrease in ox-LDL uptake and CD36 expression in macrophages treated with nGLP-1 or liraglutide. However, nGLP-1 and liraglutide did not affect the expression of other SRs SR-A and lectin-like ox-LDL SR-1. Simultaneously, there was an increase in the expression of activated protein kinase A (PKA). To examine the role of PKA in the effects of nGLP-1 or liraglutide, we treated macrophages with PK inhibitor (6-22) amide, a PKA inhibitor, followed by treatment with nGLP-1 or liraglutide. Inhibition of PKA activation markedly reversed the effect of nGLP-1 or liraglutide on ox-LDL uptake and enhanced the expression of CD36. Our results suggest that GLP-1 agonism inhibits ox-LDL uptake through PKA/CD36 pathway in macrophages. This study provides a novel insight in the mechanism of foam cell formation and the role by GLP-1 agonists therein. PMID:24705175

Dai, Yao; Dai, Dongsheng; Wang, Xianwei; Ding, Zufeng; Li, Chunlin; Mehta, Jawahar L

2014-07-01

273

TLR9 and TLR7/8 activation induces formation of keratic precipitates and giant macrophages in the mouse cornea.  

PubMed

Macrophage adherence to the inner corneal surface and formation of MGCs in the stroma are common signs of chronic inflammation following corneal infection. To determine whether macrophage adherence (known clinically as KPs) and giant cell formation were specific to innate immune activation via particular TLR ligands, macrophage activation was examined in a murine model of TLR-mediated corneal inflammation. The corneal epithelium was debrided and highly purified TLR ligands were topically applied once to the cornea of TLR7(-/-), TLR9(-/-), Cx3cr1(gfp/+), CD11c(eYFP), and IL-4(-/-) mice. At 1 week post-treatment macrophage activation and phenotype was evaluated in the cornea. Treatment with TLR2, TLR3, TLR4, and TLR5 ligands caused an increase in the number of activated stromal macrophages in the central cornea at 1 week post-treatment. However, treatment with TLR9 ligand CpG-ODN and the TLR7/8 ligand R848/Resiquimod led to an accumulation of macrophages on the corneal endothelium and formation of multinucleated giant macrophages in the corneal stroma. We suggest that giant cell formation, which is a characteristic feature of granuloma formation in many tissues, may be a unique feature of TLR9- and TLR7/8-mediated macrophage activation. PMID:25416814

Chinnery, Holly R; Leong, Cheng Mee; Chen, Weisan; Forrester, John V; McMenamin, Paul G

2015-01-01

274

Mechanism of macrophage activation induced by polysaccharide from Cordyceps militaris culture broth.  

PubMed

Mushroom-derived polysaccharides have been shown to stimulate immune responses. Our previous report showed that the novel polysaccharide PLCM isolated from the culture broth of Cordyceps militaris could induce nitric oxide production in the murine macrophage-like cell line RAW264.7. In this study, we show that PLCM enhances immunostimulatory activities such as the release of toxic molecules (nitric oxide and reactive oxygen species), secretion of the cytokine tumor necrosis factor (TNF)-?, and phagocytic uptake in RAW264.7 macrophages. In addition, all the specific inhibitors against the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-?B) (SN50, BAY11-7082, PD98059, SP600125 and SB203580) markedly suppressed the nitric oxide production and phagocytic uptake induced by PLCM. Moreover, antibodies specific to the extracellular domain of Toll-like receptor-2, Toll-like receptor-4 or the macrophage receptor Dectin-1 significantly attenuated PLCM-induced secretion of TNF-?. Our results indicate that the C. militaris polysaccharide activates macrophages through the MAPKs and NF-?B signaling pathways via Toll-like receptor 2, Toll-like receptor 4, and Dectin-1. PMID:25662684

Lee, Jong Seok; Kwon, Duck Soo; Lee, Ki Rim; Park, Jun Myoung; Ha, Suk-Jin; Hong, Eock Kee

2015-04-20

275

Modulation of Macrophage Activities in Proliferation, Lysosome, and Phagosome by the Nonspecific Immunostimulator, Mica  

PubMed Central

It was reported that the aluminosilicate material mica activated macrophages and showed its immunostimulating effects. However, the mechanisms by which it exerts these effects are unclear. To address this, we evaluated the effects of mica fine particles (MFP, 804.1 ± 0.02 nm) on the murine macrophage cell line, RAW 264.7. Specifically, RAW 264.7 cells were treated with 100 and 500 ?g/mL MFP and their proliferative response was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Changes in global gene expression upon MFP treatment for 12 and 48 h were also determined using microarrays. Following the MFP treatment, RAW 264.7 cells showed a low level of proliferation compared to nontreated cells (p < 0.01). There was a change in an expression level of 1,128 genes after 48 h treatment. Specifically, genes associated with the cell cycle, DNA replication, and pyrimidine and purine metabolisms, were down-regulated in cells treated with MFP, which resulted in reduction of cell proliferation. MFP treatment also up-regulated genes associated with lysosome and phagosome function, which are both required for macrophage activities. We speculate that activation of macrophages by mica is in part derived from up-regulation of these pathways. PMID:25668030

Jung, Myunghwan; Shin, Min-Kyoung; Jung, Yeon-Kwon; Yoo, Han Sang

2015-01-01

276

An extract of Phellinus linteus grown on germinated brown rice inhibits inflammation markers in RAW264.7 macrophages by suppressing inflammatory cytokines, chemokines, and mediators and up-regulating antioxidant activity.  

PubMed

The immunomodulatory activity of an organic extract of Phellinus linteus grown on slightly germinated brown rice (PBR) was previously demonstrated. Here, we investigated the possible anti-inflammatory activity of the PBR extract by analyzing its effect on the expression of macrophage-derived cytokines, chemokines, and mediator genes that participate in immune and inflammatory responses and diseases. The extract profoundly inhibited the induction of cytokines and chemokines, including tumor necrosis factor-?, chemokine (C-X-C motif) ligand-10, granulocyte-macrophage colony-stimulating factor, and interleukin-6, in lipopolysaccharide (LPS)-stimulated RAW264.7 mouse macrophage cells. It also greatly inhibited LPS-stimulated production of nitric oxide (NO) and prostaglandin E(2) in RAW264.7 cells by suppressing the expression of inducible NO synthase and cyclooxygenase-2. PBR extract inhibited NO production with a twofold lower half-maximal inhibitory concentration value than P. linteus extract. To elucidate the underlying mechanism of action, we examined the effect of the PBR extract on the LPS-induced phosphorylation of mitogen-activated protein kinases (MAPKs) in RAW264.7 cells. PBR extract greatly inhibited extracellular signal-regulated kinase and c-Jun N-terminal kinase phosphorylation and slightly inhibited p38 MAPK phosphorylation. It also significantly increased intracellular glutathione peroxidase activity and heme oxygenase-1 protein expression. Thus, the PBR extract has anti-inflammatory activity in LPS-stimulated RAW264.7 cells by virtue of its ability to suppress the production of inflammatory cytokines and chemokines via inhibition of MAPK activation and up-regulation of antioxidant activities. PMID:20874228

Park, Hye-Jin; Han, Eun Su; Park, Dong Ki; Lee, Chan; Lee, Ki Won

2010-12-01

277

Immunotherapy for Prostate Cancer with Gc Protein-Derived Macrophage-Activating Factor, GcMAF.  

PubMed

Serum Gc protein (known as vitamin D(3)-binding protein) is the precursor for the principal macrophage-activating factor (MAF). The MAF precursor activity of serum Gc protein of prostate cancer patients was lost or reduced because Gc protein was deglycosylated by serum alpha-N-acetylgalactosaminidase (Nagalase) secreted from cancerous cells. Therefore, macrophages of prostate cancer patients having deglycosylated Gc protein cannot be activated, leading to immunosuppression. Stepwise treatment of purified Gc protein with immobilized beta-galactosidase and sialidase generated the most potent MAF (termed GcMAF) ever discovered, which produces no adverse effect in humans. Macrophages activated by GcMAF develop a considerable variation of receptors that recognize the abnormality in malignant cell surface and are highly tumoricidal. Sixteen nonanemic prostate cancer patients received weekly administration of 100 ng of GcMAF. As the MAF precursor activity increased, their serum Nagalase activity decreased. Because serum Nagalase activity is proportional to tumor burden, the entire time course analysis for GcMAF therapy was monitored by measuring the serum Nagalase activity. After 14 to 25 weekly administrations of GcMAF (100 ng/week), all 16 patients had very low serum Nagalase levels equivalent to those of healthy control values, indicating that these patients are tumor-free. No recurrence occurred for 7 years. PMID:18633461

Yamamoto, Nobuto; Suyama, Hirofumi; Yamamoto, Nobuyuki

2008-07-01

278

[Effect of chrysotile on nitric oxide production and anti-oxidasic activity in rabbit alveolar macrophages].  

PubMed

This study aimed to explore the role of nitric oxide (NO) and nitric oxide synthase (NOS) in chrysotile asbestos-caused diseases. The production of NO2-/NO3- (the final product of NO) and the alterations of NOS, SOD and GSH-Px activity were investigated when rabbit alveolar macrophages (AM) were stimulated by UICC chrysotile. The results revealed that with the dosage elevation of UICC chrysotile, the rabbit alveolar macrophages showed: (1) increased mortality, decreased survival activity; (2) increased product of NO2-/NO3-, decreased SOD and GSH-Px activity; (3) increased NOS activity in the lower dosage groups, but decreased NOS activity in the higher dosage groups. There was significantly negative correlation between NO release and SOD (or GSH-Px) activity (r1 = -0.7125, P < 0.05; r2 = -0.8496, P < 0.05 respectively). Moreover, the significantly positive correlation between NO release and NOS activity was found in the lower dosage groups, but significantly negative correlation in the higher dosage groups. These findings suggest that chrysotile could induce the alveolar macrophages to increase NO release and to decrease SOD and GSH-Px activity, which may play a role in the process of asbestos-caused diseases. PMID:12501614

Zhan, X; Wang, Z; Yang, Q; Wang, M; Liu, Z

2000-03-01

279

Monoclonal antibody to murine gamma interferon inhibits lymphokine- induced antiviral and macrophage tumoricidal activities  

PubMed Central

Fusion of rat immune spleen cells with mouse myeloma cells resulted in the formation of a stable hybridoma that secretes monoclonal antibody (MAb) directed against murine gamma interferon ( MuIFN -gamma). This MAb specifically neutralized the antiviral activity of a variety of MuIFN -gamma preparations, including a sample produced by recombinant DNA technologies. In contrast, the antiviral activities of a mixture of MuIFN -alpha plus MuIFN -beta, as well as those of rat or human IFN- gamma, were not neutralized by this antibody. The ability of the MAb to inhibit lymphokine-induced macrophage activation was also tested. It was found that in relation to the quantity of antibody needed to completely neutralize antiviral activity, much higher concentrations of MAb were required to abolish the capacity of lymphokine preparations to induce macrophage tumoricidal activity in vitro. The MAb was also coupled to cyanogen bromide-activated Sepharose beads and used as an immunoadsorbent. By reacting lymphokines with MAb coupled to an insoluble matrix, it was possible to show that this immobilized antibody completely and specifically removed from the lymphokine preparations the ability both to invoke macrophage tumoricidal activity and to mediate antiviral activity. PMID:6425450

1984-01-01

280

The macrophage scavenger receptor type A is expressed by activated macrophages and protects the host against lethal endotoxic shock.  

PubMed

During gram-negative bacterial infections, lipopolysaccharide (LPS) stimulates primed macrophages (Mphi) to release inflammatory mediators such as tumor necrosis factor (TNF)-alpha, which can cause hypotension, organ failure, and often death. Several different receptors on Mphi have been shown to bind LPS, including the type A scavenger receptor (SR-A). This receptor is able to bind a broad range of polyanionic ligands such as modified lipoproteins and lipoteichoic acid of gram-positive bacteria, which suggests that SR-A plays a role in host defense. In this study, we used mice lacking the SR-A (SRKO) to investigate the role of SR-A in acquired immunity using a viable bacillus Calmette Guérin (BCG) infection model. We show that activated Mphi express SR-A and that this molecule is functional in assays of adhesion and endocytic uptake. After BCG infection, SRKO mice are able to recruit Mphi to sites of granuloma formation where they become activated and restrict BCG replication. However, infected mice lacking the SR-A are more susceptible to endotoxic shock and produce more TNF-alpha and interleukin-6 in response to LPS. In addition, we show that an antibody which blocks TNF-alpha activity reduces LPS-induced mortality in these mice. Thus SR-A, expressed by activated Mphi, plays a protective role in host defense by scavenging LPS as well as by reducing the release by activated Mphi of proinflammatory cytokines. Modulation of SR-A may provide a novel therapeutic approach to control endotoxic shock. PMID:9348300

Haworth, R; Platt, N; Keshav, S; Hughes, D; Darley, E; Suzuki, H; Kurihara, Y; Kodama, T; Gordon, S

1997-11-01

281

Purification and characterization of a novel immunomodulatory protein from the medicinal mushroom Trametes versicolor.  

PubMed

Bioactive proteins represent an important group of functional agents in medicinal mushrooms. Trametes versicolor (L.) Lloyd is a mushroom frequently used in traditional Chinese medicine for its anti-tumor and immunomodulatory activities. A new immunomodulatory protein from T. versicolor, named TVC, was purified by ammonium sulfate precipitation, ion-exchange chromatography and gel filtration chromatography. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of the purified protein revealed a single band with a molecular weight of 15.0 kD. Native polyacrylamide gel analysis revealed a band at 30 kD, indicating that TVC exists in solution as a homodimer. Isoelectric focusing showed that TVC was an acidic protein with an isoelectric point of 4.0. TVC was found to lack carbohydrate modifications (based on periodic acid/Schiff staining) and it does not agglutinate mouse red blood cells, suggesting that TVC is not a lectin-like protein. Biological activity assays demonstrated that TVC can enhance the proliferation of splenocytes, while it has no stimulatory effects on CD4(+) and CD8(+) T cells. TVC markedly increases the proliferation of human peripheral blood lymphocytes in a dose-dependent manner and enhances the production of both nitric oxide and tumor necrosis factor-alpha by lipopolysaccharide-induced murine macrophages. The results indicate that TVC is an immunostimulant that can boost immune response. Comparison of the N-terminal amino acid residues and mass spectrometry results with the protein database revealed no homologous proteins. PMID:21373981

Li, Feng; Wen, Huaan; Zhang, Yongjie; Aa, Min; Liu, Xingzhong

2011-04-01

282

Rapid recruitment and activation of macrophages by anti-Gal/?-Gal liposome interaction accelerates wound healing.  

PubMed

Macrophages are pivotal in promoting wound healing. We hypothesized that topical application of liposomes with glycolipids that carry Gal?1-3Gal?1-4GlcNAc-R epitopes (?-gal liposomes) on wounds may accelerate the healing process by rapid recruitment and activation of macrophages in wounds. Immune complexes of the natural anti-Gal Ab (constituting ?1% of Ig in humans) bound to its ligand, the ?-gal epitope on ?-gal liposomes would induce local activation of complement and generation of complement chemotactic factors that rapidly recruit macrophages. Subsequent binding of the Fc portion of anti-Gal coating ?-gal liposomes to Fc?Rs on recruited macrophages may activate macrophage genes encoding cytokines that mediate wound healing. We documented the efficacy of this treatment in ?1,3galactosyltrasferase knockout mice. In contrast to wild-type mice, these knockout mice lack ?-gal epitopes and can produce the anti-Gal Ab. The healing time of excisional skin wounds treated with ?-gal liposomes in these mice is twice as fast as that of control wounds. Moreover, scar formation in ?-gal liposome-treated wounds is much lower than in physiologic healing. Additional sonication of ?-gal liposomes resulted in their conversion into submicroscopic ?-gal nanoparticles. These ?-gal nanoparticles diffused more efficiently in wounds and further increased the efficacy of the treatment, resulting in 95-100% regeneration of the epidermis in wounds within 6 d. The study suggests that ?-gal liposome and ?-gal nanoparticle treatment may enhance wound healing in the clinic because of the presence of high complement activity and high anti-Gal Ab titers in humans. PMID:21357545

Wigglesworth, Kim M; Racki, Waldemar J; Mishra, Rabinarayan; Szomolanyi-Tsuda, Eva; Greiner, Dale L; Galili, Uri

2011-04-01

283

Rapid Recruitment and Activation of Macrophages by Anti-Gal/?-Gal Liposome Interaction Accelerates Wound Healing  

PubMed Central

Macrophages are pivotal in promoting wound healing. We hypothesized that topical application of liposomes with glycolipids that carry Gala1-3Galb1-4GlcNAc-R epitopes (?-gal liposomes) on wounds may accelerate the healing process by rapid recruitment and activation of macrophages in wounds. Immune complexes of the natural anti-Gal Ab (constituting ~1% of Ig in humans) bound to its ligand, the ?-gal epitope on ?-gal liposomes would induce local activation of complement and generation of complement chemotactic factors that rapidly recruit macrophages. Subsequent binding of the Fc portion of anti-Gal coating ?-gal liposomes to Fc?Rs on recruited macrophages may activate macrophage genes encoding cytokines that mediate wound healing. We documented the efficacy of this treatment in ?1,3galactosyltrasferase knockout mice. In contrast to wild-type mice, these knockout mice lack ?-gal epitopes and can produce the anti-Gal Ab. The healing time of excisional skin wounds treated with ?-gal liposomes in these mice is twice as fast as that of control wounds. Moreover, scar formation in ?-gal liposome-treated wounds is much lower than in physiologic healing. Additional sonication of ?-gal liposomes resulted in their conversion into submicroscopic ?-gal nanoparticles. These ?-gal nanoparticles diffused more efficiently in wounds and further increased the efficacy of the treatment, resulting in 95–100% regeneration of the epidermis in wounds within 6 d. The study suggests that ?-gal liposome and ?-gal nanoparticle treatment may enhance wound healing in the clinic because of the presence of high complement activity and high anti-Gal Ab titers in humans. PMID:21357545

Wigglesworth, Kim M.; Racki, Waldemar J.; Mishra, Rabinarayan; Szomolanyi-Tsuda, Eva; Greiner, Dale L.; Galili, Uri

2014-01-01

284

Obesity Activates a Program of Lysosomal-Dependent Lipid Metabolism in Adipose Tissue Macrophages Independently of Classic Activation  

PubMed Central

SUMMARY Obesity activates a complex systemic immune response that includes the recruitment of macrophages and other immune cells to key metabolic tissues. Current models postulate that obesity and excess lipids classically activate macrophages, polarizing them toward an M1 (inflammatory) state. Little is known about noninflammatory functions of adipose tissue macrophages (ATMs). Here, we show that the expansion of adipose tissue (AT) across models of obesity induces a program of lysosome biogenesis in ATMs and is associated with lipid catabolism but not a classic inflammatory phenotype. This program is induced by factors produced by AT and is tightly coupled to lipid accumulation by ATMs. Inhibition of ATM lysosome function impairs lipid metabolism and increases lipid content in ATMs and reduces whole AT lipolysis. These data argue that ATMs contribute quantitatively to the development of obesity-induced inflammation but also serve an important role in lipid trafficking independent of their inflammatory phenotype. PMID:24315368

Xu, Xiaoyuan; Grijalva, Ambar; Skowronski, Alicja; van Eijk, Marco; Serlie, Mireille J.; Ferrante, Anthony W.

2014-01-01

285

Characterization of receptors for platelet-activating factor on platelets, polymorphonuclear leukocytes and macrophages.  

PubMed Central

1. We have compared the potency of the putative platelet-activating factor (Paf) receptor antagonists (WEB 2086, L-652,731 and BN 52021) against Paf-induced aggregation of rabbit and guinea-pig platelets, aggregation of rabbit polymorphonuclear leukocytes (PMNLs) and prostacyclin generation by guinea-pig resident peritoneal macrophages. 2. On rabbit washed platelets and PMNLs WEB 2086, L-652,731 and BN 52021 each antagonized competitively Paf-induced aggregation. The rank order of potency was WEB 2086 congruent to L-652,731 greater than BN 52021 and was the same for the two cell types. 3. The pA2 values for each of the three antagonists were similar on rabbit washed platelets and PMNLs. Moreover, the pA2 for WEB 2086 on rabbit platelets (7.58) did not differ significantly from that on guinea-pig platelets (7.69). 4. On guinea-pig resident peritoneal macrophages WEB 2086 was 10 fold less potent for receptors mediating increased generation of 6-oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha) than for those mediating platelet aggregation. 5. The potencies of L-652,731 and BN 52021 were also markedly less (2 log units) for the macrophage receptors than for platelet or PMNL receptors and BN 52021 was more potent than L-652,731 in the macrophages. 6. WEB 2086 and L-652,731 significantly reduced basal 6-oxo-PGF1 alpha produced by macrophages, but none of the antagonists affected 6-oxo-PGF1 alpha production during stimulation by A23187. 7. These data raise the possibility that there may be a Paf receptor-subtype mediating prostacyclin generation in macrophages that is different from that on the platelet and PMNL.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2850058

Stewart, A. G.; Dusting, G. J.

1988-01-01

286

Antimicrobial and immunomodulatory properties of PGLa-AM1, CPF-AM1, and magainin-AM1: Potent activity against oral pathogens.  

PubMed

Cationic amphipathic ?-helical peptides are intensively studied classes of host defence peptides (HDPs). Three peptides, peptide glycine-leucine-amide (PGLa-AM1), caerulein-precursor fragment (CPF-AM1) and magainin-AM1, originally isolated from norepinephrine-stimulated skin secretions of the African volcano frog Xenopus amieti (Pipidae), were studied for their antimicrobial and immunomodulatory activities against oral and respiratory pathogens. Minimal effective concentrations (MECs), determined by radial diffusion assay, were generally lower than minimal inhibitory concentrations (MICs) determined by microbroth dilution. PGLa-AM1 and CPF-AM1 were particularly active against Streptococcus mutans and all three peptides were effective against Fusobacterium nucleatum, whereas Enterococcus faecalis and Candida albicans proved to be relatively resistant micro-organisms. A type strain of Pseudomonas aeruginosa was shown to be more susceptible than the clinical isolate studied. PGLa-AM1 displayed the greatest propensity to bind lipopolysaccharide (LPS) from Escherichia coli, P. aeruginosa and Porphyromonas gingivalis. All three peptides showed less binding to P. gingivalis LPS than to LPS from the other species studied. Oral fibroblast viability was unaffected by 50?M peptide treatments. Production of the pro-inflammatory cytokine IL-8 by oral fibroblasts was significantly increased following treatment with 1 or 10?M magainin-AM1 but not following treatment with PGLa-AM1 or CPF-AM1. In conclusion, as well as possessing potent antimicrobial actions, the X. amieti peptides bound to LPS from three human pathogens and had no effect on oral fibroblast viability. CPF-AM1 and PGLa-AM1 show promise as templates for the design of novel analogues for the treatment of oral and dental diseases associated with bacteria or fungi. PMID:25447193

McLean, Denise T F; McCrudden, Maelíosa T C; Linden, Gerard J; Irwin, Christopher R; Conlon, J Michael; Lundy, Fionnuala T

2014-11-01

287

The Ribavirin Analog ICN 17261 Demonstrates Reduced Toxicity and Antiviral Effects with Retention of both Immunomodulatory Activity and Reduction of Hepatitis-Induced Serum Alanine Aminotransferase Levels  

PubMed Central

The demonstrated utility of the nucleoside analog ribavirin in the treatment of certain viral diseases can be ascribed to its multiple distinct properties. These properties may vary in relative importance in differing viral disease conditions and include the direct inhibition of viral replication, the promotion of T-cell-mediated immune responses via an enhanced type 1 cytokine response, and a reduction of circulating alanine aminotransferase (ALT) levels associated with hepatic injury. Ribavirin also has certain known toxicities, including the induction of anemia upon chronic administration. To determine if all these properties are linked, we compared the d-nucleoside ribavirin to its l-enantiomer (ICN 17261) with regard to these properties. Strong similarities were seen for these two compounds with respect to induction of type 1 cytokine bias in vitro, enhancement of type 1 cytokine responses in vivo, and the reduction of serum ALT levels in a murine hepatitis model. In contrast, ICN 17261 had no in vitro antiviral activity against a panel of RNA and DNA viruses, while ribavirin exhibited its characteristic activity profile. Importantly, the preliminary in vivo toxicology profile of ICN 17261 is significantly more favorable than that of ribavirin. Administration of 180 mg of ICN 17261 per kg of body weight to rats by oral gavage for 4 weeks generated substantial serum levels of drug but no observable clinical pathology, whereas equivalent doses of ribavirin induced a significant anemia and leukopenia. Thus, structural modification of ribavirin can dissociate its immunomodulatory properties from its antiviral and toxicologic properties, resulting in a compound (ICN 17261) with interesting therapeutic potential. PMID:10770762

Tam, Robert C.; Ramasamy, Kanda; Bard, Josie; Pai, Bharati; Lim, Charmaine; Averett, Devron R.

2000-01-01

288

Anti-tumor and macrophage activation induced by alkali-extracted polysaccharide from Pleurotus ostreatus.  

PubMed

Pleurotus ostreatus is popularly consumed as traditional medicine and health food for enhancing immune function in China. Polysaccharides from mushroom have been demonstrated to possess a wide range of health beneficial properties. This study was carried out to elucidate the immunomodulating effects and molecular mechanism involved in the in vivo and in vitro anti-tumor activities of alkali-extracted polysaccharide (WPOP-N1) from the fruiting bodies of P. ostreatus. The results showed that WPOP-N1 significantly inhibited the tumor growth of Sarcoma 180 tumor-bearing mice, and markedly increased the secretion level of TNF-? in serum. In addition, WPOP-N1 enhanced the phagocytic capability of peritoneal macrophages in vitro. Furthermore, the secretion of TNF-? and NO and the amount of TNF-? and iNOS transcript were increased significantly when the peritoneal macrophages were exposed to WPOP-N1. Meanwhile, Western blot analysis revealed that the stimulation of peritoneal macrophages by WPOP-N1 induced the phosphorylation of p65 and a marked decrease of I?B expression. These results suggest that WPOP-N1 could activate macrophages through NF-?B signaling pathway, and the anti-tumor effects of WPOP-N1 can be achieved by its immunostimulating property. PMID:24942990

Kong, Fanli; Li, Feng-E; He, Zhongmei; Jiang, Yong; Hao, Ruoyi; Sun, Xin; Tong, Haibin

2014-08-01

289

Epithelial cells modulate genes associated with NF kappa B activation in co-cultured human macrophages.  

PubMed

Macrophages located in airways and the alveolar space are continually exposed to different signals from the respiratory mucosa. In this respect, epithelial cells represent an important source of cytokines and mediators modulating the state of activation and/or differentiation of mononuclear phagocytes. Many of the proinflammatory genes induced in macrophages during immune and immunopathological reactions are regulated by transcription factor NF kappa B. The aim of our study was to characterize changes in the expression of genes associated with NF kappa B activation and signalling in THP-1 human macrophages co-cultured with A549 respiratory epithelial cells. At least 4-fold upregulation of mRNA level was found in 29 of 84 tested genes including genes for multiple cytokines and chemokines, membrane antigens and receptors, and molecules associated with NF kappa B signalling. The mRNA induction was confirmed at the level of protein expression by evaluating the release of IL-6 and IL-8 and by ICAM-1 expression. Blocking of one NF?B subunit by p65 siRNA inhibited the production of IL-6 in both cell types while IL-8 release from THP-1 cells did not seem to be affected. We conclude from our data that unstimulated respiratory epithelial cells regulate genes associated with NF kappa B dependent immune responses in human macrophages and that these interactions may play a key role in immediate responses in the respiratory mucosa. PMID:21601940

Striz, I; Brabcova, E; Kolesar, L; Liu, X D; Brabcova, I; Sekerkova, A; Poole, J A; Jaresova, M; Slavcev, A; Rennard, S I

2011-10-01

290

Adenosine stimulates CREB activation in macrophages via a p38 MAPK-mediated mechanism  

Microsoft Academic Search

Adenosine is an endogenously released autocoid that has potent receptor-mediated modulatory effects on macrophage function. The intracellular pathways mediating these effects are incompletely understood. Since adenosine receptor occupancy has been associated with activation of the cAMP–PKA system as well as of p38 MAPK and p42\\/44 MAPK, all of which can activate the CREB transcription factor system, we hypothesized that adenosine

Zoltán H Németh; S. Joseph Leibovich; Edwin A Deitch; Beáta Sperlágh; László Virág; E. Sylvester Vizi; Csaba Szabó; György Haskó

2003-01-01

291

Oxidized LDL Regulates Macrophage Gene Expression through Ligand Activation of PPAR?  

Microsoft Academic Search

Macrophage uptake of oxidized low-density lipoprotein (oxLDL) is thought to play a central role in foam cell formation and the pathogenesis of atherosclerosis. We demonstrate here that oxLDL activates PPAR?-dependent transcription through a novel signaling pathway involving scavenger receptor-mediated particle uptake. Moreover, we identify two of the major oxidized lipid components of oxLDL, 9-HODE and 13-HODE, as endogenous activators and

Laszlo Nagy; Peter Tontonoz; Jacqueline G. A Alvarez; Hongwu Chen; Ronald M Evans

1998-01-01

292

Osteogenic differentiation of bone marrow MSCs by ?-tricalcium phosphate stimulating macrophages via BMP2 signalling pathway.  

PubMed

Immune reactions play important roles in determining the in vivo fate of bone substitute materials, either in new bone formation or inflammatory fibrous tissue encapsulation. The paradigm for the development of bone substitute materials has been shifted from inert to immunomodulatory materials, emphasizing the importance of immune cells in the material evaluation. Macrophages, the major effector cells in the immune reaction to implants, are indispensable for osteogenesis and their heterogeneity and plasticity render macrophages a primer target for immune system modulation. However, there are very few reports about the effects of macrophages on biomaterial-regulated osteogenesis. In this study, we used ?-tricalcium phosphate (?-TCP) as a model biomaterial to investigate the role of macrophages on the material stimulated osteogenesis. The macrophage phenotype switched to M2 extreme in response to ?-TCP extracts, which was related to the activation of calcium-sensing receptor (CaSR) pathway. Bone morphogenetic protein 2 (BMP2) was also significantly upregulated by the ?-TCP stimulation, indicating that macrophage may participate in the ?-TCP stimulated osteogenesis. Interestingly, when macrophage-conditioned ?-TCP extracts were applied to bone marrow mesenchymal stem cells (BMSCs), the osteogenic differentiation of BMSCs was significantly enhanced, indicating the important role of macrophages in biomaterial-induced osteogenesis. These findings provided valuable insights into the mechanism of material-stimulated osteogenesis, and a strategy to optimize the evaluation system for the in vitro osteogenesis capacity of bone substitute materials. PMID:24268199

Chen, Zetao; Wu, Chengtie; Gu, Wenyi; Klein, Travis; Crawford, Ross; Xiao, Yin

2014-02-01

293

The Immunomodulatory Activity of Meningococcal Lipoprotein Ag473 Depends on the Conformation Made up of the Lipid and Protein Moieties  

PubMed Central

We have previously demonstrated that the meningococcal antigen Ag473 in the presence of Freund’s adjuvant can elicit protective immune responses in mouse challenge model. In this study, we evaluated the structural requirement for the immunological activity and the possible signaling pathway of recombinant Ag473 antigen produced in E. coli. We found that lipidated Ag473 (L-Ag473) possesses an intrinsic adjuvant activity that could be attributed to its ability to activate dendritic cells and promote their maturation. In addition, we found that L-Ag473 can activate human monocytes and promote maturation of human monocyte-derived dendritic cells. These results provide an indirect support that L-Ag473 may also be immunogenic in human. Interestingly, the observed activity is dependent on the overall conformation of L-Ag473 because heating and proteinase K treatment can diminish and abolish the activity. Furthermore, our data suggest a species-differential TLR recognition of L-Ag473. Overall, these data suggest a new paradigm for the ligand-TLR interaction in addition to demonstrating the self-adjuvanting activity of the vaccine candidate L-Ag473. PMID:22844415

Chu, Ching-Liang; Yu, Yen-Ling; Kung, Yueh-Chen; Liao, Pei-Yu; Liu, Ko-Jiunn; Tseng, Yen-Tzu; Lin, Yuan-Chuen; Hsieh, Steve Shih-Yang; Chong, Pele Choi-Sing; Yang, Chiou-Ying

2012-01-01

294

Tumor cell alpha-N-acetylgalactosaminidase activity and its involvement in GcMAF-related macrophage activation.  

PubMed

Alpha-N-acetyl galactosaminidase (alpha-NaGalase) has been reported to accumulate in serum of cancer patients and be responsible for deglycosylation of Gc protein, which is a precursor of GcMAF-mediated macrophage activation cascade, finally leading to immunosuppression in advanced cancer patients. We studied the biochemical characterization of alpha-NaGalase from several human tumor cell lines. We also examined its effect on the potency of GcMAF to activate mouse peritoneal macrophage to produce superoxide in GcMAF-mediated macrophage activation cascade. The specific activity of alpha-NaGalases from human colon tumor cell line HCT116, human hepatoma cell line HepG2, and normal human liver cells (Chang liver cell line) were evaluated using two types of substrates; GalNAc-alpha-PNP (exo-type substrate) and Gal-beta-GalNAc-alpha-PNP (endo-type substrate). Tumor-derived alpha-NaGalase having higher activity than normal alpha-NaGalase, had higher substrate specificity to the exo-type substrate than to the endo-type substrate, and still maintained its activity at pH 7. GcMAF enhance superoxide production in mouse macrophage, and pre-treatment of GcMAF with tumor cell lysate reduce the activity. We conclude that tumor-derived alpha-NaGalase is different in biochemical characterization compared to normal alpha-NaGalase from normal Chang liver cells. In addition, tumor cell-derived alpha-NaGalase decreases the potency of GcMAF on macrophage activation. PMID:12062184

Mohamad, Saharuddin B; Nagasawa, Hideko; Uto, Yoshihiro; Hori, Hitoshi

2002-05-01

295

Progesterone-induced activation of membrane-bound progesterone receptors in murine macrophage cells.  

PubMed

Parturition is an inflammatory process mediated to a significant extent by macrophages. Progesterone (P4) maintains uterine quiescence in pregnancy, and a proposed functional withdrawal of P4 classically regulated by nuclear progesterone receptors (nPRs) leads to labor. P4 can affect the functions of macrophages despite the reported lack of expression of nPRs in these immune cells. Therefore, in this study we investigated the effects of the activation of the putative membrane-associated PR on the function of macrophages (a key cell for parturition) and discuss the implications of these findings for pregnancy and parturition. In murine macrophage cells (RAW 264.7), activation of mPRs by P4 modified to be active only extracellularly by conjugation to BSA (P4BSA, 1.0×10(-7)?mol/l) caused a pro-inflammatory shift in the mRNA expression profile, with significant upregulation of the expression of cyclooxygenase 2 (COX2 (Ptgs2)), Il1B, and Tnf and downregulation of membrane progesterone receptor alpha (Paqr7) and oxytocin receptor (Oxtr). Pretreatment with PD98059, a MEK1/2 inhibitor, significantly reduced P4BSA-induced expression of mRNA of Il1B, Tnf, and Ptgs2. Inhibition of protein kinase A (PKA) by H89 blocked P4BSA-induced expression of Il1B and Tnf mRNA. P4BSA induced rapid phosphorylation of MEK1/2 and CREB (a downstream target of PKA). This phosphorylation was inhibited by pretreatment with PD98059 and H89, respectively, revealing that MEK1/2 and PKA are two of the components involved in mPR signaling. Taken together, these results indicate that changes in membrane progesterone receptor alpha expression and signaling in macrophages are associated with the inflammatory responses; and that these changes might contribute to the functional withdrawal of P4 related to labor. PMID:25472814

Lu, Jing; Reese, Joshua; Zhou, Ying; Hirsch, Emmet

2015-02-01

296

The GAP activity of type III effector YopE triggers killing of Yersinia in macrophages.  

PubMed

The mammalian immune system has the ability to discriminate between pathogens and innocuous microbes by detecting conserved molecular patterns. In addition to conserved microbial patterns, the mammalian immune system may recognize distinct pathogen-induced processes through a mechanism which is poorly understood. Previous studies have shown that a type III secretion system (T3SS) in Yersinia pseudotuberculosis leads to decreased survival of this bacterium in primary murine macrophages by unknown mechanisms. Here, we use colony forming unit assays and fluorescence microscopy to investigate how the T3SS triggers killing of Yersinia in macrophages. We present evidence that Yersinia outer protein E (YopE) delivered by the T3SS triggers intracellular killing response against Yersinia. YopE mimics eukaryotic GTPase activating proteins (GAPs) and inactivates Rho GTPases in host cells. Unlike wild-type YopE, catalytically dead YopER144A is impaired in restricting Yersinia intracellular survival, highlighting that the GAP activity of YopE is detected as a danger signal. Additionally, a second translocated effector, YopT, counteracts the YopE triggered killing effect by decreasing the translocation level of YopE and possibly by competing for the same pool of Rho GTPase targets. Moreover, inactivation of Rho GTPases by Clostridium difficile Toxin B mimics the effect of YopE and promotes increased killing of Yersinia in macrophages. Using a Rac inhibitor NSC23766 and a Rho inhibitor TAT-C3, we show that macrophages restrict Yersinia intracellular survival in response to Rac1 inhibition, but not Rho inhibition. In summary, our findings reveal that primary macrophages sense manipulation of Rho GTPases by Yersinia YopE and actively counteract pathogenic infection by restricting intracellular bacterial survival. Our results uncover a new mode of innate immune recognition in response to pathogenic infection. PMID:25165815

Wang, Xiaoying; Parashar, Kaustubh; Sitaram, Ananya; Bliska, James B

2014-08-01

297

The GAP Activity of Type III Effector YopE Triggers Killing of Yersinia in Macrophages  

PubMed Central

The mammalian immune system has the ability to discriminate between pathogens and innocuous microbes by detecting conserved molecular patterns. In addition to conserved microbial patterns, the mammalian immune system may recognize distinct pathogen-induced processes through a mechanism which is poorly understood. Previous studies have shown that a type III secretion system (T3SS) in Yersinia pseudotuberculosis leads to decreased survival of this bacterium in primary murine macrophages by unknown mechanisms. Here, we use colony forming unit assays and fluorescence microscopy to investigate how the T3SS triggers killing of Yersinia in macrophages. We present evidence that Yersinia outer protein E (YopE) delivered by the T3SS triggers intracellular killing response against Yersinia. YopE mimics eukaryotic GTPase activating proteins (GAPs) and inactivates Rho GTPases in host cells. Unlike wild-type YopE, catalytically dead YopER144A is impaired in restricting Yersinia intracellular survival, highlighting that the GAP activity of YopE is detected as a danger signal. Additionally, a second translocated effector, YopT, counteracts the YopE triggered killing effect by decreasing the translocation level of YopE and possibly by competing for the same pool of Rho GTPase targets. Moreover, inactivation of Rho GTPases by Clostridium difficile Toxin B mimics the effect of YopE and promotes increased killing of Yersinia in macrophages. Using a Rac inhibitor NSC23766 and a Rho inhibitor TAT-C3, we show that macrophages restrict Yersinia intracellular survival in response to Rac1 inhibition, but not Rho inhibition. In summary, our findings reveal that primary macrophages sense manipulation of Rho GTPases by Yersinia YopE and actively counteract pathogenic infection by restricting intracellular bacterial survival. Our results uncover a new mode of innate immune recognition in response to pathogenic infection. PMID:25165815

Wang, Xiaoying; Parashar, Kaustubh; Sitaram, Ananya; Bliska, James B.

2014-01-01

298

Induction of Alternatively Activated Macrophages Enhances Pathogenesis during Severe Acute Respiratory Syndrome Coronavirus Infection  

PubMed Central

Infection with severe acute respiratory syndrome coronavirus (SARS-CoV) causes acute lung injury (ALI) that often leads to severe lung disease. A mouse model of acute SARS-CoV infection has been helpful in understanding the host response to infection; however, there are still unanswered questions concerning SARS-CoV pathogenesis. We have shown that STAT1 plays an important role in the severity of SARS-CoV pathogenesis and that it is independent of the role of STAT1 in interferon signaling. Mice lacking STAT1 have greater weight loss, severe lung pathology with pre-pulmonary-fibrosis-like lesions, and an altered immune response following infection with SARS-CoV. We hypothesized that STAT1 plays a role in the polarization of the immune response, specifically in macrophages, resulting in a worsened outcome. To test this, we created bone marrow chimeras and cell-type-specific knockouts of STAT1 to identify which cell type(s) is critical to protection from severe lung disease after SARS-CoV infection. Bone marrow chimera experiments demonstrated that hematopoietic cells are responsible for the pathogenesis in STAT1?/? mice, and because of an induction of alternatively activated (AA) macrophages after infection, we hypothesized that the AA macrophages were critical for disease severity. Mice with STAT1 in either monocytes and macrophages (LysM/STAT1) or ciliated lung epithelial cells (FoxJ1/STAT1) deleted were created. Following infection, LysM/STAT1 mice display severe lung pathology, while FoxJ1/STAT1 mice display normal lung pathology. We hypothesized that AA macrophages were responsible for this STAT1-dependent pathology and therefore created STAT1/STAT6?/? double-knockout mice. STAT6 is essential for the development of AA macrophages. Infection of the double-knockout mice displayed a lack of lung disease and prefibrotic lesions, suggesting that AA macrophage production may be the cause of STAT1-dependent lung disease. We propose that the control of AA macrophages by STAT1 is critical to regulating immune pathologies and for protection from long-term progression to fibrotic lung disease in a mouse model of SARS-CoV infection. PMID:23015710

Page, Carly; Goicochea, Lindsay; Matthews, Krystal; Zhang, Yong; Klover, Peter; Holtzman, Michael J.; Hennighausen, Lothar

2012-01-01

299

A Novel in vitro Human Macrophage Model to Study the Persistence of Mycobacterium tuberculosis Using Vitamin D3 and Retinoic Acid Activated THP-1 Macrophages  

PubMed Central

Mycobacterium tuberculosis (Mtb) replicates within the human macrophages and we investigated the activating effects of retinoic acid (RA) and vitamin D3 (VD) on macrophages in relation to the viability of intracellular Mtb. A combination of these vitamins (RAVD) enhanced the levels of DC-SIGN and mannose receptors on THP-1 macrophages that increased mycobacterial uptake but inhibited the subsequent intracellular growth of Mtb by inducing reactive oxygen species and autophagy. RAVD also enhanced antigen presenting and chemotactic receptors on THPs suggesting an activated phenotype for RAVD activated THPs. RAVD mediated activation was also associated with a marked phenotypic change in Mtb infected THPs that fused with adjacent THPs to form multinucleated giant cells (MNGCs). Typically, MNGCs occurred over 30?days of in vitro culture and contained non-replicating persisting Mtb for more than 60?days in culture. Latent tuberculosis occurs in over a third of mankind and we propose that RAVD mediated induction of persistent Mtb within human macrophages provides a novel model to develop therapeutic approaches and investigate pathogenesis of latency. PMID:21747789

Estrella, Jaymie L.; Kan-Sutton, Celestine; Gong, Xing; Rajagopalan, Malini; Lewis, Dorothy E.; Hunter, Robert L.; Eissa, N. Tony; Jagannath, Chinnaswamy

2010-01-01

300

A Novel in vitro Human Macrophage Model to Study the Persistence of Mycobacterium tuberculosis Using Vitamin D(3) and Retinoic Acid Activated THP-1 Macrophages.  

PubMed

Mycobacterium tuberculosis (Mtb) replicates within the human macrophages and we investigated the activating effects of retinoic acid (RA) and vitamin D(3) (VD) on macrophages in relation to the viability of intracellular Mtb. A combination of these vitamins (RAVD) enhanced the levels of DC-SIGN and mannose receptors on THP-1 macrophages that increased mycobacterial uptake but inhibited the subsequent intracellular growth of Mtb by inducing reactive oxygen species and autophagy. RAVD also enhanced antigen presenting and chemotactic receptors on THPs suggesting an activated phenotype for RAVD activated THPs. RAVD mediated activation was also associated with a marked phenotypic change in Mtb infected THPs that fused with adjacent THPs to form multinucleated giant cells (MNGCs). Typically, MNGCs occurred over 30?days of in vitro culture and contained non-replicating persisting Mtb for more than 60?days in culture. Latent tuberculosis occurs in over a third of mankind and we propose that RAVD mediated induction of persistent Mtb within human macrophages provides a novel model to develop therapeutic approaches and investigate pathogenesis of latency. PMID:21747789

Estrella, Jaymie L; Kan-Sutton, Celestine; Gong, Xing; Rajagopalan, Malini; Lewis, Dorothy E; Hunter, Robert L; Eissa, N Tony; Jagannath, Chinnaswamy

2011-01-01

301

An immunomodulatory polysaccharide-rich substance from the fruit juice of Morinda citrifolia (noni) with antitumour activity  

Microsoft Academic Search

The fruit juice of Morinda citrifolia (noni) contains a polysaccharide-rich substance (noni-ppt) with anti- tumour activity in the Lewis lung (LLC) peritoneal carcinomatosis model. Therapeutic administration of noni-ppt significantly enhanced the duration of survival of inbred syngeneic LLC tumour bearing mice. It did not exert significant cytotoxic effects in an adapted culture of LLC cells, LLC1, but could activate peritoneal

Anne Hirazumi; Eiichi Furusawa

1999-01-01

302

Pathways Involved in the Synergistic Activation of Macrophages by Lipoteichoic Acid and Hemoglobin  

PubMed Central

Lipoteichoic acid (LTA) is a Gram-positive cell surface molecule that is found in both a cell-bound form and cell-free form in the host during an infection. Hemoglobin (Hb) can synergize with LTA, a TLR2 ligand, to potently activate macrophage innate immune responses in a TLR2- and TLR4-dependent way. At low levels of LTA, the presence of Hb can result in a 200-fold increase in the secretion of IL-6 following macrophage activation. Six hours after activation, the macrophage genes that are most highly up-regulated by LTA plus Hb activation compared to LTA alone are cytokines, chemokines, receptors and interferon-regulated genes. Several of these genes exhibit a unique TLR4-dependent increase in mRNA levels that continued to rise more than eight hours after stimulation. This prolonged increase in mRNA levels could be the result of an extended period of NF-?B nuclear localization and the concurrent absence of the NF-?B inhibitor, I?B?, after stimulation with LTA plus Hb. Dynasore inhibition experiments indicate that an endocytosis-dependent pathway is required for the TLR4-dependent up-regulation of IL-6 secretion following activation with LTA plus Hb. In addition, interferon-? mRNA is present after activation with LTA plus Hb, suggesting that the TRIF/TRAM-dependent pathway may be involved. Hb alone can elicit the TLR4-dependent secretion of TNF-? from macrophages, so it may be the TLR4 ligand. Hb also led to secretion of high mobility group box 1 protein (HMGB1), which synergized with LTA to increase secretion of IL-6. The activation of both the TLR2 and TLR4 pathways by LTA plus Hb leads to an enhanced innate immune response. PMID:23071790

Cox, Kathleen H.; Cox, Michelle E.; Woo-Rasberry, Virginia; Hasty, David L.

2012-01-01

303

Mefloquine and Its Enantiomers Are Active against Mycobacterium tuberculosis In Vitro and in Macrophages  

PubMed Central

Objective. Tuberculosis is a serious problem of public health. The increase on the number of clinical cases of tuberculosis infected with multidrug resistant (MDR) M. tuberculosis calls for the development of novel therapy. Design. We investigated the effect of mefloquine and two enantiomers, (+)erythro-mefloquine and (+)threo-mefloquine against M. tuberculosis strains in the environment resembling the aspects of the granuloma environment and in macrophages. Results. The results suggest that mefloquine (racemic mixture) and (+)erythro-mefloquine have bactericidal activity against M. tuberculosis strains both in acidic, low oxygen tension and in macrophages. The activity, however, was impaired under increased osmolarity. Conclusion. Identification of the target for mefloquine in the pathogen will allow for the development of novel drugs with antituberculosis activity. PMID:25580293

Bermudez, Luiz E.; Meek, Laura

2014-01-01

304

Dectin-1-dependent LC3 recruitment to phagosomes enhances fungicidal activity in macrophages.  

PubMed

Autophagy has been postulated to play role in mammalian host defense against fungal pathogens, although the molecular details remain unclear. Here, we show that primary macrophages deficient in the autophagic factor LC3 demonstrate diminished fungicidal activity but increased cytokine production in response to Candida albicans stimulation. LC3 recruitment to fungal phagosomes requires activation of the fungal pattern receptor dectin-1. LC3 recruitment to the phagosome also requires Syk signaling but is independent of all activity by Toll-like receptors and does not require the presence of the adaptor protein Card9. We further demonstrate that reactive oxygen species generation by NADPH oxidase is required for LC3 recruitment to the fungal phagosome. These observations directly link LC3 to the inflammatory pathway against C. albicans in macrophages. PMID:24842831

Tam, Jenny M; Mansour, Michael K; Khan, Nida S; Seward, Michael; Puranam, Sravanthi; Tanne, Antoine; Sokolovska, Anna; Becker, Christine E; Acharya, Mridu; Baird, Michelle A; Choi, Augustine M K; Davidson, Michael W; Segal, Brahm H; Lacy-Hulbert, Adam; Stuart, Lynda M; Xavier, Ramnik J; Vyas, Jatin M

2014-12-01

305

Immune activation of human brain microvascular endothelial cells inhibits HIV replication in macrophages  

PubMed Central

There is limited information about the role of blood-brain barrier (BBB) endothelial cells (ECs) in the central nervous system (CNS) and their innate immunity against HIV. We examined whether brain ECs can be immunologically activated to produce antiviral factors that inhibit HIV replication in macrophages. Human brain microvascular ECs expressed functional toll-like receptor 3 (TLR3) that could be activated by polyinosinic-polycytidylic acid (PolyI:C), resulting in the induction of endogenous interferon-? (IFN-?) and IFN-?. The TLR3 activation of ECs also induced the phosphorylation of interferon regulatory transcription factor 3 (IRF3) and IRF7, the key regulators of IFN signaling pathway. When supernatant (SN) of PolyI:C-activated EC cultures was applied to infected macrophage cultures, HIV replication was significantly suppressed. This SN action of ECs on HIV was mediated through both IFN-? and IFN-? because antibodies to their receptors could neutralize the SN-mediated anti-HIV effect. The role of IFNs in EC-mediated anti-HIV activity is further supported by the observation that treatment with SN from EC cultures induced the expression of IFN-stimulated genes (ISGs: ISG56, OAS-1, and MxA) in macrophages. These observations indicate that brain microvascular ECs may be a key regulatory bystander, playing a crucial role in the BBB innate immunity against HIV infection. PMID:23401273

Li, Jieliang; Wang, Yizhong; Wang, Xu; Ye, Li; Zhou, Yu; Persidsky, Yuri

2013-01-01

306

Macrophage CGI-58 deficiency promotes IL-1? transcription by activating the SOCS3-FOXO1 pathway.  

PubMed

Overnutrition induces low-grade inflammation that dampens insulin sensitivity, but the underlying molecular mediators are not fully understood. Comparative Gene Identification-58 (CGI-58) is an intracellular lipolytic activator. Here we show that in mouse visceral fat-derived macrophages or human peripheral blood monocytes CGI-58 negatively and IL-1? positively correlate with obesity. Saturated free fatty acid (FFA) suppresses CGI-58 expression in macrophages, and this suppression activates FOXO1 through inhibition of FOXO1 phosphorylation. Activated FOXO1 binds to an insulin-responsive element in IL-1? promoter region to potentiate IL-1? transcription. Gain- and loss-of-function studies demonstrate that FFA-induced CGI-58 suppression activates FOXO1 to augment IL-1? transcription by dampening insulin signaling through induction of SOCS3 expression. CGI-58 deficiency-induced SOCS3 expression is NLRP3 inflammasome-dependent. Our data thus identified a vicious cycle (IL-1?-SOCS3-FOXO1-IL-1?) that amplifies IL-1? secretion and is initiated by CGI-58 deficiency-induced activation of the NLRP3 inflammasome in macrophages. We further show that blocking this cycle with a FOXO1 inhibitor, an antioxidant that inhibits FOXO1, or IL-1 receptor antagonist alleviates chronic inflammation and insulin resistance in high fat diet-fed mice. Collectively our data suggest that obesity-associated factors such as FFA and lipopolysaccharide likely adopt this vicious cycle to promote inflammation and insulin resistance. PMID:25431838

Miao, Hongming; Ou, Juanjuan; Zhang, Xuan; Chen, Yujuan; Xue, Bingzhong; Shi, Hang; Gan, Lixia; Yu, Liqing; Liang, Houjie

2014-11-28

307

Inhibitory effect of azelastine hydrochloride on synthesis and release of platelet activating factor from human alveolar macrophages  

Microsoft Academic Search

The effect of azelastine hydrochloride (azelastine) on synthesis and release of platelet activating factor (PAF) in alveolar macrophages obtained from asthmatic and non-asthmatic subjects was examined. Alveolar macrophages (AMs) were preincubated with or without azelastine and stimulated with f-Met-Leu-Phe (fMLP, 10 ?M) for 15 min. PAF activity was detected by aggregation of washed guinea pig platelets. PAF activity released from

K. Shindo; M. Machida; Y. Hirai; M. Fukumura

1997-01-01

308

PPAR-? and PPAR-? activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway  

Microsoft Academic Search

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate lipid and glucose metabolism and cellular differentiation. PPAR-? and PPAR-? are both expressed in human macrophages where they exert anti-inflammatory effects. The activation of PPAR-? may promote foam-cell formation by inducing expression of the macrophage scavenger receptor CD36. This prompted us to investigate the influence of different PPAR- activators on cholesterol

Giulia Chinetti; Sophie Lestavel; Virginie Bocher; Alan T. Remaley; Bernadette Neve; Inés Pineda Torra; Elisabeth Teissier; Anne Minnich; Michael Jaye; Nicolas Duverger; H. Bryan Brewer; Jean-Charles Fruchart; Véronique Clavey; Bart Staels

2001-01-01

309

Phlebotomus papatasi Saliva Inhibits Protein Phosphatase Activity and Nitric Oxide Production by Murine Macrophages  

PubMed Central

Leishmania parasites, transmitted by phlebotomine sand flies, are obligate intracellular parasites of macrophages. The sand fly Phlebotomus papatasi is the vector of Leishmania major, a causative agent of cutaneous leishmaniasis in the Old World, and its saliva exacerbates parasite proliferation and lesion growth in experimental cutaneous leishmaniasis. Here we show that P. papatasi saliva contains a potent inhibitor of protein phosphatase 1 and protein phosphatase 2A of murine macrophages. We further demonstrate that P. papatasi saliva down regulates expression of the inducible nitric oxide synthase gene and reduces nitric oxide production in murine macrophages. Partial biochemical characterization of the protein phosphatase and nitric oxide inhibitor indicated that it is a small, ethanol-soluble molecule resistant to boiling, proteolysis, and DNase and RNase treatments. We suggest that the P. papatasi salivary protein phosphatase inhibitor interferes with the ability of activated macrophages to transmit signals to the nucleus, thereby preventing up regulation of the induced nitric oxide synthase gene and inhibiting the production of nitric oxide. Since nitric oxide is toxic to intracellular parasites, the salivary protein phosphatase inhibitor may be the mechanism by which P. papatasi saliva exacerbates cutaneous leishmaniasis. PMID:9529078

Waitumbi, John; Warburg, Alon

1998-01-01

310

Effect of angiotensin II on the Fc receptor activity of rat macrophages.  

PubMed Central

Angiotensin II (At II) in the concentration range of 10(-5) to 5 x 10(-7) M inhibited active and passive erythrocyte-antibody (EA) rosette formation on monolayers of rat peritoneal macrophages (PM) but stimulated it in the range of 10(-7) -10(08) M. Cytochalasin B (CB) and vinblastin (Vb) inhibited the dose-dependent biphasic effect of At II on the Fc receptor (FcR) expression of macrophages. The hormone acts on the last step of rosette formation, i.e. on the binding of sheep red blood cells (SRBC) but does not interfere with the binding of 125I-Ig to FcR. The influence of At II on macrophage rosette formation can be modified by changes in the density of FcR-Ig complexes on the surface of target cells, by the nature of the immunoglobulin (sub)classes involved in rosette formation, and by the biological properties of rosette-forming corpuscular antigen. Based upon the above results we suggest that At II exerts its effect on the contractile elements associated with the cytoskeleton of the macrophage. PMID:7461731

Dezsö, B; Fóris, G

1981-01-01

311

Ionizing Radiation Induces Macrophage Foam Cell Formation and Aggregation Through JNK-Dependent Activation of CD36 Scavenger Receptors  

SciTech Connect

Purpose: Irradiated arteries of cancer patients can be associated with atherosclerosis-like lesions containing cholesterol-laden macrophages (foam cells). Endothelial cell damage by irradiation does not completely explain the foam cell formation. We investigated the possible underlying mechanisms for ionizing radiation (IR)-induced foam cell formation. Methods and Materials: Human peripheral blood monocytes were activated by macrophage colony-stimulating factor and then treated with varying doses of IR in vitro in the absence of endothelial cells. Scavenger receptor expression and foam cell formation of IR-treated macrophages were investigated in the presence or absence of oxidized low-density lipoprotein. We also assessed the importance of mitogen-activated protein kinase activity in the macrophage colony-stimulating factor-activated human monocytes (macrophages) for the foam cell formation. Results: We found that IR treatment of macrophage colony-stimulating factor-activated human peripheral blood monocytes resulted in the enhanced expression of CD36 scavenger receptors and that cholesterol accumulated in the irradiated macrophages with resultant foam cell formation in the presence of oxidized low-density lipoprotein. Furthermore, when cultured on collagen gels, human macrophages formed large foam cell aggregates in response to IR. Antibodies against CD36 inhibited the IR-induced foam cell formation and aggregation, indicating that the IR-induced foam cell formation and the subsequent aggregation are dependent on functional CD36. In addition, we found that IR of human macrophages resulted in c-Jun N-terminal kinase activation and that c-Jun N-terminal kinase inhibition suppressed IR-induced CD36 expression and the subsequent foam cell formation and aggregation. Conclusion: Taken together, these results suggest that IR-induced foam cell formation is mediated by c-Jun N-terminal kinase-dependent CD36 activation.

Katayama, Ikuo; Hotokezaka, Yuka [Department of Radiology and Cancer Biology, Nagasaki University School of Dentistry, Nagasaki (Japan); Matsuyama, Toshifumi [Division of Cytokine Signaling, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (Japan); Sumi, Tadateru [Department of Radiology and Cancer Biology, Nagasaki University School of Dentistry, Nagasaki (Japan); Nakamura, Takashi [Department of Radiology and Cancer Biology, Nagasaki University School of Dentistry, Nagasaki (Japan)], E-mail: taku@nagasaki-u.ac.jp

2008-03-01

312

Evaluation of immunomodulatory potential of ethanolic extract of Roscoea procera rhizomes in mice  

PubMed Central

Purpose: The aim of present study was to evaluate immunomodulatory potential of ethanolic extract of Roscoea procera (Zingiberaceae) rhizomes by using delayed-type hypersensitivity (DTH) and carbon clearance method in comparison to standard established immunosuppressant drug, cyclophosphamide (30 mg/kg, i.p.) in mice. Material and Methods: The extract was comprised to acute toxicity (OECD-423 guideline), DTH and carbon clearance method for their immunomodulatory potential. Ethanolic extract of Roscoea procera rhizomes administered orally at doses 300 mg/kg and 600 mg/kg, p.o. to mice. Result and Conclusion: Result of our study revealed that, the foot pat thickness of ethanolic extract group (P<0.05) significantly enhanced the production of circulating antibody titre in response to Sheep red blood cells (SRBC) and phagocytic functions of mononuclear macrophages and non-specific immunity. Result were also supported by serological and haematological tests data. Hence, the present investigation reveals that, ethanolic extract of Roscoea procera rhizomes possesses immunostimulant properties. Further studies to identify the active moieties and elucidation of the mechanism of action are recommended. PMID:21180470

Sahu, Mahesh S.; Mali, Prashant Y.; Waikar, Shekhar B.; Rangari, Vinod D.

2010-01-01

313

Macrophages contribute to the antitumor activity of the anti-CD30 antibody SGN-30.  

PubMed

Increased expression of CD30 is associated with a variety of hematologic malignancies, including Hodgkin disease (HD) and anaplastic large cell lymphoma (ALCL). The anti-CD30 monoclonal antibody SGN-30 induces direct antitumor activity by promoting growth arrest and DNA fragmentation of CD30(+) tumor cells. In this study, we investigated the contributions of Fc-mediated effector cell functions to SGN-30 activity. We determined that antibody-dependent cellular phagocytosis, mediated by macrophages, to contribute significantly to antitumor activity in vitro. To delineate the identity of the host effector cells involved in mediating antitumor activity in vivo, we studied the effects of effector cell ablation in a disseminated model of HD (L540cy). Depletion of macrophages markedly reduced efficacy of SGN-30, demonstrating that macrophages contribute significantly to SGN-30 efficacy in this model. These findings may have implications for patient stratification or combination treatment strategies in clinical trials conducted with SGN-30 in HD and ALCL. PMID:17909075

Oflazoglu, Ezogelin; Stone, Ivan J; Gordon, Kristine A; Grewal, Iqbal S; van Rooijen, Nico; Law, Che-Leung; Gerber, Hans-Peter

2007-12-15

314

Healthy HIV-1-Infected Individuals on Highly Active Antiretroviral Therapy Harbor HIV-1 in Their Alveolar Macrophages.  

PubMed

Abstract In a prospective cross-sectional study we quantified HIV viral load within the alveolar macrophage in a cohort of healthy HIV-infected subjects who did not have medical comorbidities or smoke cigarettes to determine if alveolar macrophage proviral DNA was associated with alveolar macrophage phagocytic immune dysfunction. We enrolled 23 subjects who underwent bronchoscopy and bronchoalveolar lavage. Alveolar macrophages were isolated and HIV-1 RNA was quantified in the cells using the Abbott RealTime HIV-1 Assay. Proviral DNA was qualitatively measured using a modified version of the HIV-1 RNA assay. Phagocytosis measured by incubating alveolar macrophages with FITC-labeled Staphylococcus aureus and determining fluorescence with a Zeiss inverted microscope. Phagocytic index was calculated as (% positive cells×mean channel fluorescence)/100. Sixteen subjects had (+) proviral DNA and seven had (-) proviral DNA in their alveolar macrophages. Of all subjects 100% in both groups were on highly active antiretroviral therapy (HAART). The median plasma viral load was 0 in both groups. HIV-1-infected subjects with (+) proviral DNA in their alveolar macrophages had a significantly lower median alveolar macrophage phagocytic index compared to those with (-) proviral DNA in their alveolar macrophages [11.8 (IQR 4.8-39.0) vs. 64.9 (IQR 14.0-166.0), p=0.05]. Alveolar macrophages harbor HIV even in otherwise healthy subjects with undetectable plasma viral loads, representing a potential reservoir for the virus. In addition, HIV viral replication within the macrophage may impair phagocytosis and other immune functions in the lung, leading to an increased risk for lung infection. PMID:25134819

Cribbs, Sushma K; Lennox, Jeffrey; Caliendo, Angela M; Brown, Lou Ann; Guidot, David M

2015-01-01

315

Increase in Hypotonic Stress-Induced Endocytic Activity in Macrophages via ClC-3  

PubMed Central

Extracellular hypotonic stress can affect cellular function. Whether and how hypotonicity affects immune cell function remains to be elucidated. Macrophages are immune cells that play key roles in adaptive and innate in immune reactions. The purpose of this study was to investigate the role and underlying mechanism of hypotonic stress in the function of bone marrow-derived macrophages (BMDMs). Hypotonic stress increased endocytic activity in BMDMs, but there was no significant change in the expression of CD80, CD86, and MHC class II molecules, nor in the secretion of TNF-? or IL-10 by BMDMs. Furthermore, the enhanced endocytic activity of BMDMs triggered by hypotonic stress was significantly inhibited by chloride channel-3 (ClC-3) siRNA. Our findings suggest that hypotonic stress can induce endocytosis in BMDMs and that ClC-3 plays a central role in the endocytic process. PMID:24850147

Yan, Yutao; Ding, Yu; Ming, Bingxia; Du, Wenjiao; Kong, Xiaoling; Tian, Li; Zheng, Fang; Fang, Min; Tan, Zheng; Gong, Feili

2014-01-01

316

Fibrinogen drives dystrophic muscle fibrosis via a TGF?/alternative macrophage activation pathway  

PubMed Central

In the fatal degenerative Duchenne muscular dystrophy (DMD), skeletal muscle is progressively replaced by fibrotic tissue. Here, we show that fibrinogen accumulates in dystrophic muscles of DMD patients and mdx mice. Genetic loss or pharmacological depletion of fibrinogen in these mice reduced fibrosis and dystrophy progression. Our results demonstrate that fibrinogen–Mac-1 receptor binding, through induction of IL-1?, drives the synthesis of transforming growth factor-? (TGF?) by mdx macrophages, which in turn induces collagen production in mdx fibroblasts. Fibrinogen-produced TGF? further amplifies collagen accumulation through activation of profibrotic alternatively activated macrophages. Fibrinogen, by engaging its ?v?3 receptor on fibroblasts, also directly promotes collagen synthesis. These data unveil a profibrotic role of fibrinogen deposition in muscle dystrophy. PMID:18593877

Vidal, Berta; Serrano, Antonio L.; Tjwa, Marc; Suelves, Mňnica; Ardite, Esther; De Mori, Roberta; Baeza-Raja, Bernat; Martínez de Lagrán, María; Lafuste, Peggy; Ruiz-Bonilla, Vanessa; Jardí, Mercč; Gherardi, Romain; Christov, Christo; Dierssen, Mara; Carmeliet, Peter; Degen, Jay L.; Dewerchin, Mieke; Muńoz-Cánoves, Pura

2008-01-01

317

ELECTROSTATIC CHARGE ON NANO-PARTICLES ACTIVATES CNS MACROPHAGES (MICROGLIA).  

EPA Science Inventory

Nanometer size particles carry free radical activity on their surface and can produce oxidative stress (OS)-mediated damage upon impact to target cells. The initiating event of phage cell activation (i.e., the oxidative burst) is unknown, although many proximal events have been i...

318

In vitro analysis of STAT5 activation by granulocyte-macrophage colony-stimulating factor  

Microsoft Academic Search

Background: The granulocyte-macrophage colony-sti- mulating factor (GM-CSF) receptor activates multiple and complex signalling pathways in response to GM- CSF stimulation. Biochemical studies suggested that signalling pathways are transmitted through protein\\/ protein interactions, but how these biochemical cascades are initiated and transmitted in response to cytokine stimulation is largely unknown. Results: To investigate these events biochemically, we established an in vitro

Yoshiko Sakurai; Ken-ichi Arai; Sumiko Watanabe

2000-01-01

319

Macrophage peroxisome proliferator-activated receptor ? deficiency delays skin wound healing through impairing apoptotic cell clearance in mice.  

PubMed

Skin wound macrophages are key regulators of skin repair and their dysfunction causes chronic, non-healing skin wounds. Peroxisome proliferator-activated receptor gamma (PPAR?) regulates pleiotropic functions of macrophages, but its contribution in skin wound healing is poorly defined. We observed that macrophage PPAR? expression was upregulated during skin wound healing. Furthermore, macrophage PPAR? deficiency (PPAR?-knock out (KO)) mice exhibited impaired skin wound healing with reduced collagen deposition, angiogenesis and granulation formation. The tumor necrosis factor alpha (TNF-?) expression in wounds of PPAR?-KO mice was significantly increased and local restoration of TNF-? reversed the healing deficit in PPAR?-KO mice. Wound macrophages produced higher levels of TNF-? in PPAR?-KO mice compared with control. In vitro, the higher production of TNF-? by PPAR?-KO macrophages was associated with impaired apoptotic cell clearance. Correspondingly, increased apoptotic cell accumulation was found in skin wound of PPAR?-KO mice. Mechanically, peritoneal and skin wound macrophages expressed lower levels of various phagocytosis-related molecules. In addition, PPAR? agonist accelerated wound healing and reduced local TNF-? expression and wound apoptotic cells accumulation in wild type but not PPAR?-KO mice. Therefore, PPAR? has a pivotal role in controlling wound macrophage clearance of apoptotic cells to ensure efficient skin wound healing, suggesting a potential new therapeutic target for skin wound healing. PMID:25590807

Chen, H; Shi, R; Luo, B; Yang, X; Qiu, L; Xiong, J; Jiang, M; Liu, Y; Zhang, Z; Wu, Y

2015-01-01

320

Macrophages from the synovium of active rheumatoid arthritis exhibit an activin A-dependent pro-inflammatory profile.  

PubMed

Rheumatoid arthritis (RA) is a chronic inflammatory disease whose pathogenesis and severity correlates with the presence of macrophage-derived pro-inflammatory cytokines within the inflamed synovium. Macrophage-derived cytokines fuel the pathological processes in RA and are targets of clinically successful therapies. However, although macrophage polarization determines cytokine production, the polarization state of macrophages in RA joints remains poorly defined. To dissect the molecular basis for the tissue-damaging effects of macrophages in RA joints, we undertook the phenotypic and transcriptomic characterization of ex vivo isolated CD14(+) RA synovial fluid (RA-SF) macrophages. Flow cytometry and gene profiling indicated that RA-SF macrophages express pro-inflammatory polarization markers (MMP12, EGLN3, CCR2), lack expression of markers associated with homeostatic and anti-inflammatory polarization (IGF1, HTR2B) and exhibit a transcriptomic profile that resembles the activin A-dependent gene signature of pro-inflammatory in vitro-generated macrophages. In fact, high levels of Smad-activating activin A were found in RA-SF and, accordingly, the Smad signalling pathway was activated in ex vivo-isolated RA-SF macrophages. In vitro experiments on monocytes and macrophages indicated that RA-SF promoted the acquisition of pro-inflammatory markers (INHBA, MMP12, EGLN3, CCR2) but led to a significant reduction in the expression of genes associated with homeostasis and inflammation resolution (FOLR2, SERPINB2, IGF1, CD36), thus confirming the pro-inflammatory polarization ability of RA-SF. Importantly, the macrophage-polarizing ability of RA-SF was inhibited by an anti-activin A-neutralizing antibody, thus demonstrating that activin A mediates the pro-inflammatory macrophage-polarizing ability of RA-SF. Moreover, and in line with these findings, multicolour immunofluorescence evidenced that macrophages within RA synovial membranes (RA-SM) also express pro-inflammatory polarization markers whose expression is activin A-dependent. Altogether, our results demonstrate that macrophages from RA synovial fluids and membranes exhibit an MMP12(+) EGLN3(+) CCR2(+) pro-inflammatory polarization state whose acquisition is partly dependent on activin A from the synovial fluid. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:25319955

Soler Palacios, Blanca; Estrada-Capetillo, Lizbeth; Izquierdo, Elena; Criado, Gabriel; Nieto, Concha; Municio, Cristina; González-Alvaro, Isidoro; Sánchez-Mateos, Paloma; Pablos, Jose Luis; Corbí, Angel L; Puig-Kröger, Amaya

2015-02-01

321

The role of macrophage activation and of Bcg-encoded macrophage function(s) in the control of Mycobacterium avium infection in mice.  

PubMed Central

Following the intraperitoneal inoculation of 2.5 x 10(8) colony-forming units of Mycobacterium avium strain ATCC 25291, there was bacillary growth in the liver, spleen and peritoneal cavity of C57BL/6, C57BL/10, DBA/1 and BALB/c mice whereas DBA/2, C3H/He, CBA/Ca and CD-1 mice controlled the infection showing constant or slightly decreasing numbers of viable bacteria in the liver and spleen and effective clearance of the bacilli from the peritoneal cavities. The acquisition of non-specific resistance (NSR) to Listeria monocytogenes during the infection by M. avium was high in C57BL/6, BALB/c and C3H/He mice and negligible in DBA/2 and CD-1 mice. The magnitude of the acquisition of NSR was reduced in T cell-deficient mice and was directly proportional to the dose of the inoculum of M. avium. The production of hydrogen peroxide by phorbol myristate acetate-stimulated peritoneal macrophages of M. avium-infected mice was higher in C57BL/6 and BALB/c mice than in CD-1, DBA/2 and C3H/He animals. BALB/c. Bcgr (C.D2) mice, unlike their congenic strain BALB/c, restricted bacterial growth following the intravenous inoculation of 2.5 x 10(8) CFU of M. avium as efficiently as DBA/2 mice. C.D2 and BALB/c peritoneal macrophages from infected mice produced similar amounts of H2O2 but BALB/c mice developed higher levels of NSR to listeria than C.D2 mice. The production of nitrite by peritoneal macrophages from infected mice was found to be enhanced in DBA/2 and C3H/He but not in BALB/c, C57BL/6, DC-1 and C.D2 mice. Resident peritoneal macrophages from C.D2 mice were more bacteriostatic in vitro for M. avium than macrophages from BALB/c mice. The same relative differences between the two macrophage populations were observed when the cells were activated with lymphokines. The results show that the populations were observed when the cells were activated with lymphokines. The results show that the resistance to M. avium infection in mice is under the control of the Bcg gene and that susceptibility may be due to some defect in macrophage antibacterial function not completely overcome by the activation of this phagocyte in the susceptible strains of mice. PMID:2115416

Appelberg, R; Sarmento, A M

1990-01-01

322

Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes  

PubMed Central

Type 2 diabetes mellitus (T2DM) progresses from compensated insulin resistance to beta ceil failure resulting in uncompensated hyperglycemia, a process replicated in the Zucker diabetic fatty (ZDF) rat. The Nlrp3 inflammasome has been implicated in obesity-induced insulin resistance and beta cell failure. Endocannabinoids contribute to insuiin resistance through activation of peripheral CB1 receptors (CB1Rs) and also promote beta cell failure. Here we show that beta cell failure in adult ZDF rats is not associated with CB1R signaling in beta ceils, but rather in M1 macrophages infiltrating into pancreatic islets, and that this leads to activation of the Nlrp3-ASC inflammasome in the macrophages. These effects are replicated in vitro by incubating wild-type human or rodent macrophages, but not macrophages from CB1R-deficient [Cnr1?/?) or Nlrp3?/? mice, with the endocannabinoid anandamide. Peripheral CB1R blockade, in vivo depletion of macrophages or macrophage-specific knockdown of CB1R reverses or prevents these changes and restores normoglycemia and glucose-induced insulin secretion. These findings implicate endocannabinoids and inflammasome activation in beta cell failure and identify macrophage-expressed CB1R as a therapeutic target in T2DM. PMID:23955712

Jourdan, Tony; Godlewski, Grzegorz; Cinar, Resat; Bertola, Adeline; Szanda, Gergö; Liu, Jie; Tarn, Joseph; Han, Tiffany; Mukhopadhyay, Bani; Skarulis, Monica C; Ju, Cynthia; Aouadis, Myriam; Czech, Michael P; Kunos, George

2014-01-01

323

Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes.  

PubMed

Type 2 diabetes mellitus (T2DM) progresses from compensated insulin resistance to beta cell failure resulting in uncompensated hyperglycemia, a process replicated in the Zucker diabetic fatty (ZDF) rat. The Nlrp3 inflammasome has been implicated in obesity-induced insulin resistance and beta cell failure. Endocannabinoids contribute to insulin resistance through activation of peripheral CB1 receptors (CB?Rs) and also promote beta cell failure. Here we show that beta cell failure in adult ZDF rats is not associated with CB?R signaling in beta cells, but rather in M1 macrophages infiltrating into pancreatic islets, and that this leads to activation of the Nlrp3-ASC inflammasome in the macrophages. These effects are replicated in vitro by incubating wild-type human or rodent macrophages, but not macrophages from CB?R-deficient (Cnr1(-/-)) or Nlrp3(-/-) mice, with the endocannabinoid anandamide. Peripheral CB?R blockade, in vivo depletion of macrophages or macrophage-specific knockdown of CB?R reverses or prevents these changes and restores normoglycemia and glucose-induced insulin secretion. These findings implicate endocannabinoids and inflammasome activation in beta cell failure and identify macrophage-expressed CB?R as a therapeutic target in T2DM. PMID:23955712

Jourdan, Tony; Godlewski, Grzegorz; Cinar, Resat; Bertola, Adeline; Szanda, Gerg?; Liu, Jie; Tam, Joseph; Han, Tiffany; Mukhopadhyay, Bani; Skarulis, Monica C; Ju, Cynthia; Aouadi, Myriam; Czech, Michael P; Kunos, George

2013-09-01

324

Modulation of Macrophage Activation State Protects Tissue from Necrosis during Critical Limb Ischemia in Thrombospondin-1-Deficient Mice  

PubMed Central

Background Macrophages, key regulators of healing/regeneration processes, strongly infiltrate ischemic tissues from patients suffering from critical limb ischemia (CLI). However pro-inflammatory markers correlate with disease progression and risk of amputation, suggesting that modulating macrophage activation state might be beneficial. We previously reported that thrombospondin-1 (TSP-1) is highly expressed in ischemic tissues during CLI in humans. TSP-1 is a matricellular protein that displays well-known angiostatic properties in cancer, and regulates inflammation in vivo and macrophages properties in vitro. We therefore sought to investigate its function in a mouse model of CLI. Methods and Findings Using a genetic model of tsp-1?/? mice subjected to femoral artery excision, we report that tsp-1?/? mice were clinically and histologically protected from necrosis compared to controls. Tissue protection was associated with increased postischemic angiogenesis and muscle regeneration. We next showed that macrophages present in ischemic tissues exhibited distinct phenotypes in tsp-1?/? and wt mice. A strong reduction of necrotic myofibers phagocytosis was observed in tsp-1?/? mice. We next demonstrated that phagocytosis of muscle cell debris is a potent pro-inflammatory signal for macrophages in vitro. Consistently with these findings, macrophages that infiltrated ischemic tissues exhibited a reduced postischemic pro-inflammatory activation state in tsp-1?/? mice, characterized by a reduced Ly-6C expression and a less pro-inflammatory cytokine expression profile. Finally, we showed that monocyte depletion reversed clinical and histological protection from necrosis observed in tsp-1?/? mice, thereby demonstrating that macrophages mediated tissue protection in these mice. Conclusion This study defines targeting postischemic macrophage activation state as a new potential therapeutic approach to protect tissues from necrosis and promote tissue repair during CLI. Furthermore, our data suggest that phagocytosis plays a crucial role in promoting a deleterious intra-tissular pro-inflammatory macrophage activation state during critical injuries. Finally, our results describe TSP-1 as a new relevant physiological target during critical leg ischemia. PMID:19079608

Bréchot, Nicolas; Gomez, Elisa; Bignon, Marine; Khallou-Laschet, Jamila; Dussiot, Michael; Cazes, Aurélie; Alanio-Bréchot, Cécile; Durand, Mélanie; Philippe, Josette; Silvestre, Jean-Sébastien; Van Rooijen, Nico; Corvol, Pierre; Nicoletti, Antonino; Chazaud, Bénédicte; Germain, Stéphane

2008-01-01

325

Immunomodulatory and Antibacterial Effects of Cystatin 9 against Francisella tularensis  

PubMed Central

Cystatin 9 (CST9) is a member of the type 2 cysteine protease inhibitor family, which has been shown to have immunomodulatory effects that restrain inflammation, but its functions against bacterial infections are unknown. Here, we report that purified human recombinant (r)CST9 protects against the deadly bacterium Francisella tularensis (Ft) in vitro and in vivo. Macrophages infected with the Ft human pathogen Schu 4 (S4), then given 50 pg of rCST9 exhibited significantly decreased intracellular bacterial replication and increased killing via preventing the escape of S4 from the phagosome. Further, rCST9 induced autophagy in macrophages via the regulation of the mammalian target of rapamycin (mTOR) signaling pathways. rCST9 promoted the upregulation of macrophage proteins involved in antiinflammation and antiapoptosis, while restraining proinflammatory-associated proteins. Interestingly, the viability and virulence of S4 also was decreased directly by rCST9. In a mouse model of Ft inhalation, rCST9 significantly decreased organ bacterial burden and improved survival, which was not accompanied by excessive cytokine secretion or subsequent immune cell migration. The current report is the first to show the immunomodulatory and antimicrobial functions of rCST9 against Ft. We hypothesize that the attenuation of inflammation by rCST9 may be exploited for therapeutic purposes during infection. PMID:23922243

Eaves-Pyles, Tonyia; Patel, Jignesh; Arigi, Emma; Cong, Yingzi; Cao, Anthony; Garg, Nisha; Dhiman, Monisha; Pyles, Richard B; Arulanandam, Bernard; Miller, Aaron L; Popov, Vsevolod L; Soong, Lynn; Carlsen, Eric D; Coletta, Ciro; Szabo, Csaba; Almeida, Igor C.

2013-01-01

326

Effect of estragole on leukocyte behavior and phagocytic activity of macrophages.  

PubMed

Estragole, a chemical constituent of the essential oils of many aromatic plants, is used as flavoring in beverage and food industries. In vivo and in vitro experimental assays have shown that EST has sedative, anticonvulsant, antioxidant, antimicrobial, and anesthetic activity. In this work, we evaluate the effect of EST on leukocyte behavior and phagocytic activity of macrophages. In the peritonitis model, EST (500 and 750?mg/kg) decreased the infiltration of peritoneal exudate leukocytes. In vitro chemotaxis assay showed that EST (3, 10, 30, and 60??g/mL) inhibited neutrophil migration toward fMLP. In the in vivo microcirculation assay, EST at doses of 250, 500, and 750?mg/kg significantly reduced the number of rolling and adherent leukocytes and at doses of 250 and 500?mg/kg decreased number of leukocyte migrated to perivascular tissue. The results showed that EST (3, 10, and 30??g/mL) was able to stimulate the macrophages phagocytosis but only at concentration of 10??g/mL promoted an increase in nitric oxide (NO) production. In conclusion, this study showed that EST had potential anti-inflammatory effects, likely by inhibiting leukocyte migration and by stimulating macrophages phagocytosis. PMID:25152763

Silva-Comar, Francielli Maria de Souza; Wiirzler, Luiz Alexandre Marques; Silva-Filho, Saulo Euclides; Kummer, Raquel; Pedroso, Raissa Bocchi; Spironello, Ricardo Alexandre; Silva, Expedito Leite; Bersani-Amado, Ciomar Aparecida; Cuman, Roberto Kenji Nakamura

2014-01-01

327

Quantitative Proteomics Reveals the Induction of Mitophagy in Tumor Necrosis Factor-?-activated (TNF?) Macrophages*  

PubMed Central

Macrophages play an important role in innate and adaptive immunity as professional phagocytes capable of internalizing and degrading pathogens to derive antigens for presentation to T cells. They also produce pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-?) that mediate local and systemic responses and direct the development of adaptive immunity. The present work describes the use of label-free quantitative proteomics to profile the dynamic changes of proteins from resting and TNF-?-activated mouse macrophages. These analyses revealed that TNF-? activation of macrophages led to the down-regulation of mitochondrial proteins and the differential regulation of several proteins involved in vesicle trafficking and immune response. Importantly, we found that the down-regulation of mitochondria proteins occurred through mitophagy and was specific to TNF-?, as other cytokines such as IL-1? and IFN-? had no effect on mitochondria degradation. Furthermore, using a novel antigen presentation system, we observed that the induction of mitophagy by TNF-? enabled the processing and presentation of mitochondrial antigens at the cell surface by MHC class I molecules. These findings highlight an unsuspected role of TNF-? in mitophagy and expanded our understanding of the mechanisms responsible for MHC presentation of self-antigens. PMID:23674617

Bell, Christina; English, Luc; Boulais, Jonathan; Chemali, Magali; Caron-Lizotte, Olivier; Desjardins, Michel; Thibault, Pierre

2013-01-01

328

Biologic activities of the beta-chemokine TCA3 on neutrophils and macrophages.  

PubMed

Previous in vivo and in vitro studies demonstrated that the murine beta-chemokine TCA3 is a chemoattractant for monocytes/macrophages and neutrophils. The ability of TCA3 to activate these cell populations is now evaluated. Treatment with 10 to 20 nM rTCA3 induced a respiratory burst with the production of superoxide and hydrogen peroxide in both casein-elicited and unstimulated neutrophil and macrophage populations. In addition, TCA3 treatment induced the production of reactive nitrogen intermediates, whereas stimulation with higher concentrations (100 nM) of TCA3 induced the exocytosis of lysozyme and elastase in the presence of cytochalasin B (7 micrograms/ml). Subnanomolar concentrations (100 pM) of TCA3 also caused integrin-mediated increases of adhesiveness to fibrinogen by neutrophils and macrophages. Increased adhesiveness is the most sensitive assay for TCA3 bioactivity. TCA3 treatment appears to involve signaling through a G-protein-linked receptor as Pertussis toxin abolished the TCA3-mediated increase of adhesiveness and the production of reactive nitrogen intermediates. The dose dependence of the TCA3-mediated activities indicate a coordinated inflammatory response mediated by varying concentrations of TCA3. PMID:7730638

Devi, S; Laning, J; Luo, Y; Dorf, M E

1995-05-15

329

Macrophage activation syndrome in a patient with pulmonary inflammatory myofibroblastic tumour  

PubMed Central

We describe for the first time a case of macrophage activation syndrome (MAS) in a patient with a history of inflammatory myofibroblastic tumour (inflammatory pseudotumour, IPT) of the lung and thoracic spine. The patient was admitted to the intensive care unit with a history of prolonged remitting fever, hepatosplenomegaly, bilaterally enlarged thoracic lymph nodes and an acute severe inflammatory response syndrome (SIRS). Up-regulated cytokine production (e.g. IL-1ß and IL-6), increased levels of ferritin and circulating soluble interleukin-2 receptor (sIL-2R, sCD25) led to the differential diagnosis of MAS. Bone marrow aspiration, the main tool for a definite diagnosis, revealed macrophages phagocytosing haematopoietic cells. Immunosuppressive therapy with corticosteroids and cyclosporine was an effective treatment in this patient. PMID:22607519

2012-01-01

330

Structurally well-defined macrophage activating factor derived from vitamin D3-binding protein has a potent adjuvant activity for immunization.  

PubMed

Freund's adjuvant produced severe inflammation that augments development of antibodies. Thus, mixed administration of antigens with adjuvant was not required as long as inflammation was induced in the hosts. Since macrophage activation for phagocytosis and antigen processing is the first step of antibody development, inflammation-primed macrophage activation plays a major role in immune development. Therefore, macrophage activating factor should act as an adjuvant for immunization. The inflammation-primed macrophage activation process is the major macrophage activating cascade that requires participation of serum vitamin D3-binding protein (DBP; human DBP is known as Gc protein) and glycosidases of B and T lymphocytes. Stepwise incubation of Gc protein with immobilized beta-galactosidase and sialidase efficiently generated the most potent macrophage activating factor (designated GcMAF) we have ever encountered. Administration of GcMAF (20 or 100 pg/mouse) resulted in stimulation of the progenitor cells for extensive mitogenesis and activation of macrophages. Administration of GcMAF (100 pg/mouse) along with immunization of mice with sheep red blood cells (SRBC) produced a large number of anti-SRBC antibody secreting splenic cells in 2-4 days. Thus, GcMAF has a potent adjuvant activity for immunization. Although malignant tumours are poorly immunogenic, 4 days after GcMAF-primed immunization of mice with heat-killed Ehrlich ascites tumour cells, the ascites tumour was no longer transplantable in these mice. PMID:9682967

Yamamoto, N; Naraparaju, V R

1998-06-01

331

Epigenome-Guided Analysis of the Transcriptome of Plaque Macrophages during Atherosclerosis Regression Reveals Activation of the Wnt Signaling Pathway  

PubMed Central

We report the first systems biology investigation of regulators controlling arterial plaque macrophage transcriptional changes in response to lipid lowering in vivo in two distinct mouse models of atherosclerosis regression. Transcriptome measurements from plaque macrophages from the Reversa mouse were integrated with measurements from an aortic transplant-based mouse model of plaque regression. Functional relevance of the genes detected as differentially expressed in plaque macrophages in response to lipid lowering in vivo was assessed through analysis of gene functional annotations, overlap with in vitro foam cell studies, and overlap of associated eQTLs with human atherosclerosis/CAD risk SNPs. To identify transcription factors that control plaque macrophage responses to lipid lowering in vivo, we used an integrative strategy – leveraging macrophage epigenomic measurements – to detect enrichment of transcription factor binding sites upstream of genes that are differentially expressed in plaque macrophages during regression. The integrated analysis uncovered eight transcription factor binding site elements that were statistically overrepresented within the 5? regulatory regions of genes that were upregulated in plaque macrophages in the Reversa model under maximal regression conditions and within the 5? regulatory regions of genes that were upregulated in the aortic transplant model during regression. Of these, the TCF/LEF binding site was present in promoters of upregulated genes related to cell motility, suggesting that the canonical Wnt signaling pathway may be activated in plaque macrophages during regression. We validated this network-based prediction by demonstrating that ?-catenin expression is higher in regressing (vs. control group) plaques in both regression models, and we further demonstrated that stimulation of canonical Wnt signaling increases macrophage migration in vitro. These results suggest involvement of canonical Wnt signaling in macrophage emigration from the plaque during lipid lowering-induced regression, and they illustrate the discovery potential of an epigenome-guided, systems approach to understanding atherosclerosis regression. PMID:25474352

Menon, Prashanthi; Podolsky, Irina; Feig, Jonathan E.; Aderem, Alan; Fisher, Edward A.; Gold, Elizabeth S.

2014-01-01

332

Helminth induced suppression of macrophage activation is correlated with inhibition of calcium channel activity.  

PubMed

Helminth parasites cause persistent infections in humans and yet many infected individuals are asymptomatic. Neurocysticercosis (NCC), a disease of the central nervous system (CNS) caused by the cestode Taenia solium, has a long asymptomatic phase correlated with an absence of brain inflammation. However, the mechanisms of immune suppression remain poorly understood. Here we report that murine NCC displays a lack of cell surface maturation markers in infiltrating myeloid cells. Furthermore, soluble parasite ligands (PL) failed to induce maturation of macrophages, and inhibited TLR-induced inflammatory cytokine production. Importantly, PL treatment abolished both LPS and thapsigargin-induced store operated Ca2+ entry (SOCE). Moreover, electrophysiological recordings demonstrated PL-mediated inhibition of LPS or Tg-induced currents that were TRPC1-dependent. Concomitantly STIM1-TRPC1 complex was also impaired that was essential for SOCE and sustained Ca2+ entry. Likewise loss of SOCE due to PL further inhibited NFkB activation. Overall, our results indicate that the negative regulation of agonist induced Ca2+ signaling pathway by parasite ligands may be a novel immune suppressive mechanism to block the initiation of the inflammatory response associated with helminth infections. PMID:25013939

Chauhan, Arun; Sun, Yuyang; Pani, Biswaranjan; Quenumzangbe, Fredice; Sharma, Jyotika; Singh, Brij B; Mishra, Bibhuti B

2014-01-01

333

Macrophage immunomodulation by breast cancer-derived exosomes requires Toll-like receptor 2-mediated activation of NF-?B  

PubMed Central

Growing evidence links tumor progression with chronic inflammatory processes and dysregulated activity of various immune cells. In this study, we demonstrate that various types of macrophages internalize microvesicles, called exosomes, secreted by breast cancer and non-cancerous cell lines. Although both types of exosomes targeted macrophages, only cancer-derived exosomes stimulated NF-?B activation in macrophages resulting in secretion of pro-inflammatory cytokines such as IL-6, TNF?, GCSF, and CCL2. In vivo mouse experiments confirmed that intravenously injected exosomes are efficiently internalized by macrophages in the lung and brain, which correlated with upregulation of inflammatory cytokines. In mice bearing xenografted human breast cancers, tumor-derived exosomes were internalized by macrophages in axillary lymph nodes thereby triggering expression of IL-6. Genetic ablation of Toll-like receptor 2 (TLR2) or MyD88, a critical signaling adaptor in the NF-?B pathway, completely abolished the effect of tumor-derived exosomes. In contrast, inhibition of TLR4 or endosomal TLRs (TLR3/7/8/9) failed to abrogate NF-?B activation by exosomes. We further found that palmitoylated proteins present on the surface of tumor-secreted exosomes contributed to NF-?B activation. Thus, our results highlight a novel mechanism used by breast cancer cells to induce pro-inflammatory activity of distant macrophages through circulating exosomal vesicles secreted during cancer progression. PMID:25034888

Chow, Amy; Zhou, Weiying; Liu, Liang; Fong, Miranda Y.; Champer, Jackson; Van Haute, Desiree; Chin, Andrew R.; Ren, Xiubao; Gugiu, Bogdan Gabriel; Meng, Zhipeng; Huang, Wendong; Ngo, Vu; Kortylewski, Marcin; Wang, Shizhen Emily

2014-01-01

334

A Novel Polysaccharide in Insects Activates the Innate Immune System in Mouse Macrophage RAW264 Cells  

PubMed Central

A novel water-soluble polysaccharide was identified in the pupae of the melon fly (Bactrocera cucurbitae) as a molecule that activates the mammalian innate immune response. We attempted to purify this innate immune activator using nitric oxide (NO) production in mouse RAW264 macrophages as an indicator of immunostimulatory activity. A novel acidic polysaccharide was identified, which we named “dipterose”, with a molecular weight of 1.01×106 and comprising nine monosaccharides. Dipterose was synthesized in the melon fly itself at the pupal stage. The NO-producing activity of dipterose was approximately equal to that of lipopolysaccharide, a potent immunostimulator. Inhibition of Toll-like receptor 4 (TLR4) led to the suppression of NO production by dipterose. Furthermore, dipterose induced the expression of proinflammatory cytokines and interferon ? (IFN?) and promoted the activation of nuclear factor kappa B (NF-?B) in macrophages, indicating that it stimulates the induction of various cytokines in RAW264 cells via the TLR4 signaling pathway. Our results thus suggest that dipterose activates the innate immune response against various pathogenic microorganisms and viral infections. This is the first identification of an innate immune-activating polysaccharide from an animal. PMID:25490773

Ohta, Takashi; Ido, Atsushi; Kusano, Kie; Miura, Chiemi; Miura, Takeshi

2014-01-01

335

A Novel Polysaccharide in Insects Activates the Innate Immune System in Mouse Macrophage RAW264 Cells.  

PubMed

A novel water-soluble polysaccharide was identified in the pupae of the melon fly (Bactrocera cucurbitae) as a molecule that activates the mammalian innate immune response. We attempted to purify this innate immune activator using nitric oxide (NO) production in mouse RAW264 macrophages as an indicator of immunostimulatory activity. A novel acidic polysaccharide was identified, which we named "dipterose", with a molecular weight of 1.01×106 and comprising nine monosaccharides. Dipterose was synthesized in the melon fly itself at the pupal stage. The NO-producing activity of dipterose was approximately equal to that of lipopolysaccharide, a potent immunostimulator. Inhibition of Toll-like receptor 4 (TLR4) led to the suppression of NO production by dipterose. Furthermore, dipterose induced the expression of proinflammatory cytokines and interferon ? (IFN?) and promoted the activation of nuclear factor kappa B (NF-?B) in macrophages, indicating that it stimulates the induction of various cytokines in RAW264 cells via the TLR4 signaling pathway. Our results thus suggest that dipterose activates the innate immune response against various pathogenic microorganisms and viral infections. This is the first identification of an innate immune-activating polysaccharide from an animal. PMID:25490773

Ohta, Takashi; Ido, Atsushi; Kusano, Kie; Miura, Chiemi; Miura, Takeshi

2014-01-01

336

Intracellular Pathogen Leishmania donovani Activates Hypoxia Inducible Factor-1 by Dual Mechanism for Survival Advantage within Macrophage  

PubMed Central

Recent evidence established a crucial role for mammalian oxygen sensing transcription factor hypoxia inducible factor-1 (HIF-1) in innate immunity against intracellular pathogens. In response to most of these pathogens host phagocytes increase transcription of HIF-1?, the regulatory component of HIF-1 to express various effector molecules against invaders. Leishmania donovani (LD), a protozoan parasite and the causative agent of fatal visceral leishmaniasis resides in macrophages within mammalian host. The mechanism of HIF-1 activation or its role in determining the fate of LD in infected macrophages is still not known. To determine that J774 macrophages were infected with LD and about four-fold increase in HIF-1 activity and HIF-1? expression were detected. A strong increase in HIF-1? expression and nuclear localization was also detected in LD-infected J774 cells, peritoneal macrophages and spleen derived macrophages of LD-infected BALB/c mice. A two-fold increase in HIF-1? mRNA was detected in LD-infected macrophages suggesting involvement of a transcriptional mechanism that was confirmed by promoter activity. We further revealed that LD also induced HIF-1? expression by depleting host cellular iron pool to affect prolyl hydroxylase activity resulting in to stabilization of HIF-1?. To determine the role of HIF-1 on intracellular LD, cells were transfected with HIF-1? siRNA to attenuate its expression and then infected with LD. Although, initial infection rate of LD in HIF-1? attenuated cells was not affected but intracellular growth of LD was significantly inhibited; while, over-expression of stabilized form of HIF-1? promoted intracellular growth of LD in host macrophage. Our results strongly suggest that LD activates HIF-1 by dual mechanism for its survival advantage within macrophage. PMID:22701652

Singh, Amit Kumar; Mukhopadhyay, Chaitali; Biswas, Sudipta; Singh, Vandana Kumari; Mukhopadhyay, Chinmay K.

2012-01-01

337

Activation of J77A.1 Macrophages by Three Phospholipases A2 Isolated from Bothrops atrox Snake Venom  

PubMed Central

In the present study, we investigated the in vitro effects of two basic myotoxic phospholipases A2 (PLA2), BaTX-I, a catalytically inactive Lys-49 variant, and BaTX-II, a catalytically active Asp-49, and of one acidic myotoxic PLA2, BaPLA2, a catalytically active Asp-49, isolated from Bothrops atrox snake venom, on the activation of J774A.1 macrophages. At noncytotoxic concentrations, the toxins did not affect the adhesion of the macrophages, nor their ability to detach. The data obtained showed that only BaTX-I stimulated complement receptor-mediated phagocytosis. However, BaTX-I, BaTX-II, and BaPLA2 induced the release of the superoxide anion by J774A.1 macrophages. Additionally, only BaTX-I raised the lysosomal volume of macrophages after 15?min of incubation. After 30?min, all the phospholipases increased this parameter, which was not observed within 60?min. Moreover, BaTX-I, BaTX-II, and BaPLA2 increased the number of lipid bodies on macrophages submitted to phagocytosis and not submitted to phagocytosis. However, BaTX-II and BaPLA2 induced the release of TNF-? by J774A.1 macrophages. Taken together, the data show that, despite differences in enzymatic activity, the three toxins induced inflammatory events and whether the enzyme is acidic or basic does not seem to contribute to these effects. PMID:24592395

Furtado, Juliana L.; Oliveira, George A.; Pontes, Adriana S.; Setúbal, Sulamita da S.; Xavier, Caroline V.; Lacouth-Silva, Fabianne; Lima, Beatriz F.; Zaqueo, Kayena D.; Kayano, Anderson M.; Calderon, Leonardo A.; Stábeli, Rodrigo G.; Soares, Andreimar M.; Zuliani, Juliana P.

2014-01-01

338

Expression and secretion of type beta transforming growth factor by activated human macrophages.  

PubMed Central

Alveolar macrophages activated with concanavalin A and peripheral blood monocytes activated with lipopolysaccharide secrete type beta transforming growth factor (TGF-beta). There is minimal TGF-beta secretion in unactivated monocytes, even though TGF-beta mRNA is expressed in these cells at a level similar to that in activated, lipopolysaccharide-treated cultures. U937 lymphoma cells, which have monocytic characteristics, also express mRNA for TGF-beta. Freshly isolated monocytes, both control and lipopolysaccharide-treated, secrete an acid-labile binding protein that inhibits TGF-beta action. We conclude the following: (i) that expression of TGF-beta mRNA is unrelated to monocyte activation, (ii) that secretion of TGF-beta is induced by monocyte activation, and (iii) that cosecretion of TGF-beta and its monocyte/macrophage-derived binding protein may modulate growth factor action. In contrast, monocytic expression of other growth factor genes, such as the B chain of platelet-derived growth factor, is not constitutive and requires activation. Images PMID:2888109

Assoian, R K; Fleurdelys, B E; Stevenson, H C; Miller, P J; Madtes, D K; Raines, E W; Ross, R; Sporn, M B

1987-01-01

339

Primary alveolar macrophages exposed to diesel particulate matter increase RAGE expression and activate RAGE signaling.  

PubMed

Receptors for advanced glycation end-products (RAGE) are members of the immunoglobulin superfamily of cell-surface receptors implicated in mechanisms of pulmonary inflammation. In the current study, we test the hypothesis that RAGE mediates inflammation in primary alveolar macrophages (AMs) exposed to diesel particulate matter (DPM). Quantitative RT-PCR and immunoblotting revealed that RAGE was up-regulated in Raw264.7 cells, an immortalized murine macrophage cell line and primary AMs exposed to DPM for 2 h. Because DPM increased RAGE expression, we exposed Raw264.7 cells and primary AMs isolated from RAGE null and wild-type (WT) mice to DPM prior to the assessment of inflammatory signaling intermediates. DPM led to the activation of Rat sarcoma GTPase (Ras), p38 MAPK and NF-?B in WT AMs and, when compared to WT AMs, these intermediates were diminished in DPM-exposed AMs isolated from RAGE null mice. Furthermore, cytokines implicated in inflammation, including IL-4, IL-12, IL-13 and TNF?, were all significantly decreased in DPM-exposed RAGE null AMs compared to similarly exposed WT AMs. These results demonstrate that diesel-induced inflammatory responses by primary AMs are mediated, at least in part, via RAGE signaling mechanisms. Further work may show that RAGE signaling in both alveolar epithelial cells and resident macrophages is a potential target in the treatment of inflammatory lung diseases exacerbated by environmental pollution. PMID:24859220

Barton, David B; Betteridge, Bryce C; Earley, Tyler D; Curtis, Cameron S; Robinson, Adam B; Reynolds, Paul R

2014-10-01

340

Pleural macrophage recruitment and activation in asbestos-induced pleural injury.  

PubMed Central

The pathogenesis of asbestos-induced pleural fibrosis is poorly understood. Moreover, there has been a long-standing controversy regarding the relative potential of different commercial types of asbestos to cause pleural disease. We postulated that inhaled asbestos fibers translocate to the pleural space where they stimulate the recruitment and activation of pleural macrophages. To test this hypothesis, and to determine whether there are differences between inhaled amphibole and serpentine asbestos, Fischer 344 rats were exposed by intermittent inhalation (6 hr/day for 5 days/week over 2 weeks) to either National Institute of Environmental Health Sciences (NIEHS) crocidolite (average concentration 7.55 mg/m3) or NIEHS chrysotile fibers (average concentration 8.51 mg/m3). Comparisons were made with sham-exposed rats. The rats were sacrificed at 1 and 6 weeks after the cessation of exposure. More pleural macrophages were recovered at 1 and 6 weeks after crocidolite and chrysotile exposure than after sham exposure. Small numbers of crocidolite fibers (approximately 1 per 4000 cells) were detected in the pleural cell pellet of one crocidolite-exposed rat by scanning electron microscopy. Pleural macrophage supernatants were assayed for production of nitric oxide (NO) (by the Griess reaction) and tumor necrosis factor alpha (TNF-alpha) (by an enzyme-linked immunosorbent assay method). Significantly greater amounts of NO as well as TNF-alpha were generated by pleural macrophages at 1 and 6 weeks after either crocidolite or chrysotile inhalation than after sham exposure. Conceivably, translocation of asbestos fibers to the pleural space may provide a stimulus for persistent pleural space inflammation, cytokine production, and the generation of toxic oxygen and nitrogen radicals. Enhanced cytokine secretion within the pleural space may in turn upregulate adhesion molecule expression and the synthesis of extracellular matrix constituents by pleural mesothelial cells. Thus, our findings may have significance for the development of asbestos-induced pleural injury. Images Figure 1. PMID:9400734

Choe, N; Tanaka, S; Xia, W; Hemenway, D R; Roggli, V L; Kagan, E

1997-01-01

341

Pneumolysin Activates Macrophage Lysosomal Membrane Permeabilization and Executes Apoptosis by Distinct Mechanisms without Membrane Pore Formation  

PubMed Central

ABSTRACT Intracellular killing of Streptococcus pneumoniae is complemented by induction of macrophage apoptosis. Here, we show that the toxin pneumolysin (PLY) contributes both to lysosomal/phagolysosomal membrane permeabilization (LMP), an upstream event programing susceptibility to apoptosis, and to apoptosis execution via a mitochondrial pathway, through distinct mechanisms. PLY is necessary but not sufficient for the maximal induction of LMP and apoptosis. PLY’s ability to induce both LMP and apoptosis is independent of its ability to form cytolytic pores and requires only the first three domains of PLY. LMP involves TLR (Toll-like receptor) but not NLRP3/ASC (nucleotide-binding oligomerization domain [Nod]-like receptor family, pyrin domain-containing protein 3/apoptosis-associated speck-like protein containing a caspase recruitment domain) signaling and is part of a PLY-dependent but phagocytosis-independent host response that includes the production of cytokines, including interleukin-1 beta (IL-1?). LMP involves progressive and selective permeability to 40-kDa but not to 250-kDa fluorescein isothiocyanate (FITC)-labeled dextran, as PLY accumulates in the cytoplasm. In contrast, the PLY-dependent execution of apoptosis requires phagocytosis and is part of a host response to intracellular bacteria that also includes NO generation. In cells challenged with PLY-deficient bacteria, reconstitution of LMP using the lysomotrophic detergent LeuLeuOMe favored cell necrosis whereas PLY reconstituted apoptosis. The results suggest that PLY contributes to macrophage activation and cytokine production but also engages LMP. Following bacterial phagocytosis, PLY triggers apoptosis and prevents macrophage necrosis as a component of a broad-based antimicrobial strategy. This illustrates how a key virulence factor can become the focus of a multilayered and coordinated innate response by macrophages, optimizing pathogen clearance and limiting inflammation. PMID:25293758

Bewley, Martin A.; Naughton, Michael; Preston, Julie; Mitchell, Andrea; Holmes, Ashleigh; Marriott, Helen M.; Read, Robert C.; Mitchell, Timothy J.; Whyte, Moira K. B.

2014-01-01

342

Pleural macrophage recruitment and activation in asbestos-induced pleural injury.  

PubMed

The pathogenesis of asbestos-induced pleural fibrosis is poorly understood. Moreover, there has been a long-standing controversy regarding the relative potential of different commercial types of asbestos to cause pleural disease. We postulated that inhaled asbestos fibers translocate to the pleural space where they stimulate the recruitment and activation of pleural macrophages. To test this hypothesis, and to determine whether there are differences between inhaled amphibole and serpentine asbestos, Fischer 344 rats were exposed by intermittent inhalation (6 hr/day for 5 days/week over 2 weeks) to either National Institute of Environmental Health Sciences (NIEHS) crocidolite (average concentration 7.55 mg/m3) or NIEHS chrysotile fibers (average concentration 8.51 mg/m3). Comparisons were made with sham-exposed rats. The rats were sacrificed at 1 and 6 weeks after the cessation of exposure. More pleural macrophages were recovered at 1 and 6 weeks after crocidolite and chrysotile exposure than after sham exposure. Small numbers of crocidolite fibers (approximately 1 per 4000 cells) were detected in the pleural cell pellet of one crocidolite-exposed rat by scanning electron microscopy. Pleural macrophage supernatants were assayed for production of nitric oxide (NO) (by the Griess reaction) and tumor necrosis factor alpha (TNF-alpha) (by an enzyme-linked immunosorbent assay method). Significantly greater amounts of NO as well as TNF-alpha were generated by pleural macrophages at 1 and 6 weeks after either crocidolite or chrysotile inhalation than after sham exposure. Conceivably, translocation of asbestos fibers to the pleural space may provide a stimulus for persistent pleural space inflammation, cytokine production, and the generation of toxic oxygen and nitrogen radicals. Enhanced cytokine secretion within the pleural space may in turn upregulate adhesion molecule expression and the synthesis of extracellular matrix constituents by pleural mesothelial cells. Thus, our findings may have significance for the development of asbestos-induced pleural injury. PMID:9400734

Choe, N; Tanaka, S; Xia, W; Hemenway, D R; Roggli, V L; Kagan, E

1997-09-01

343

25-Hydroxycholesterol Activates the Integrated Stress Response to Reprogram Transcription and Translation in Macrophages*  

PubMed Central

25-Hydroxycholesterol (25OHC) is an enzymatically derived oxidation product of cholesterol that modulates lipid metabolism and immunity. 25OHC is synthesized in response to interferons and exerts broad antiviral activity by as yet poorly characterized mechanisms. To gain further insights into the basis for antiviral activity, we evaluated time-dependent responses of the macrophage lipidome and transcriptome to 25OHC treatment. In addition to altering specific aspects of cholesterol and sphingolipid metabolism, we found that 25OHC activates integrated stress response (ISR) genes and reprograms protein translation. Effects of 25OHC on ISR gene expression were independent of liver X receptors and sterol-response element-binding proteins and instead primarily resulted from activation of the GCN2/eIF2?/ATF4 branch of the ISR pathway. These studies reveal that 25OHC activates the integrated stress response, which may contribute to its antiviral activity. PMID:24189069

Shibata, Norihito; Carlin, Aaron F.; Spann, Nathanael J.; Saijo, Kaoru; Morello, Christopher S.; McDonald, Jeffrey G.; Romanoski, Casey E.; Maurya, Mano R.; Kaikkonen, Minna U.; Lam, Michael T.; Crotti, Andrea; Reichart, Donna; Fox, Jesse N.; Quehenberger, Oswald; Raetz, Christian R. H.; Sullards, M. Cameron; Murphy, Robert C.; Merrill, Alfred H.; Brown, H. Alex; Dennis, Edward A.; Fahy, Eoin; Subramaniam, Shankar; Cavener, Douglas R.; Spector, Deborah H.; Russell, David W.; Glass, Christopher K.

2013-01-01

344

Immunomodulatory functions of type I interferons  

PubMed Central

Interferon-? (IFN?) and IFN?, collectively known as type I IFNs, are the major effector cytokines of the host immune response against viral infections. However, the production of type I IFNs is also induced in response to bacterial ligands of innate immune receptors and/or bacterial infections, indicating a broader physiological role for these cytokines in host defence and homeostasis than was originally assumed. The main focus of this Review is the underappreciated immunomodulatory functions of type I IFNs in health and disease. We discuss their function in the regulation of innate and adaptive immune responses, the response to bacterial ligands, inflammasome activation, intestinal homeostasis and inflammatory and autoimmune diseases. PMID:22222875

González-Navajas, José M.; Lee, Jongdae; David, Michael; Raz, Eyal

2013-01-01

345

Mycobacterium bovis ornithine carbamoyltransferase, MB1684, induces proinflammatory cytokine gene expression by activating NF-?B in macrophages.  

PubMed

Mycobacterium bovis is the etiological factor of bovine tuberculosis (BTB), posing a significant problem to domestic cattle. The bacterium is also zoonotic, affecting human health worldwide. Macrophage evasion of the bacterium involves mycobacterial molecules such as MB1684 (ornithine carbamoyltransferase). In this study, we confirmed a concentration-dependent decrease in proliferation of Ana-1 macrophages when treated with rMB1684 when compared with mycobacterium bovis purified protein derivative of tuberculosis (MbPPD) or phosphate buffer solution incubation groups. We examined the activation of nuclear factor-kappa B (NF-?B) upon exposure to MB1684, and its role in MB1684-induced upregulation of interferon (IFN)-? and proinflammatory cytokines (interleukin [IL]-1?, IL-6, and tumor necrosis factor-?) in Ana-1 macrophages. The levels of proinflammatory cytokines and IFN-? were significantly high in MB1684-treated Ana-1 macrophages. The treatment led to an increase in NF-?B activation and a high expression of the just mentioned proinflammatory cytokines. NF-?B inhibition significantly abrogated MB1684-induced upregulation of proinflammatory cytokine mRNA expression, which suggests that MB1684-induced activation of NF-?B in turn stimulates gene expression of IFN-? and proinflammatory cytokines in Ana-1 macrophages. The experiment was repeated in bone marrow macrophages, a more in-vivo-like model system, and similar results validated our conclusion. Further, we identified the possibility of the application of MB1684 antigen for the detection of BTB in cattle serum. PMID:24568683

Zhao, Wei; Zhou, Xiangmei; Lu, Yun; Peng, Yun; Lin, Zhu; Lin, Jingjun; Yang, Lifeng; Yin, Xiaomin; Zhao, Deming

2014-05-01

346

Quercus infectoria galls possess antioxidant activity and abrogates oxidative stress-induced functional alterations in murine macrophages.  

PubMed

The present study reports the antioxidant activity of ethanolic extract of Quercus infectoria galls. The antioxidant potency of galls was investigated employing several established in vitro model systems. Their protective efficacy on oxidative modulation of murine macrophages was also explored. Gall extract was found to contain a large amount of polyphenols and possess a potent reducing power. HPTLC analysis of the extract suggested it to contain 19.925% tannic acid (TA) and 8.75% gallic acid (GA). The extract potently scavenged free radicals including DPPH (IC(50)~0.5 microg/ml), ABTS (IC(50)~1 microg/ml), hydrogen peroxide (H(2)O(2)) (IC(50)~2.6 microg/ml) and hydroxyl (*OH) radicals (IC(50)~6 microg/ml). Gall extract also chelated metal ions and inhibited Fe(3+) -ascorbate-induced oxidation of protein and peroxidation of lipids. Exposure of rat peritoneal macrophages to tertiary butyl hydroperoxide (tBOOH) induced oxidative stress in them and altered their phagocytic functions. These macrophages showed elevated secretion of lysosomal hydrolases, and attenuated phagocytosis and respiratory burst. Activity of macrophage mannose receptor (MR) also diminished following oxidant exposure. Pretreatment of macrophages with gall extract preserved antioxidant armory near to control values and significantly protected against all the investigated functional mutilations. MTT assay revealed gall extract to enhance percent survival of tBOOH exposed macrophages. These results indicate that Q. infectoria galls possess potent antioxidant activity, when tested both in chemical as well as biological models. PMID:18076871

Kaur, Gurpreet; Athar, Mohammad; Alam, M Sarwar

2008-02-15

347

The protein synthesis inhibitor anisomycin induces macrophage apoptosis in rabbit atherosclerotic plaques through p38 mitogen-activated protein kinase.  

PubMed

Because macrophages play a major role in atherosclerotic plaque destabilization, selective removal of macrophages represents a promising approach to stabilize plaques. We showed recently that the protein synthesis inhibitor cycloheximide, in contrast to puromycin, selectively depleted macrophages in rabbit atherosclerotic plaques without affecting smooth muscle cells (SMCs). The mechanism of action of these two translation inhibitors is dissimilar and could account for the differential effects on SMC viability. It is not known whether selective depletion of macrophages is confined to cycloheximide or whether it can also be achieved with translation inhibitors that have a similar mechanism of action. Therefore, in the present study, we investigated the effect of anisomycin, a translation inhibitor with a mechanism of action similar to cycloheximide, on macrophage and SMC viability. In vitro, anisomycin induced apoptosis of macrophages in a concentration-dependent manner, whereas SMCs were only affected at higher concentrations. In vivo, anisomycin selectively decreased the macrophage content of rabbit atherosclerotic plaques through apoptosis. The p38 mitogen-activated protein kinase (MAPK) inhibitor SB202190 [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole] prevented anisomycin-induced macrophage death, without affecting SMC viability. SB202190 decreased anisomycin-induced p38 MAPK phosphorylation, did not alter c-Jun NH(2)-terminal kinase (JNK) phosphorylation, and increased extracellular signal-regulated kinase (ERK) 1/2 phosphorylation. The latter effect was abolished by the mitogen-activated protein kinase kinase 1/2 inhibitor U0126 [1,4-diamino-2,3-dicyano-1,4-bis(2-aminophynyltio)butadiene ethanolate], although the prevention of anisomycin-induced macrophage death by SB202190 remained unchanged. The JNK phosphorylation inhibitor SP600125 did not affect anisomycin-induced macrophage or SMC death. In conclusion, anisomycin selectively decreased the macrophage content in rabbit atherosclerotic plaques, indicating that this effect is not confined to cycloheximide. p38 MAPK, but not ERK1/2 or JNK, plays a major role in anisomycin-induced macrophage death. PMID:19286921

Croons, Valerie; Martinet, Wim; Herman, Arnold G; Timmermans, Jean-Pierre; De Meyer, Guido R Y

2009-06-01

348

Acrolein activates matrix metalloproteinases by increasing reactive oxygen species in macrophages  

SciTech Connect

Acrolein is a ubiquitous component of environmental pollutants such as automobile exhaust, cigarette, wood, and coal smoke. It is also a natural constituent of several foods and is generated endogenously during inflammation or oxidation of unsaturated lipids. Because increased inflammation and episodic exposure to acrolein-rich pollutants such as traffic emissions or cigarette smoke have been linked to acute myocardial infarction, we examined the effects of acrolein on matrix metalloproteinases (MMPs), which destabilize atherosclerotic plaques. Our studies show that exposure to acrolein resulted in the secretion of MMP-9 from differentiated THP-1 macrophages. Acrolein-treatment of macrophages also led to an increase in reactive oxygen species (ROS), free intracellular calcium ([Ca{sup 2+}]{sub i}), and xanthine oxidase (XO) activity. ROS production was prevented by allopurinol, but not by rotenone or apocynin and by buffering changes in [Ca{sup 2+}]{sub I} with BAPTA-AM. The increase in MMP production was abolished by pre-treatment with the antioxidants Tiron and N-acetyl cysteine (NAC) or with the xanthine oxidase inhibitors allopurinol or oxypurinol. Finally, MMP activity was significantly stimulated in aortic sections from apoE-null mice containing advanced atherosclerotic lesions after exposure to acrolein ex vivo. These observations suggest that acrolein exposure results in MMP secretion from macrophages via a mechanism that involves an increase in [Ca{sup 2+}]{sub I}, leading to xanthine oxidase activation and an increase in ROS production. ROS-dependent activation of MMPs by acrolein could destabilize atherosclerotic lesions during brief episodes of inflammation or pollutant exposure.

O'Toole, Timothy E. [Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, KY 40202 (United States)], E-mail: teotoo01@gwise.louisville.edu; Zheng Yuting; Hellmann, Jason; Conklin, Daniel J.; Barski, Oleg; Bhatnagar, Aruni [Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, KY 40202 (United States)

2009-04-15

349

EPR demonstration of iron-nitrosyl complex formation by cytotoxic activated macrophages  

SciTech Connect

Activated macrophage cytotoxicity is characterized by loss of intracellular iron and inhibition of certain enzymes that have catalytically active nonheme-iron coordinated to sulfur. This phenomenon involves the oxidation of one of the terminal guanidino nitrogen atoms of L-arginine, which results in the production of citrulline and inorganic nitrogen oxides (NO2-, NO3-, and NO). We report here the results of an electron paramagnetic resonance spectroscopic study performed on cytotoxic activated macrophage (CAM) effector cells, which develop the same pattern of metabolic inhibition as their targets. Examination of activated macrophages from mice infected with Mycobacterium bovis (strain bacillus Calmette-Guerin) that were cultured in medium with lipopolysaccharide and L-arginine showed the presence of an axial signal at g = 2.039, which is similar to previously described iron-nitrosyl complexes formed from the destruction of iron-sulfur centers by nitric oxide (NO). Inhibition of the L-arginine-dependent pathway by addition of NG-monomethyl-L-arginine (methyl group on a terminal guanidino nitrogen) inhibits the production of nitrite, nitrate, citrulline, and the g = 2.039 signal. Comparison of the hyperfine structure of the signal from cells treated with L-arginine with terminal guanidino nitrogen atoms of natural abundance N14 atoms or labeled with N15 atoms showed that the nitrosyl group in this paramagnetic species arises from one of these two atoms. These results show that loss of iron-containing enzyme function in CAM is a result of the formation of iron-nitrosyl complexes induced by the synthesis of nitric oxide from the oxidation of a terminal guanidino nitrogen atom of L-arginine.

Lancaster, J.R. Jr.; Hibbs, J.B. Jr. (Utah State Univ., Logan (USA))

1990-02-01

350

CX3CR1 deficiency suppresses activation and neurotoxicity of microglia/macrophage in experimental ischemic stroke  

PubMed Central

Background Chemokine (C-X3-C motif) ligand 1 (CX3CL1)/ CX3C chemokine receptor 1 (CX3CR1) signaling is important in modulating the communication between neurons and resident microglia/migrated macrophages in the central nervous system (CNS). Although CX3CR1 deficiency is associated with an improved outcome following ischemic brain injury, the mechanism of this observation is largely unknown. The aim of this study was to investigate how CX3CR1 deficiency influences microglia/macrophage functions in the context of its protection following brain ischemia. Methods Wild-type (WT) and CX3CR1-deficient (CX3CR1-/-) mice were subjected to transient middle cerebral artery occlusion (MCAO) and reperfusion. The ischemic brain damage was monitored by rodent high-field magnetic resonance imaging. Neurological deficit was assessed daily. Neuronal apoptotic death and reactive oxygen species (ROS) production were analyzed by immunostaining and live imaging. Activation/inflammatory response of microglia/macrophage were assessed using immunohistochemistry, flow cytometry, 5-bromo-2-deoxyuridine labeling, cytokine ELISA, and real-time PCR. Results CX3CR1-/- mice displayed significantly smaller infarcts and less severe neurological deficits compared to WT controls, following MCAO. In addition, CX3CR1-/- MCAO mice displayed fewer apoptotic neurons and reduced ROS levels. Impaired CX3CR1 signaling abrogated the recruitment of monocyte-derived macrophages from the periphery, suppressed the proliferation of CNS microglia and infiltrated macrophage, facilitated the alternative activation (M2 state) of microglia/macrophages, and attenuated their ability to synthesize and release inflammatory cytokines. Conclusion Our results suggest that inhibition of CX3CR1 signaling could function as a therapeutic modality in ischemic brain injury, by reducing recruitment of peripheral macrophages and expansion/activation of CNS microglia and macrophages, resulting in protection of neurological function. PMID:24490760

2014-01-01

351

The Orosomucoid 1 protein is involved in the vitamin D – mediated macrophage de-activation process  

SciTech Connect

Orosomucoid 1 (ORM1), also named Alpha 1 acid glycoprotein A (AGP-A), is an abundant plasma protein characterized by anti-inflammatory and immune-modulating properties. The present study was designed to identify a possible correlation between ORM1 and Vitamin D3 (1,25(OH)2D3), a hormone exerting a widespread effect on cell proliferation, differentiation and regulation of the immune system. In particular, the data described here indicated that ORM1 is a 1,25(OH)2D3 primary response gene, characterized by the presence of a VDRE element inside the 1 kb sequence of its proximal promoter region. This finding was demonstrated with gene expression studies, Chromatin Immunoprecipitation and luciferase transactivation experiments and confirmed by VDR full length and dominant negative over-expression. In addition, several experiments carried out in human normal monocytes demonstrated that the 1,25(OH)2D3 – VDR – ORM1 pathway plays a functional role inside the macrophage de-activation process and that ORM1 may be considered as a signaling molecule involved in the maintenance of tissue homeostasis and remodeling. - Highlights: • ORM1 is a Vitamin D primary response gene. • VD and its receptor VDR are involved in the de-activation process mediated by human resident macrophages. • The signaling pathway VD-VDR-ORM1 plays an important role in the control of macrophage de-activation process. • ORM1 may be defined as a signaling molecule implicated in the maintenance of tissue homeostasis and remodeling.

Gemelli, Claudia, E-mail: claudia.gemelli@unimore.it [Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena (Italy); Center for Regenerative Medicine, University of Modena and Reggio Emilia, Via Gottardi 100, 41125 Modena (Italy); Martello, Andrea; Montanari, Monica; Zanocco Marani, Tommaso; Salsi, Valentina; Zappavigna, Vincenzo; Parenti, Sandra; Vignudelli, Tatiana; Selmi, Tommaso; Ferrari, Sergio; Grande, Alexis [Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena (Italy)

2013-12-10

352

CpGB DNA activates dermal macrophages and specifically recruits inflammatory monocytes into the skin.  

PubMed

Toll-like receptor 9 (TLR9) drives innate immune responses after recognition of foreign or endogenous DNA containing unmethylated CpG motifs. DNA-mediated TLR9 activation is highly implicated in the pathogenesis of several autoimmune skin diseases, yet its contribution to the inflammation seen in these diseases remains unclear. In this study, TLR9 ligand, CpGB DNA, was administered to mice via a subcutaneous osmotic pump with treatment lasting 1 or 4 weeks. Gene expression and immunofluorescence analyses were used to determine chemokine expression and cell recruitment in the skin surrounding the pump outlet. CpGB DNA skin treatment dramatically induced a marked influx of CD11b(+) F4/80(+) macrophages, increasing over 4 weeks of treatment, and induction of IFN? and TNF? expression. Chemokines, CCL2, CCL4, CCL5, CXCL9 and CXCL10, were highly induced in CpGB DNA-treated skin, although abrogation of these signalling pathways individually did not alter macrophage accumulation. Flow cytometry analysis showed that TLR9 activation in the skin increased circulating CD11b(+) CD115(+) Ly6C(hi) inflammatory monocytes following 1 week of CpGB DNA treatment. Additionally, skin-resident CD11b(+) cells were found to initially take up subcutaneous CpGB DNA and propagate the subsequent immune response. Using diphtheria toxin-induced monocyte depletion mouse model, gene expression analysis demonstrated that CD11b+ cells are responsible for the CpGB DNA-induced cytokine and chemokine response. Overall, these data demonstrate that chronic TLR9 activation induces a specific inflammatory response, ultimately leading to a striking and selective accumulation of macrophages in the skin. PMID:25425469

Mathes, Allison L; Rice, Lisa; Affandi, Alsya J; DiMarzio, Michael; Rifkin, Ian R; Stifano, Giuseppina; Christmann, Romy B; Lafyatis, Robert

2015-02-01

353

Glycodelin A, an immunomodulatory protein in the endometrium, inhibits proliferation and induces apoptosis in monocytic cells.  

PubMed

Glycodelin A (GdA), is a lipocalin with an immunomodulatory role, secreted by the endometrium under progesterone regulation and proposed to play a role in protecting the fetus from maternal immune attack. Glycodelin A has an inhibitory effect on the proliferation of T cells and B cells and also on the activity of natural killer cells. We have earlier demonstrated that the inhibitory effect of glycodelin A on T cell proliferation is due to apoptosis induced in these cells through the caspase-dependent intrinsic mitochondrial pathway. Studies reported until now have shown that glycodelin modulates the adaptive immune responses. We, therefore, decided to look at its effect, if any, on the innate immune system. The effect of glycodelin on monocytes was studied using human monocytic cell lines, THP1 and U937, and primary human monocytes as model systems. We demonstrated that glycodelin inhibited the proliferation of THP1 and U937 and induced apoptosis in these cells as well as in primary monocytes. We found that this signaling was caspase-independent but followed the intrinsic mitochondrial pathway of apoptosis. No effect of glycodelin was seen on the phagocytic ability of monocytes post-differentiation into macrophages. These observations suggest that, at the fetomaternal interface, glycodelin plays a protective role by deleting the monocytes that could become pro-inflammatory. Importantly, leaving the macrophages untouched to carry on with efficient clearance of the apoptotic cells. PMID:18996219

Alok, Anshula; Mukhopadhyay, Debaditya; Karande, Anjali A

2009-05-01

354

CX3CL1-mediated macrophage activation contributed to paclitaxel-induced DRG neuronal apoptosis and painful peripheral neuropathy.  

PubMed

Painful peripheral neuropathy is a dose-limiting side effect of paclitaxel therapy, which hampers the optimal clinical management of chemotherapy in cancer patients. Currently the underlying mechanisms remain largely unknown. Here we showed that the clinically relevant dose of paclitaxel (3×8mg/kg, cumulative dose 24mg/kg) induced significant upregulation of the chemokine CX3CL1 in the A-fiber primary sensory neurons in vivo and in vitro and infiltration of macrophages into the dorsal root ganglion (DRG) in rats. Paclitaxel treatment also increased cleaved caspase-3 expression, induced the loss of primary afferent terminal fibers and decreased sciatic-evoked A-fiber responses in the spinal dorsal horn, indicating DRG neuronal apoptosis induced by paclitaxel. In addition, the paclitaxel-induced DRG neuronal apoptosis occurred exclusively in the presence of macrophage in vitro study. Intrathecal or systemic injection of CX3CL1 neutralizing antibody blocked paclitaxel-induced macrophage recruitment and neuronal apoptosis in the DRG, and also attenuated paclitaxel-induced allodynia. Furthermore, depletion of macrophage by systemic administration of clodronate inhibited paclitaxel-induced allodynia. Blocking CX3CL1 decreased activation of p38 MAPK in the macrophage, and inhibition of p38 MAPK activity blocked the neuronal apoptosis and development of mechanical allodynia induced by paclitaxel. These findings provide novel evidence that CX3CL1-recruited macrophage contributed to paclitaxel-induced DRG neuronal apoptosis and painful peripheral neuropathy. PMID:24681252

Huang, Zhen-Zhen; Li, Dai; Liu, Cui-Cui; Cui, Yu; Zhu, He-Quan; Zhang, Wen-Wen; Li, Yong-Yong; Xin, Wen-Jun

2014-08-01

355

Monosodium urate activates Src/Pyk2/PI3 kinase and cathepsin dependent unconventional protein secretion from human primary macrophages.  

PubMed

Monosodium urate (MSU) is an endogenous danger signal that is crystallized from uric acid released from injured cells. MSU is known to activate inflammatory response in macrophages but the molecular mechanisms involved have remained uncharacterized. Activated macrophages start to secrete proteins to activate immune response and to recruit other immune cells to the site of infection and/or tissue damage. Secretome characterization after activation of innate immune system is essential to unravel the details of early phases of defense responses. Here, we have analyzed the secretome of human primary macrophages stimulated with MSU using quantitative two-dimensional gel electrophoresis based proteomics as well as high-throughput qualitative GeLC-MS/MS approach combining protein separation by SDS-PAGE and protein identification by liquid chromatography-MS/MS. Both methods showed that MSU stimulation induced robust protein secretion from lipopolysaccharide-primed human macrophages. Bioinformatic analysis of the secretome data showed that MSU stimulation strongly activates unconventional, vesicle mediated protein secretion. The unconventionally secreted proteins included pro-inflammatory cytokines like IL-1? and IL-18, interferon-induced proteins, and danger signal proteins. Also active forms of lysosomal proteases cathepsins were secreted on MSU stimulation, and cathepsin activity was essential for MSU-induced unconventional protein secretion. Additionally, proteins associated to phosphorylation events including Src family tyrosine kinases were increased in the secretome of MSU-stimulated cells. Our functional studies demonstrated that Src, Pyk2, and PI3 kinases act upstream of cathepsins to activate the overall protein secretion from macrophages. In conclusion, we provide the first comprehensive characterization of protein secretion pathways activated by MSU in human macrophages, and reveal a novel role for cathepsins and Src, Pyk2, PI3 kinases in the activation of unconventional protein secretion. PMID:23292187

Välimäki, Elina; Miettinen, Juho J; Lietzén, Niina; Matikainen, Sampsa; Nyman, Tuula A

2013-03-01

356

Intracellular activity of tedizolid phosphate and ACH-702 versus Mycobacterium tuberculosis infected macrophages  

PubMed Central

Background Due to the emergency of multidrug-resistant strains of Mycobacterium tuberculosis, is necessary the evaluation of new compounds. Findings Tedizolid, a novel oxazolidinone, and ACH-702, a new isothiazoloquinolone, were tested against M. tuberculosis infected THP-1 macrophages. These two compounds significantly decreased the number of intracellular mycobacteria at 0.25X, 1X, 4X and 16X the MIC value. The drugs were tested either in nanoparticules or in free solution. Conclusion Tedizolid and ACH-702 have a good intracellular killing activity comparable to that of rifampin or moxifloxacin. PMID:24708819

2014-01-01