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Sample records for mediates tumor necrosis

  1. Matrix metalloproteinase-mediation of tumor targeting human recombinant tumor necrosis factor-α fusion protein.

    PubMed

    Ren, Hui; Shao, Xin; Zeng, Liang; Wang, Fa; Huang, Di-Nan; Hou, Gan

    2015-08-01

    The aim of the present study was to use genetic engineering in order to establish an efficient tumor necrosis factor (TNF)-α fusion protein with low toxicity, which may be used to target tumors. Four types of matrix metalloproteinase (MMP)-mediated tumor targeting human recombinant TNF-α (rhTNF-α) fusion protein vectors were constructed. These were subsequently introduced into Escherichia coli. rhTNF-α fusion protein with a glutathione S-transferase (GST)-tag was purified using GST resin affinity chromatography, and GST-tags were digested using factor Xa. The cytotoxic effects of the fusion protein on L929 cells were determined using MTT assays. At a concentration of 1 pM, the GST-tagged fusion protein exerted no cytotoxic effects on the cells, compared with the negative control cells (P=0.975>0.05). However, at a concentration of 1000 pM, the deblocking fusion protein exerted greater cytotoxic effects on L929 cells, compared with positive control cells (P<0.05). Treatment with the fusion protein also induced cell apoptosis in the nasopharyngeal cancer cell line, CNE-2Z, which secretes high levels of MMP-1. In conclusion, the results of the present study suggested that MMP-mediated rhTNF-α fusion protein induces CNE-2Z cells apoptosis. rhTNF-α exhibits high efficacy and tumor cell targeting capability, with low toxicity effects on healthy cells. PMID:25891416

  2. Lithium chloride potentiates tumor necrosis factor-mediated cytotoxicity in vitro and in vivo.

    PubMed Central

    Beyaert, R; Vanhaesebroeck, B; Suffys, P; Van Roy, F; Fiers, W

    1989-01-01

    Tumor necrosis factor (TNF) is cytotoxic for several transformed cell lines in vitro. In the presence of LiCl, the murine fibrosarcoma cell lines L929 and WEHI 164 clone 13 became greater than 10 times more sensitive to TNF-mediated cytotoxicity. The human tumor cell lines BT20 and HeLa D98/AH2 were also responsive to the cytotoxicity-enhancing effect of LiCl. Other monovalent or divalent cations did not affect TNF-mediated cytotoxicity. The potentiating effect of LiCl on TNF cytotoxicity was largely independent of transcription, and LiCl could be added to the cells as early as 2 hr before or as late as 4 hr after TNF without loss of effectiveness. The mechanism by which LiCl increases the cytotoxic response seems to differ from the sensitizing effect of actinomycin D or interferon gamma, since the latter treatments overcame TNF resistance of several cell lines, whereas LiCl did not. Evidence is presented that LiCl acts, either directly or indirectly, via the TNF-activated phospholipase A2 pathway. In nude mice, a combination of TNF and LiCl led to hemorrhagic necrosis and growth inhibition of L929 tumors, whereas little effect was observed when TNF was administered alone. HeLa D98/AH2 tumors also were sensitive to the potentiating effect of LiCl in vivo. We conclude that LiCl enhances the effectiveness of TNF in vitro and in vivo, results that may have therapeutic implications. PMID:2556714

  3. Tumor necrosis factor gene expression is mediated by protein kinase C following activation by ionizing radiation.

    SciTech Connect

    Hallahan, D. E.; Virudachalam, S.; Sherman, M. L.; Huberman, E.; Kufe, D. W.; Weichselbaum, R. R.; Univ. of Chicago; Dana-Farber Cancer Inst.; Univ. of Chicago

    1991-01-01

    Tumor necrosis factor (TNF) production following X-irradiation has been implicated in the biological response to ionizing radiation. Protein kinase C (PKC) is suggested to participate in TNF transcriptional induction and X-ray-mediated gene expression. We therefore studied radiation-mediated TNF expression in HL-60 cells with diminished PKC activity produced by either pretreatment with protein kinase inhibitors or prolonged 12-O-tetradecanoylphorbol-13-acetate treatment. Both treatments resulted in attenuation of radiation-mediated TNF induction. Consistent with these results, we found no detectable induction of TNF expression following X-irradiation in the HL-60 variant deficient in PKC-mediated signal transduction. The rapid activation of PKC following {gamma}-irradiation was established using an in vitro assay measuring phosphorylation of a PKC specific substrate. A 4.5-fold increase in PKC activity occurred 15 to 30 s following irradiation, which declined to baseline at 60 s. Two-dimensional gel electrophoresis of phosphoproteins extracted from irradiated cells demonstrated in vivo phosphorylation of the PKC specific substrate Mr 80,000 protein at 45 s following X-irradiation. These findings indicate that signal transduction via the PKC pathway is required for the induction of TNF gene expression by ionizing radiation.

  4. Mitochondria mediate tumor necrosis factor-alpha/NF-kappaB signaling in skeletal muscle myotubes

    NASA Technical Reports Server (NTRS)

    Li, Y. P.; Atkins, C. M.; Sweatt, J. D.; Reid, M. B.; Hamilton, S. L. (Principal Investigator)

    1999-01-01

    Tumor necrosis factor-alpha (TNF-alpha) is implicated in muscle atrophy and weakness associated with a variety of chronic diseases. Recently, we reported that TNF-alpha directly induces muscle protein degradation in differentiated skeletal muscle myotubes, where it rapidly activates nuclear factor kappaB (NF-kappaB). We also have found that protein loss induced by TNF-alpha is NF-kappaB dependent. In the present study, we analyzed the signaling pathway by which TNF-alpha activates NF-kappaB in myotubes differentiated from C2C12 and rat primary myoblasts. We found that activation of NF-kappaB by TNF-alpha was blocked by rotenone or amytal, inhibitors of complex I of the mitochondrial respiratory chain. On the other hand, antimycin A, an inhibitor of complex III, enhanced TNF-alpha activation of NK-kappaB. These results suggest a key role of mitochondria-derived reactive oxygen species (ROS) in mediating NF-kappaB activation in muscle. In addition, we found that TNF-alpha stimulated protein kinase C (PKC) activity. However, other signal transduction mediators including ceramide, Ca2+, phospholipase A2 (PLA2), and nitric oxide (NO) do not appear to be involved in the activation of NF-kappaB.

  5. Disturbance of Tumor Necrosis Factor Alpha-Mediated Beta Interferon Signaling in Cervical Carcinoma Cells

    PubMed Central

    Bachmann, Anastasia; Hanke, Brigitte; Zawatzky, Rainer; Soto, Ubaldo; van Riggelen, Jan; zur Hausen, Harald; Rösl, Frank

    2002-01-01

    In the present study we show that malignant human papillomavirus (HPV)-positive cells lost their ability to synthesize endogenous beta interferon (IFN-β) upon tumor necrosis factor alpha (TNF-α) treatment. IFN-β transcription, however, was reinducible in nonmalignant HPV-positive cells, which was confirmed in functional protection assays against encephalomyocarditis virus or vesicular stomatitis virus infections. Addition of neutralizing antibodies against IFN-β blocked the antiviral effect, excluding the possibility that other IFN types were involved. Conversely, both malignant and immortalized cells could be protected against viral cytolysis when either IFN-β, IFN-α, or IFN-γ was added exogenously. This indicates that only the cross talk between TNF-α and the IFN-β pathways, and not IFN-α/β and IFN-γ signaling in general, is perturbed in cervical carcinoma cells. Notably, full virus protection was restricted exclusively to nonmalignant cells, indicating that the antiviral effect correlates with the growth-inhibitory and virus-suppressive properties of TNF-α. The IFN-regulatory factors IRF-1 and p48 (ISGF3γ) emerged as key regulatory molecules in the differential IFN-β response, since their transcription was either absent or only inefficiently enhanced in tumorigenic cells upon treatment with TNF-α. Inducibility of both genes, however, became reestablished in cervical carcinoma cells, which were complemented to nontumorigenicity after somatic cell hybridization. Complementation was paralleled by the entire reconstitution of cytokine-mediated IFN-β expression and the ability of TNF-α to exert an antiviral state. In contrast, under conditions where tumor suppression was not accomplished upon somatic cell hybridization, neither expression of IRF-1, p48, and IFN-β nor antiviral activity could be restored. PMID:11739693

  6. Tumor necrosis factor-alpha mediates changes in tissue protein turnover in a rat cancer cachexia model.

    PubMed Central

    Costelli, P; Carbó, N; Tessitore, L; Bagby, G J; Lopez-Soriano, F J; Argilés, J M; Baccino, F M

    1993-01-01

    Rats bearing the Yoshida AH-130 ascites hepatoma showed enhanced fractional rates of protein degradation in gastrocnemius muscle, heart, and liver, while fractional synthesis rates were similar to those in non-tumor bearing rats. This hypercatabolic pattern was associated with marked perturbations of the hormonal homeostasis and presence of tumor necrosis factor in the circulation. The daily administration of a goat anti-murine TNF IgG to tumor-bearing rats decreased protein degradation rates in skeletal muscle, heart, and liver as compared with tumor-bearing rats receiving a nonimmune goat IgG. The anti-TNF treatment was also effective in attenuating early perturbations in insulin and corticosterone homeostasis. Although these results suggest that tumor necrosis factor plays a significant role in mediating the changes in protein turnover and hormone levels elicited by tumor growth, the inability of such treatment to prevent a reduction in body weight implies that other mediators or tumor-related events were also involved. PMID:8254032

  7. Adrenomedullin mediates tumor necrosis factor-α-induced responses in dorsal root ganglia in rats.

    PubMed

    Chen, Yajuan; Zhang, Yan; Huo, Yuanhui; Wang, Dongmei; Hong, Yanguo

    2016-08-01

    Adrenomedullin (AM), a member of the calcitonin gene-related peptide (CGRP) family, has been demonstrated to be a pain peptide. This study investigated the possible involvement of AM in tumor necrosis factor-alpha (TNF-α)-induced responses contributing to neuronal plasticity in the dorsal root ganglia (DRG). Exposure of the DRG explant cultures to TNF-α (5nM) for 48h upregulated the expression of AM mRNA. The treatment with TNF-α also increased the level of CGRP, CCL-2 and MMP-9 mRNA in the cultured DRG. This increase was attenuated by the co-treatment with the selective AM receptor antagonist AM22-52 (2μM). The blockade of AM receptors inhibited TNF-α-induced increase of the glial fibrillary acidic protein (GFAP), interleukin-1β (IL-1β), phosphorylated cAMP response element binding protein (pCREB) and nuclear factor kappa B (pNF-κB) proteins. On the other hand, the treatment with the AM receptor agonist AM1-50 (10nM) for 96h induced an increase in the level of GFAP, IL-1β, pCREB and pNF-κB proteins. The inhibition of AM activity did not change TNF-α-induced phosphorylation of extracellular signal-related kinase (pERK) while the treatment with AM1-50 still increased the level of pERK in the cultured DRG. Immunofluorescence assay showed the colocalization of AM-like immunoreactivity (IR) with TNF-α-IR in DRG neurons. The present study suggests that the increased AM receptor signaling mediated the many, but not all, TNF-α-induced activities, contributing to peripheral sensitization in neuropathic pain. PMID:27184601

  8. Imaging Tumor Necrosis with Ferumoxytol

    PubMed Central

    Aghighi, Maryam; Golovko, Daniel; Ansari, Celina; Marina, Neyssa M.; Pisani, Laura; Kurlander, Lonnie; Klenk, Christopher; Bhaumik, Srabani; Wendland, Michael; Daldrup-Link, Heike E.

    2015-01-01

    Objective Ultra-small superparamagnetic iron oxide nanoparticles (USPIO) are promising contrast agents for magnetic resonance imaging (MRI). USPIO mediated proton relaxation rate enhancement is strongly dependent on compartmentalization of the agent and can vary depending on their intracellular or extracellular location in the tumor microenvironment. We compared the T1- and T2-enhancement pattern of intracellular and extracellular USPIO in mouse models of cancer and pilot data from patients. A better understanding of these MR signal effects will enable non-invasive characterizations of the composition of the tumor microenvironment. Materials and Methods Six 4T1 and six MMTV-PyMT mammary tumors were grown in mice and imaged with ferumoxytol-enhanced MRI. R1 relaxation rates were calculated for different tumor types and different tumor areas and compared with histology. The transendothelial leakage rate of ferumoxytol was obtained by our measured relaxivity of ferumoxytol and compared between different tumor types, using a t-test. Additionally, 3 patients with malignant sarcomas were imaged with ferumoxytol-enhanced MRI. T1- and T2-enhancement patterns were compared with histopathology in a descriptive manner as a proof of concept for clinical translation of our observations. Results 4T1 tumors showed central areas of high signal on T1 and low signal on T2 weighted MR images, which corresponded to extracellular nanoparticles in a necrotic core on histopathology. MMTV-PyMT tumors showed little change on T1 but decreased signal on T2 weighted images, which correlated to compartmentalized nanoparticles in tumor associated macrophages. Only 4T1 tumors demonstrated significantly increased R1 relaxation rates of the tumor core compared to the tumor periphery (p<0.001). Transendothelial USPIO leakage was significantly higher for 4T1 tumors (3.4±0.9x10-3 mL/min/100cm3) compared to MMTV-PyMT tumors (1.0±0.9x10-3 mL/min/100 cm3). Likewise, ferumoxytol imaging in patients

  9. Claudin 1 mediates tumor necrosis factor alpha-induced cell migration in human gastric cancer cells

    PubMed Central

    Shiozaki, Atsushi; Shimizu, Hiroki; Ichikawa, Daisuke; Konishi, Hirotaka; Komatsu, Shuhei; Kubota, Takeshi; Fujiwara, Hitoshi; Okamoto, Kazuma; Iitaka, Daisuke; Nakashima, Shingo; Nako, Yoshito; Liu, Mingyao; Otsuji, Eigo

    2014-01-01

    AIM: To investigate the role of claudin 1 in the regulation of genes involved in cell migration and tumor necrosis factor alpha (TNF-α)-induced gene expression in human gastric adenocarcinoma cells. METHODS: Knockdown experiments were conducted with claudin 1 small interfering RNA (siRNA), and the effects on the cell cycle, apoptosis, migration and invasion were analyzed in human gastric adenocarcinoma MKN28 cells. The gene expression profiles of cells were analyzed by microarray and bioinformatics. RESULTS: The knockdown of claudin 1 significantly inhibited cell proliferation, migration and invasion, and increased apoptosis. Microarray analysis identified 245 genes whose expression levels were altered by the knockdown of claudin 1. Pathway analysis showed that the top-ranked molecular and cellular function was the cellular movement related pathway, which involved MMP7, TNF-SF10, TGFBR1, and CCL2. Furthermore, TNF- and nuclear frctor-κB were the top-ranked upstream regulators related to claudin 1. TNF-α treatment increased claudin 1 expression and cell migration in MKN28 cells. Microarray analysis indicated that the depletion of claudin 1 inhibited 80% of the TNF-α-induced mRNA expression changes. Further, TNF-α did not enhance cell migration in the claudin 1 siRNA transfected cells. CONCLUSION: These results suggest that claudin 1 is an important messenger that regulates TNF-α-induced gene expression and migration in gastric cancer cells. A deeper understanding of these cellular processes may be helpful in establishing new therapeutic strategies for gastric cancer. PMID:25548484

  10. Tumor-necrosis factor impairs CD4(+) T cell-mediated immunological control in chronic viral infection.

    PubMed

    Beyer, Marc; Abdullah, Zeinab; Chemnitz, Jens M; Maisel, Daniela; Sander, Jil; Lehmann, Clara; Thabet, Yasser; Shinde, Prashant V; Schmidleithner, Lisa; Köhne, Maren; Trebicka, Jonel; Schierwagen, Robert; Hofmann, Andrea; Popov, Alexey; Lang, Karl S; Oxenius, Annette; Buch, Thorsten; Kurts, Christian; Heikenwalder, Mathias; Fätkenheuer, Gerd; Lang, Philipp A; Hartmann, Pia; Knolle, Percy A; Schultze, Joachim L

    2016-05-01

    Persistent viral infections are characterized by the simultaneous presence of chronic inflammation and T cell dysfunction. In prototypic models of chronicity-infection with human immunodeficiency virus (HIV) or lymphocytic choriomeningitis virus (LCMV)-we used transcriptome-based modeling to reveal that CD4(+) T cells were co-exposed not only to multiple inhibitory signals but also to tumor-necrosis factor (TNF). Blockade of TNF during chronic infection with LCMV abrogated the inhibitory gene-expression signature in CD4(+) T cells, including reduced expression of the inhibitory receptor PD-1, and reconstituted virus-specific immunity, which led to control of infection. Preventing signaling via the TNF receptor selectively in T cells sufficed to induce these effects. Targeted immunological interventions to disrupt the TNF-mediated link between chronic inflammation and T cell dysfunction might therefore lead to therapies to overcome persistent viral infection. PMID:26950238

  11. Glycyrrhizin Protects against Acetaminophen-Induced Acute Liver Injury via Alleviating Tumor Necrosis Factor α–Mediated Apoptosis

    PubMed Central

    Yan, Tingting; Wang, Hong; Zhao, Min; Yagai, Tomoki; Chai, Yingying; Krausz, Kristopher W.; Xie, Cen; Cheng, Xuefang; Zhang, Jun; Che, Yuan; Li, Feiyan; Wu, Yuzheng; Brocker, Chad N.; Gonzalez, Frank J.

    2016-01-01

    Acetaminophen (APAP) overdose is the leading cause of drug-induced acute liver failure in Western countries. Glycyrrhizin (GL), a potent hepatoprotective constituent extracted from the traditional Chinese medicine liquorice, has potential clinical use in treating APAP-induced liver failure. The present study determined the hepatoprotective effects and underlying mechanisms of action of GL and its active metabolite glycyrrhetinic acid (GA). Various administration routes and pharmacokinetics–pharmacodynamics analyses were used to differentiate the effects of GL and GA on APAP toxicity in mice. Mice deficient in cytochrome P450 2E1 enzyme (CYP2E1) or receptor interacting protein 3 (RIPK3) and their relative wild-type littermates were subjected to histologic and biochemical analyses to determine the potential mechanisms. Hepatocyte death mediated by tumor necrosis factor α (TNFα)/caspase was analyzed by use of human liver-derived LO2 cells. The pharmacokinetics–pharmacodynamics analysis using various administration routes revealed that GL but not GA potently attenuated APAP-induced liver injury. The protective effect of GL was found only with intraperitoneal and intravenous administration and not with gastric administration. CYP2E1-mediated metabolic activation and RIPK3-mediated necroptosis were unrelated to GL’s protective effect. However, GL inhibited hepatocyte apoptosis via interference with TNFα-induced apoptotic hepatocyte death. These results demonstrate that GL rapidly attenuates APAP-induced liver injury by directly inhibiting TNFα-induced hepatocyte apoptosis. The protective effect against APAP-induced liver toxicity by GL in mice suggests the therapeutic potential of GL for the treatment of APAP overdose. PMID:26965985

  12. Glycyrrhizin Protects against Acetaminophen-Induced Acute Liver Injury via Alleviating Tumor Necrosis Factor α-Mediated Apoptosis.

    PubMed

    Yan, Tingting; Wang, Hong; Zhao, Min; Yagai, Tomoki; Chai, Yingying; Krausz, Kristopher W; Xie, Cen; Cheng, Xuefang; Zhang, Jun; Che, Yuan; Li, Feiyan; Wu, Yuzheng; Brocker, Chad N; Gonzalez, Frank J; Wang, Guangji; Hao, Haiping

    2016-05-01

    Acetaminophen (APAP) overdose is the leading cause of drug-induced acute liver failure in Western countries. Glycyrrhizin (GL), a potent hepatoprotective constituent extracted from the traditional Chinese medicine liquorice, has potential clinical use in treating APAP-induced liver failure. The present study determined the hepatoprotective effects and underlying mechanisms of action of GL and its active metabolite glycyrrhetinic acid (GA). Various administration routes and pharmacokinetics-pharmacodynamics analyses were used to differentiate the effects of GL and GA on APAP toxicity in mice. Mice deficient in cytochrome P450 2E1 enzyme (CYP2E1) or receptor interacting protein 3 (RIPK3) and their relative wild-type littermates were subjected to histologic and biochemical analyses to determine the potential mechanisms. Hepatocyte death mediated by tumor necrosis factorα(TNFα)/caspase was analyzed by use of human liver-derived LO2 cells. The pharmacokinetics-pharmacodynamics analysis using various administration routes revealed that GL but not GA potently attenuated APAP-induced liver injury. The protective effect of GL was found only with intraperitoneal and intravenous administration and not with gastric administration. CYP2E1-mediated metabolic activation and RIPK3-mediated necroptosis were unrelated to GL's protective effect. However, GL inhibited hepatocyte apoptosis via interference with TNFα-induced apoptotic hepatocyte death. These results demonstrate that GL rapidly attenuates APAP-induced liver injury by directly inhibiting TNFα-induced hepatocyte apoptosis. The protective effect against APAP-induced liver toxicity by GL in mice suggests the therapeutic potential of GL for the treatment of APAP overdose. PMID:26965985

  13. Role of tumor necrosis factor alpha in disease using a mouse model of Shiga toxin-mediated renal damage.

    PubMed

    Lentz, Erin K; Cherla, Rama P; Jaspers, Valery; Weeks, Bradley R; Tesh, Vernon L

    2010-09-01

    Mice have been extensively employed as an animal model of renal damage caused by Shiga toxins. In this study, we examined the role of the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) in the development of toxin-mediated renal disease in mice. Mice pretreated with TNF-alpha and challenged with Shiga toxin type 1 (Stx1) showed increased survival compared to that of mice treated with Stx1 alone. Conversely, mice treated with Stx1 before TNF-alpha administration succumbed more quickly than mice given Stx1 alone. Increased lethality in mice treated with Stx1 followed by TNF-alpha was associated with evidence of glomerular damage and the loss of renal function. No differences in renal histopathology were noted between animals treated with Stx1 alone and the TNF-alpha pretreatment group, although we noted a sparing of renal function when TNF-alpha was administered before toxin. Compared to that of treatment with Stx1 alone, treatment with TNF-alpha after toxin altered the renal cytokine profile so that the expression of proinflammatory cytokines TNF-alpha and interleukin-1beta (IL-1beta) increased, and the expression of the anti-inflammatory cytokine IL-10 decreased. Increased lethality in mice treated with Stx1 followed by TNF-alpha was associated with higher numbers of dUTP-biotin nick end labeling-positive renal tubule cells, suggesting that increased lethality involved enhanced apoptosis. These data suggest that the early administration of TNF-alpha is a candidate interventional strategy blocking disease progression, while TNF-alpha production after intoxication exacerbates disease. PMID:20605983

  14. Tumor necrosis factor-α mediates interactions between macrophages and epithelial cells underlying proinflammatory gene expression induced by particulate matter.

    PubMed

    Musah, Sadiatu; DeJarnett, Natasha; Hoyle, Gary W

    2012-09-28

    Ambient particulate matter (PM) exposure is known to have adverse effects on respiratory health, but the underlying mechanisms remain obscure. We tested the hypothesis that macrophages and epithelial cells synergize to produce maximal cytokine release in response to PM exposure, thereby promoting inflammatory responses. We developed a co-culture model using MLE-12 (mouse lung epithelial) cells and RAW 264.7 (mouse monocyte/macrophage) cells. MLE-12 cells produced KC (Cxcl1) but not tumor necrosis factor-α (TNF), and KC was upregulated only at high levels of urban particulate matter (UPM; NIST 1648a). RAW 264.7 cells produced TNF but not KC, and TNF production was increased by treatment with UPM. In contrast, KC production was upregulated by co-culture of MLE-12 and RAW 264.7 cells, and it was further increased by treatment with a concentration of UPM that had no effect on MLE-12 cells alone. Multiplex cytokine assay revealed a similar pattern of synergistic production of MIG (Cxcl9) and IP-10 (Cxcl10) in co-cultures in response to UPM. TNF was implicated as mediating the synergistic increase in KC production because TNF upregulated KC production in MLE-12 cells, and UPM-induced KC production in co-cultures could be inhibited by a TNF blocking antibody. Intratracheal instillation of UPM into both wild-type and TNF receptor knockout mice resulted in increased TNF production in lavage fluid and increased TNF mRNA expression in cells recovered from lavage fluid. Additionally, UPM instillation into wild-type mice resulted in increased neutrophils and KC in lavage fluid, and these were inhibited in UPM-exposed TNF receptor knockout mice. These results are consistent with a model in which PM activates TNF production in macrophages which in turn stimulates epithelial cells to produce proinflammatory cytokines such as KC. The findings suggest a potential mechanism by which inhaled PM induces inflammation in the lung. PMID:22634322

  15. Borage oil reduction of rheumatoid arthritis activity may be mediated by increased cAMP that suppresses tumor necrosis factor-alpha.

    PubMed

    Kast, R E

    2001-11-01

    Recent double blind studies have shown some benefit of borage oil in treatment of rheumatoid arthritis. Tumor necrosis factor-alpha has been shown to be a central mediator of inflammatory and joint destructive processes in rheumatoid arthritis. In this paper, evidence from published research is reviewed that indicates gamma linolenic acid component of borage oil increases prostaglandin E levels that increase cAMP levels that in turn suppress tumor necrosis factor-alpha synthesis. If this biochemical path of borage oil is correct then (1) concomitant non-steroidal anti-inflammatory drug use would tend to undermine borage oil effects, and (2) borage oil would be contraindicated in pregnancy given the teratogenic and labor inducing effects of prostaglandin E agonists. PMID:11710548

  16. Expression of Tumor Necrosis Factor-Alpha-Mediated Genes Predicts Recurrence-Free Survival in Lung Cancer

    PubMed Central

    Zhou, Lianya; Zhang, Helin; Duan, Lin; He, Wenshu; Zhu, Yihua; Bai, Yunfei; Zhu, Miao

    2014-01-01

    In this study, we conducted a meta-analysis on high-throughput gene expression data to identify TNF-α-mediated genes implicated in lung cancer. We first investigated the gene expression profiles of two independent TNF-α/TNFR KO murine models. The EGF receptor signaling pathway was the top pathway associated with genes mediated by TNF-α. After matching the TNF-α-mediated mouse genes to their human orthologs, we compared the expression patterns of the TNF-α-mediated genes in normal and tumor lung tissues obtained from humans. Based on the TNF-α-mediated genes that were dysregulated in lung tumors, we developed a prognostic gene signature that effectively predicted recurrence-free survival in lung cancer in two validation cohorts. Resampling tests suggested that the prognostic power of the gene signature was not by chance, and multivariate analysis suggested that this gene signature was independent of the traditional clinical factors and enhanced the identification of lung cancer patients at greater risk for recurrence. PMID:25548907

  17. Lysosomal serine protease CLN2 regulates tumor necrosis factor-alpha-mediated apoptosis in a Bid-dependent manner.

    PubMed

    Autefage, Hélène; Albinet, Virginie; Garcia, Virginie; Berges, Hortense; Nicolau, Marie-Laure; Therville, Nicole; Altié, Marie-Françoise; Caillaud, Catherine; Levade, Thierry; Andrieu-Abadie, Nathalie

    2009-04-24

    Apoptosis is a highly organized, energy-dependent program by which multicellular organisms eliminate damaged, superfluous, and potentially harmful cells. Although caspases are the most prominent group of proteases involved in the apoptotic process, the role of lysosomes has only recently been unmasked. This study investigated the role of the lysosomal serine protease CLN2 in apoptosis. We report that cells isolated from patients affected with late infantile neuronal ceroid lipofuscinosis (LINCL) having a deficient activity of CLN2 are resistant to the toxic effect of death ligands such as tumor necrosis factor (TNF), CD95 ligand, or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) but not to receptor-independent stress agents. CLN2-deficient cells exhibited a defect in TNF-induced Bid cleavage, release of cytochrome c, and caspase-9 and -3 activation. Moreover, extracts from CLN2-overexpressing cells or a CLN2 recombinant protein were able to catalyze the in vitro cleavage of Bid. Noteworthy, correction of the lysosomal enzyme defect of LINCL fibroblasts using a medium enriched in CLN2 protein enabled restoration of TNF-induced Bid and caspase-3 processing and toxicity. Conversely, transfection of CLN2-corrected cells with small interfering RNA targeting Bid abrogated TNF-induced cell death. Altogether, our study demonstrates that genetic deletion of the lysosomal serine protease CLN2 and the subsequent loss of its catalytic function confer resistance to TNF in non-neuronal somatic cells, indicating that CLN2 plays a yet unsuspected role in TNF-induced cell death. PMID:19246452

  18. Canarypox Virus-Induced Maturation of Dendritic Cells Is Mediated by Apoptotic Cell Death and Tumor Necrosis Factor Alpha Secretion

    PubMed Central

    Ignatius, Ralf; Marovich, Mary; Mehlhop, Erin; Villamide, Loreley; Mahnke, Karsten; Cox, William I.; Isdell, Frank; Frankel, Sarah S.; Mascola, John R.; Steinman, Ralph M.; Pope, Melissa

    2000-01-01

    Recombinant avipox viruses are being widely evaluated as vaccines. To address how these viruses, which replicate poorly in mammalian cells, might be immunogenic, we studied how canarypox virus (ALVAC) interacts with primate antigen-presenting dendritic cells (DCs). When human and rhesus macaque monocyte-derived DCs were exposed to recombinant ALVAC, immature DCs were most susceptible to infection. However, many of the infected cells underwent apoptotic cell death, and dying infected cells were engulfed by uninfected DCs. Furthermore, a subset of DCs matured in the ALVAC-exposed DC cultures. DC maturation coincided with tumor necrosis factor alpha (TNF-α) secretion and was significantly blocked in the presence of anti-TNF-α antibodies. Interestingly, inhibition of apoptosis with a caspase 3 inhibitor also reduced some of the maturation induced by exposure to ALVAC. This indicates that both TNF-α and the presence of primarily apoptotic cells contributed to DC maturation. Therefore, infection of immature primate DCs with ALVAC results in apoptotic death of infected cells, which can be internalized by noninfected DCs driving DC maturation in the presence of the TNF-α secreted concomitantly by exposed cells. This suggests an important mechanism that may influence the immunogenicity of avipox virus vectors. PMID:11070033

  19. Development of a synthetic receptor protein for sensing inflammatory mediators interferon-γ and tumor necrosis factor-α.

    PubMed

    Aurand, T Christopher; March, John C

    2016-03-01

    Intestinal inflammation has been implicated in a number of diseases, including diabetes, Crohn's disease, and irritable bowel syndrome. Important components of inflammation are interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α), which are elevated both on the luminal and submucosal sides of the intestinal epithelial barrier in several diseases. Here, we developed a novel Escherichia coli based detection system for IFN-γ and TNF-α comprised of a chimeric protein and a simple signal transduction construct, which could be deployed on the luminal side of the intestine. OmpA of E. coli was engineered to detect IFN-γ or TNF-α through the replacement of extracellular loops with peptide fragments from OprF of P. aeruginosa. OmpA/OprF chimeras were developed, capable of binding IFN-γ or TNF-α. The specific peptide fragments that bind IFN-γ were identified. IFN-γ or TNF-α binding the OmpA/OprF chimera induced the pspA promoter, driving β-galactosidase production. The OmpA/OprF chimera had a detection limit of 300 pM for IFN-γ and 150 pM for TNF-α. This work will further the development of bacteria based therapeutics for the treatment of inflammatory diseases of the gut. PMID:26370067

  20. RNAseq Analyses Identify Tumor Necrosis Factor-Mediated Inflammation as a Major Abnormality in ALS Spinal Cord.

    PubMed

    Brohawn, David G; O'Brien, Laura C; Bennett, James P

    2016-01-01

    ALS is a rapidly progressive, devastating neurodegenerative illness of adults that produces disabling weakness and spasticity arising from death of lower and upper motor neurons. No meaningful therapies exist to slow ALS progression, and molecular insights into pathogenesis and progression are sorely needed. In that context, we used high-depth, next generation RNA sequencing (RNAseq, Illumina) to define gene network abnormalities in RNA samples depleted of rRNA and isolated from cervical spinal cord sections of 7 ALS and 8 CTL samples. We aligned >50 million 2X150 bp paired-end sequences/sample to the hg19 human genome and applied three different algorithms (Cuffdiff2, DEseq2, EdgeR) for identification of differentially expressed genes (DEG's). Ingenuity Pathways Analysis (IPA) and Weighted Gene Co-expression Network Analysis (WGCNA) identified inflammatory processes as significantly elevated in our ALS samples, with tumor necrosis factor (TNF) found to be a major pathway regulator (IPA) and TNFα-induced protein 2 (TNFAIP2) as a major network "hub" gene (WGCNA). Using the oPOSSUM algorithm, we analyzed transcription factors (TF) controlling expression of the nine DEG/hub genes in the ALS samples and identified TF's involved in inflammation (NFkB, REL, NFkB1) and macrophage function (NR1H2::RXRA heterodimer). Transient expression in human iPSC-derived motor neurons of TNFAIP2 (also a DEG identified by all three algorithms) reduced cell viability and induced caspase 3/7 activation. Using high-density RNAseq, multiple algorithms for DEG identification, and an unsupervised gene co-expression network approach, we identified significant elevation of inflammatory processes in ALS spinal cord with TNF as a major regulatory molecule. Overexpression of the DEG TNFAIP2 in human motor neurons, the population most vulnerable to die in ALS, increased cell death and caspase 3/7 activation. We propose that therapies targeted to reduce inflammatory TNFα signaling may be helpful

  1. Trichostatin A modulates thiazolidinedione-mediated suppression of tumor necrosis factor α-induced lipolysis in 3T3-L1 adipocytes.

    PubMed

    Lu, Juu-Chin; Chang, Yu-Tzu; Wang, Chih-Tien; Lin, Yu-Chun; Lin, Chun-Ken; Wu, Zhong-Sheng

    2013-01-01

    In obesity, high levels of tumor necrosis factor α (TNFα) stimulate lipolysis in adipocytes, leading to hyperlipidemia and insulin resistance. Thiazolidinediones (TZDs), the insulin-sensitizing drugs, antagonize TNFα-induced lipolysis in adipocytes, thereby increasing insulin sensitivity in diabetes patients. The cellular target of TZDs is peroxisome proliferator-activated receptor γ (PPARγ), a nuclear receptor that controls many adipocyte functions. As a transcription factor, PPARγ is closely modulated by coregulators, which include coactivators and corepressors. Previous studies have revealed that in macrophages, the insulin-sensitizing effect of PPARγ may involve suppression of proinflammatory gene expression by recruiting the corepressor complex that contains corepressors and histone deacetylases (HDACs). Therefore, we investigated whether the corepressor complex is involved in TZD-mediated suppression of TNFα-induced lipolysis in 3T3-L1 adipocytes. Trichostatin A (TSA), a pan HDAC inhibitor (HDACI) that inhibits class I and II HDACs, was used to examine the involvement of HDACs in the actions of TZDs. TSA alone increased basal lipolysis and attenuated TZD-mediated suppression of TNFα-induced lipolysis. Increased basal lipolysis may in part result from class I HDAC inhibition because selective class I HDACI treatment had similar results. However, attenuation of TZD-mediated TNFα antagonism may be specific to TSA and related hydroxamate-based HDACI rather than to HDAC inhibition. Consistently, corepressor depletion did not affect TZD-mediated suppression. Interestingly, TSA treatment greatly reduced PPARγ levels in differentiated adipocytes. Finally, extracellular signal-related kinase 1/2 (ERK1/2) mediated TNFα-induced lipolysis, and TZDs suppressed TNFα-induced ERK phosphorylation. We determined that TSA increased basal ERK phosphorylation, and attenuated TZD-mediated suppression of TNFα-induced ERK phosphorylation, consistent with TSA's effects

  2. RNAseq Analyses Identify Tumor Necrosis Factor-Mediated Inflammation as a Major Abnormality in ALS Spinal Cord

    PubMed Central

    Brohawn, David G.; O’Brien, Laura C.; Bennett, James P.

    2016-01-01

    ALS is a rapidly progressive, devastating neurodegenerative illness of adults that produces disabling weakness and spasticity arising from death of lower and upper motor neurons. No meaningful therapies exist to slow ALS progression, and molecular insights into pathogenesis and progression are sorely needed. In that context, we used high-depth, next generation RNA sequencing (RNAseq, Illumina) to define gene network abnormalities in RNA samples depleted of rRNA and isolated from cervical spinal cord sections of 7 ALS and 8 CTL samples. We aligned >50 million 2X150 bp paired-end sequences/sample to the hg19 human genome and applied three different algorithms (Cuffdiff2, DEseq2, EdgeR) for identification of differentially expressed genes (DEG’s). Ingenuity Pathways Analysis (IPA) and Weighted Gene Co-expression Network Analysis (WGCNA) identified inflammatory processes as significantly elevated in our ALS samples, with tumor necrosis factor (TNF) found to be a major pathway regulator (IPA) and TNFα-induced protein 2 (TNFAIP2) as a major network “hub” gene (WGCNA). Using the oPOSSUM algorithm, we analyzed transcription factors (TF) controlling expression of the nine DEG/hub genes in the ALS samples and identified TF’s involved in inflammation (NFkB, REL, NFkB1) and macrophage function (NR1H2::RXRA heterodimer). Transient expression in human iPSC-derived motor neurons of TNFAIP2 (also a DEG identified by all three algorithms) reduced cell viability and induced caspase 3/7 activation. Using high-density RNAseq, multiple algorithms for DEG identification, and an unsupervised gene co-expression network approach, we identified significant elevation of inflammatory processes in ALS spinal cord with TNF as a major regulatory molecule. Overexpression of the DEG TNFAIP2 in human motor neurons, the population most vulnerable to die in ALS, increased cell death and caspase 3/7 activation. We propose that therapies targeted to reduce inflammatory TNFα signaling may be

  3. Unimpaired Autoreactive T-Cell Traffic Within the Central Nervous System During Tumor Necrosis Factor Receptor-Mediated inhibition of Experimental Autoimmune Encephalomyelitis

    NASA Astrophysics Data System (ADS)

    Korner, Heinrich; Goodsall, Anna L.; Lemckert, Frances A.; Scallon, Bernard J.; Ghrayeb, John; Ford, Andrew L.; Sedgwick, Jonathon D.

    1995-11-01

    The critical role of tumor necrosis factor (TNF) as a mediator in autoimmune inflammatory processes is evident from in vivo studies with TNF-blocking agents. However, the mechanisms by which TNF, and possibly also its homologue lymphotoxin α, contributes to development of pathology in rheumatoid arthritis and Crohn disease and in animal models like experimental autoimmune encephalomyelitis is unclear. Possibilities include regulation of vascular adhesion molecules enabling leukocyte movement into tissues or direct cytokine-mediated effector functions such as mediation of tissue damage. Here we show that administration of a TNF receptor (55 kDa)-IgG fusion protein prevented clinical signs of actively induced experimental autoimmune encephalomyelitis. Significantly, the total number of CD4^+ T lymphocytes isolated from the central nervous system of clinically healthy treated versus diseased control animals was comparable. By using a CD45 congenic model of passively transferred experimental autoimmune encephalomyelitis to enable tracking of myelin basic protein-specific effector T lymphocytes, prevention of clinical signs of disease was again demonstrated in treated animals but without quantitative or qualitative impediment to the movement of autoreactive T lymphocytes to and within the central nervous system. Thus, despite the uninterrupted movement of specific T lymphocytes into the target tissue, subsequent disease development was blocked. This provides compelling evidence for a direct effector role of TNF/lymphotoxin α in autoimmune tissue damage.

  4. The role of slow and persistent TTX-resistant sodium currents in acute tumor necrosis factor-α-mediated increase in nociceptors excitability

    PubMed Central

    Gudes, Sagi; Barkai, Omer; Caspi, Yaki; Katz, Ben; Lev, Shaya

    2014-01-01

    Tetrodotoxin-resistant (TTX-r) sodium channels are key players in determining the input-output properties of peripheral nociceptive neurons. Changes in gating kinetics or in expression levels of these channels by proinflammatory mediators are likely to cause the hyperexcitability of nociceptive neurons and pain hypersensitivity observed during inflammation. Proinflammatory mediator, tumor necrosis factor-α (TNF-α), is secreted during inflammation and is associated with the early onset, as well as long-lasting, inflammation-mediated increase in excitability of peripheral nociceptive neurons. Here we studied the underlying mechanisms of the rapid component of TNF-α-mediated nociceptive hyperexcitability and acute pain hypersensitivity. We showed that TNF-α leads to rapid onset, cyclooxygenase-independent pain hypersensitivity in adult rats. Furthermore, TNF-α rapidly and substantially increases nociceptive excitability in vitro, by decreasing action potential threshold, increasing neuronal gain and decreasing accommodation. We extended on previous studies entailing p38 MAPK-dependent increase in TTX-r sodium currents by showing that TNF-α via p38 MAPK leads to increased availability of TTX-r sodium channels by partial relief of voltage dependence of their slow inactivation, thereby contributing to increase in neuronal gain. Moreover, we showed that TNF-α also in a p38 MAPK-dependent manner increases persistent TTX-r current by shifting the voltage dependence of activation to a hyperpolarized direction, thus producing an increase in inward current at functionally critical subthreshold voltages. Our results suggest that rapid modulation of the gating of TTX-r sodium channels plays a major role in the mediated nociceptive hyperexcitability of TNF-α during acute inflammation and may lead to development of effective treatments for inflammatory pain, without modulating the inflammation-induced healing processes. PMID:25355965

  5. Association of tumor necrosis factor-alpha -308G>A polymorphism with IgE-mediated allergy to betalactams in an Italian population.

    PubMed

    Guéant-Rodriguez, R-M; Guéant, J-L; Viola, M; Tramoy, D; Gaeta, F; Romano, A

    2008-04-01

    Tumor necrosis factor-alpha (TNF-alpha) is released from mast cells via an immunoglobulin E (IgE)-dependent mechanism. The variant G>A at -308 of TNFA is part of an extended haplotype HLA-A1-B8-DR3-DQ2 and influences the gene expression. We evaluated this variant in relation to IgE-mediated reactions to betalactams, in 427 subjects, including 167 cases and 260 age- and gender-paired controls. TNFA GG genotype was a significant independent predictor of the primary risk of betalactam allergy, concurrently with total IgE level, with an age- and sex-adjusted odds ratio estimated at 2.45 (95% confidence interval: 1.18-5.08, P=0.0163). Cases with -308AA genotype had a higher serum level of specific IgE than those with -308GA/GG genotype, with median levels (relative units) of 4.6 (inter-quartiles: 3.9-10.6) and 2.2 (1.4-4.3), respectively (P=0.0046). In conclusion, our results suggest an ambivalent influence of a genetic determinant of pro-inflammatory pathways on IgE-mediated hypersensitivity to betalactams. PMID:17471286

  6. Loss of ADAM17-Mediated Tumor Necrosis Factor Alpha Signaling in Intestinal Cells Attenuates Mucosal Atrophy in a Mouse Model of Parenteral Nutrition

    PubMed Central

    Feng, Yongjia; Tsai, Yu-Hwai; Xiao, Weidong; Ralls, Matthew W.; Stoeck, Alex; Wilson, Carole L.; Raines, Elaine W.

    2015-01-01

    Total parenteral nutrition (TPN) is commonly used clinically to sustain patients; however, TPN is associated with profound mucosal atrophy, which may adversely affect clinical outcomes. Using a mouse TPN model, removing enteral nutrition leads to decreased crypt proliferation, increased intestinal epithelial cell (IEC) apoptosis and increased mucosal tumor necrosis factor alpha (TNF-α) expression that ultimately produces mucosal atrophy. Upregulation of TNF-α signaling plays a central role in mediating TPN-induced mucosal atrophy without intact epidermal growth factor receptor (EGFR) signaling. Currently, the mechanism and the tissue-specific contributions of TNF-α signaling to TPN-induced mucosal atrophy remain unclear. ADAM17 is an ectodomain sheddase that can modulate the signaling activity of several cytokine/growth factor receptor families, including the TNF-α/TNF receptor and ErbB ligand/EGFR pathways. Using TPN-treated IEC-specific ADAM17-deficient mice, the present study demonstrates that a loss of soluble TNF-α signaling from IECs attenuates TPN-induced mucosal atrophy. Importantly, this response remains dependent on the maintenance of functional EGFR signaling in IECs. TNF-α blockade in wild-type mice receiving TPN confirmed that soluble TNF-α signaling is responsible for downregulation of EGFR signaling in IECs. These results demonstrate that ADAM17-mediated TNF-α signaling from IECs has a significant role in the development of the proinflammatory state and mucosal atrophy observed in TPN-treated mice. PMID:26283731

  7. Tumor necrosis factor receptor p75 mediates cell-specific activation of nuclear factor kappa B and induction of human cytomegalovirus enhancer.

    PubMed

    Laegreid, A; Medvedev, A; Nonstad, U; Bombara, M P; Ranges, G; Sundan, A; Espevik, T

    1994-03-11

    The functional role of human tumor necrosis factor receptor (TNFR) p75 was studied by the use of TNFR p75-specific agonistic antibodies. Human SW480T adenocarcinoma cells, stably transfected with a reporter construct containing beta-galactosidase under the control of human cytomegalovirus immediate early enhancer, were stimulated with anti-TNFR p75 polyclonal antiserum or monoclonal antibodies followed by measurement of beta-galactosidase activity and analysis by electrophoretic mobility shift assays. It was found that cross-linking of TNFR p75 led to strong induction of the human cytomegalovirus enhancer as well as activation of nuclear factor-kappa B (NF-kappa B). Stimulation of TNFR p75 also mediated activation of NF-kappa B in human KYM-1 rhabdomyosarcoma cells but not in other cell types such as U937 and HL-60 monocytic cells or in Eahy 926 endothelial cells. NF-kappa B activation induced by TNFR p75 was delayed approximately 15 min compared with NF-kappa B activation induced by TNFR p55, indicating that the two TNFRs activate NF-kappa B through different signaling pathways. The data presented in this study identify intracellular responses mediated by TNFR p75 which have not been reported previously and suggest that TNFR p75-induced activation of NF-kappa B is strictly cell type-specific. PMID:8126005

  8. Disruption of Tumor Necrosis Factor Receptor-Associated Factor 5 Exacerbates Murine Experimental Colitis via Regulating T Helper Cell-Mediated Inflammation

    PubMed Central

    Shang, Jian; Li, Lixia; Wang, Xiaobing; Pan, Huaqin; Liu, Shi; He, Ruohang; Li, Jin; Zhao, Qiu

    2016-01-01

    Tumor necrosis factor (TNF) receptor-associated factor 5 (TRAF5) is a key mediator of TNF receptor superfamily members and is important in both T helper (Th) cell immunity and the regulation of multiple signaling pathways. To clarify TRAF5's influence on inflammatory bowel diseases (IBDs), we investigated TRAF5 deficiency's effect on dextran sulfate sodium- (DSS-) induced colitis. Colitis was induced in TRAF5 knockout (KO) mice and their wild-type (WT) littermates by administering 3% DSS orally for 7 days. The mice were then sacrificed, and their colons were removed. Our data suggested that KO mice were more susceptible to DSS-induced colitis. TRAF5 deficiency significantly enhanced IFN-γ, IL-4, and IL-17a mRNA and protein levels in the colons of DSS-fed mice, and the mRNA expression of T-bet and GATA-3 was also markedly elevated. However, ROR-α and ROR-γt mRNA levels did not differ between DSS-induced KO and WT mice. Flow cytometry showed increased frequencies of Th2 and IFN-γ/IL-17a-coproducing CD4+ T cells in the colons of DSS-induced KO mice. Additionally, TRAF5 deficiency significantly enhanced the activation of NF-κB in CD4+ T cells after DSS administration. These results indicated that TRAF5 deficiency significantly aggravated DSS-induced colitis, most likely by regulating Th cell-mediated inflammation. PMID:27110068

  9. Tumor necrosis factor-alpha mediates activation of NF-κB and JNK signaling cascades in retinal ganglion cells and astrocytes in opposite ways

    PubMed Central

    Dvoriantchikova, Galina; Ivanov, Dmitry

    2014-01-01

    Tumor necrosis factor-alpha (TNF) is an important mediator of the innate immune response in the retina. TNF can activate various signaling cascades, including NF-κB, nuclear factor kappa B (NF-κB) and c-Jun N-terminal kinase (JNK) pathways. The harmful role of these pathways, as well as of TNF, has previously been shown in several retinal neurodegenerative conditions including glaucoma and retinal ischemia. However, TNF and TNF-regulated signaling cascades are capable not only of mediating neurotoxicity, but of being protective. We performed this study to delineate the beneficial and detrimental effects of TNF signaling in the retina. To this end, we used TNF-treated primary retinal ganglion cell (RGC) and astrocyte cultures. Levels of expression of NF-κB subunits in RGCs and astrocytes were evaluated by quantitative RT-PCR (qRT-PCR) and Western blot (WB) analysis. NF-κB and JNK activity in TNF-treated cells was determined in a time-dependent manner using ELISA and WB. Gene expression in TNF-treated astrocytes was measured by qRT-PCR. We found that NF-κB family members were present in RGCs and astrocytes at the mRNA and protein levels. RGCs failed to activate NF-κB in the presence of TNF, a phenomenon that was associated with sustained JNK activation and RGC death. However, TNF initiated the activation of NF-κB and mediated transient JNK activation in astrocytes. These events were associated with glial survival and increased expression of neurotoxic pro-inflammatory factors. Our findings suggest that, in the presence of TNF, NF-κB and JNK signaling cascades are activated in opposite ways in RGCs and astrocytes. These events can directly and indirectly facilitate RGC death. PMID:25160799

  10. RAC1 regulate tumor necrosis factor-α-mediated impaired osteogenic differentiation of dental pulp stem cells.

    PubMed

    Feng, Guijuan; Shen, Qijie; Lian, Min; Gu, Zhifeng; Xing, Jing; Lu, Xiaohui; Huang, Dan; Li, Liren; Huang, Shen; Wang, Yi; Zhang, Jinlong; Shi, Jiahai; Zhang, Dongmei; Feng, Xingmei

    2015-09-01

    Human dental pulp contains a rapidly proliferative subpopulation of precursor cells termed dental pulp stem cells (DPSCs) that show self-renewal and multilineage differentiation, including neurogenic, chondrogenic, osteogenic and adipogenic. We previously reported that tomuor necrosis factor-α (TNF-α) (10 ng/mL) triggered osteogenic differentiation of human DPSCs via the nuclear factor-κB (NF-κB) signaling pathway. While previous studies showed that cells treated with TNF-α at higher concentrations showed decreased osteogenic differentiation capability. In this study we analyze the function of TNF-α (100 ng/mL) on osteogenic differentiation of human DPSCs for the first time and identify the underlying molecule mechanisms. Our data revealed that TNF-α with higher concentration significantly reduced mineralization and the expression of bone morphogenetic protein 2 (BMP2), alkaline phosphatase (ALP) and runt-related transcription factor 2 (RUNX2). Further, we revealed that TNF-α could suppress the osteogenic differentiation of DPSCs via increasing the expression of RAC1, which could activate the Wnt/β-catenin signaling pathway and liberate β-catenin to translocate into the nucleus. Genetic silencing of RAC1 expression using siRNA restored osteogenic differentiation of DPSCs. Our findings may provide a potential approach to bone regeneration in inflammatory microenvironments. PMID:26219349

  11. Tumor necrosis factor α induces epithelial-mesenchymal transition and promotes metastasis via NF-κB signaling pathway-mediated TWIST expression in hypopharyngeal cancer.

    PubMed

    Yu, Liang; Mu, Yakui; Sa, Na; Wang, Haibo; Xu, Wei

    2014-01-01

    Epithelial-mesenchymal transition (EMT) is an important mechanism in cancer metastasis. Tumor necrosis factor α (TNFα) can induce cancer invasion and metastasis associated with EMT. However, the underlying mechanisms are not entirely clear. Therefore, we investigated whether TNFα has an effect on EMT and invasion and metastasis in human hypopharyngeal cancer FaDu cells, and further explored the potential mechanisms. In the present study, we demonstrated that TNFα induced EMT in FaDu cells and promoted FaDu cell migration and invasion. TNFα-induced EMT was characterized by a change from well organized cell-cell adhesion and cell polarity to loss of cell-cell contacts, cell scattering and increased expression of vimentin and N-cadherin accompanied by a decrease in E-cadherin. Furthermore, we found that p65 translocated to the nucleus after TNFα stimulation and increased the nuclear expression of TWIST. We demonstrated that TNFα treatment also increased the expression of TWIST by activating the NF-κB signaling pathway. While p65 was inhibited by siRNA-65 or BAY11-7082 (inhibitor of NF-κB), TWIST expression was also decreased. Therefore, we conclude that TNFα induces EMT and promotes metastasis via NF-κB signaling pathway-mediated TWIST expression in hypopharyngeal cancer. PMID:24220622

  12. Tumor necrosis factor α-converting enzyme (TACE/ADAM17) mediates ectodomain shedding of the scavenger receptor CD163.

    PubMed

    Etzerodt, Anders; Maniecki, Maciej Bogdan; Møller, Kirsten; Møller, Holger Jon; Moestrup, Søren Kragh

    2010-12-01

    CD163 is expressed specifically in the monocyte/macrophage lineage, where it mediates uptake of haptoglobin-hemoglobin complexes, leading to metabolism of the oxidative heme molecule. Shedding of the CD163 ectodomain from the cell surface produces a sCD163 plasma protein, and a positive correlation is seen between the sCD163 plasma level and the severity of various infectious and inflammatory diseases. In the present analysis of the phorbol ester-induced shedding of sCD163 in CD163 cDNA-transfected HEK293 cells, we used metalloproteinase inhibitors and siRNA-mediated inhibition of metalloproteinases to identify TACE/ADAM17 as an enzyme responsible for PMA-induced cleavage of the membrane-proximal region of CD163. As TACE/ADAM17-mediated shedding of TNF-α is up-regulated in macrophages subjected to inflammatory stimuli, the present results now provide a likely explanation for the strong empirical relationship between the sCD163 plasma level and infectious/inflammatory diseases relating to macrophage activity. PMID:20807704

  13. Tumor Necrosis Factor-α and Lymphotoxin-α Mediate Myocardial Ischemic Injury via TNF Receptor 1, but Are Cardioprotective When Activating TNF Receptor 2

    PubMed Central

    Lau, Wayne Bond; Jiao, Li-Yuan; Liu, Baojiang; Yuan, Yuexing; Wang, Xiaoliang; Gao, Erhe; Koch, Walter J.; Ma, Xin-Liang; Wang, Yajing

    2013-01-01

    Objective This study determines the roles of tumor necrosis factor-α (TNFα) and lymphotoxin-α (LTα) in post-myocardial infarction (post-MI) cardiac injury, and identifies the TNF receptor type responsible for TNFα- and LTα-mediated cardiac injury. Methods and Results Adult male wild type (WT), TNFα−/−, LTα−/−, TNFR1−/−, and TNFR2−/− mice were subjected to MI via coronary artery occlusion. Functional, histological, and biochemical analyses were performed 1 to 7 days post-MI. In WT mice, MI significantly increased both TNFα and LTα levels in plasma, but in distinct temporal manner. Plasma TNFα peaked 1 day after MI, and decreased toward baseline 3 days after MI. In contrast, plasma LTα became significantly increased 3 days post-MI, and remained elevated thereafter. TNFα deletion significantly improved cardiac function 3 days, but not 7 days, after MI. In contrast, LTα deletion had no effect upon cardiac dysfunction 3 days after MI, but improved cardiac function 7 days after MI. More importantly, knockout of TNFR1 and TNFR2 had opposite effects upon post-MI cardiac dysfunction, which was markedly attenuated by TNFR1 deletion (P<0.01 vs. WT), but exacerbated by TNFR2 deletion (P<0.05 vs. WT). Conclusion Our study demonstrates that TNFα and LTα overproduction contribute to early and late cardiac dysfunction after MI, respectively. We provide clear evidence that both TNFα and LTα mediate post-MI cardiac dysfunction via TNFR1 stimulation, whereas TNFR2 activation is cardioprotective against ischemic injury. Simultaneous inhibition of TNFα and LTα or specific TNFR1 function blockade may represent superior cardioprotective approaches over general TNF activity suppression. PMID:23704873

  14. Genetic Delineation of the Pathways Mediated by Bid and JNK in Tumor Necrosis Factor-α-induced Liver Injury in Adult and Embryonic Mice*S⃞

    PubMed Central

    Ni, Hong-Min; Chen, Xiaoyun; Shi, Ying-Hong; Liao, Yong; Beg, Amer A.; Fan, Jia; Yin, Xiao-Ming

    2009-01-01

    Tumor necrosis factor-α (TNFα)-induced hepatocyte death and liver injury can be mediated by multiple mechanisms, which could be evaluated by different animal models. Previous studies have defined the importance of Bid in mitochondrial apoptosis activation in adult mice treated with lipopolysaccharides in the presence of galactosamine (GalN), which suppresses NF-κB activation, but not in embryonic mice in which NF-κB activation is suppressed by genetic deletion of p65RelA. JNK has also been found important in TNFα-induced mitochondria activation and liver injury in the lipopolysaccharide/GalN and concanavalin A (ConA)/GalN models, but not in a ConA-only model in which NF-κB activation was not suppressed. To determine the mechanistic relationship of pathways mediated by Bid and JNK, we investigated these two molecules in TNFα injury models that had not been previously examined. Most importantly, we created and studied mice deficient in both Bid and JNK. We found that, like JNK, Bid was also required for TNFα-induced injury induced by concanavalin A/GalN but not by ConA alone. Furthermore, our results indicate that these two molecules function in a largely overlapped manner, with Bid being downstream of JNK in the adult livers. However, JNK, but not Bid, was able to contribute to the TNFα-induced liver apoptosis in RelA-deficient embryos. The Bid-independent role of JNK was also observed in the adult mice, mainly in the promotion of the lethal progression of the TNFα injury. This work defined both linear and parallel relationships of Bid and JNK in TNFα-induced hepatocyte apoptosis and liver injury. PMID:19060338

  15. Mechanisms for virus-induced liver disease: tumor necrosis factor-mediated pathology independent of natural killer and T cells during murine cytomegalovirus infection.

    PubMed Central

    Orange, J S; Salazar-Mather, T P; Opal, S M; Biron, C A

    1997-01-01

    The contribution of endogenous NK cells and cytokines to virus-induced liver pathology was evaluated during murine cytomegalovirus infections of mice. In immunocompetent C57BL/6 mice, the virus induced a self-limited liver disease characterized by hepatitis, with focal inflammation, and large grossly visible subcapsular necrotic foci. The inflammatory foci were most numerous and contained the greatest number of cells 3 days after infection; they colocalized with areas of viral antigen expression. The largest number of necrotic foci was found 2 days after infection. Overall hepatic damage, assessed as increased expression of liver enzymes in serum, accompanied the development of inflammatory and necrotic foci. Experiments with neutralizing antibodies demonstrated that although virus-induced tumor necrosis factor (TNF) can have antiviral effects, it also mediated significant liver pathology. TNF was required for development of hepatic necrotic foci and increased levels of liver enzymes in serum but not for increased numbers of inflammatory foci. The necrotic foci and liver enzyme indications of pathology occurred independently of NK and T cells, because mice rendered NK-cell deficient by treatment with antibodies, T- and B-cell-deficient Rag-/- mice, and NK- and T-cell-deficient E26 mice all manifested both parameters of disease. Development of necrotic foci and maximally increased levels of liver enzymes in serum also were TNF dependent in NK-cell-deficient mice. Moreover, in the immunodeficient E26 mice, virus-induced liver disease was progressive, with eventual death of the host, and neutralization of TNF significantly increased longevity. These results establish conditions separating hepatitis from significant liver damage and demonstrate a cytokine-mediated component to viral pathogenesis. PMID:9371583

  16. Excessive Ovarian Production of Nerve Growth Factor Elicits Granulosa Cell Apoptosis by Setting in Motion a Tumor Necrosis Factor alpha/Stathmin$Mediated Death Signaling Pathway

    PubMed Central

    Garcia-Rudaz, Cecilia; Dorfman, Mauricio; Nagalla, Srinivasa; Svechnikov, Konstantin; Söder, Olle; Ojeda, Sergio R.; Dissen, Gregory A.

    2012-01-01

    Excessive nerve growth factor (NGF) production by the ovary, achieved via a transgenic approach, results in arrested antral follicle growth, reduced ovulatory capacity, and a predisposition to cyst formation in response to mildly elevated LH levels. Two salient features in these mutant mice (termed 17NF) are an elevated production of 17-alpha hydroxyprogesterone (17-OHP4), testosterone (T4) and estradiol (E2) in response to gonadotropins, and an increased frequency of granulosa cell (GC) apoptosis. Here we show that the increase in steroidal response is associated with enhanced expression of Cyp17a1, Hsd17b, and Cyp19a1, which encode the enzymes catalyzing the synthesis of 17-OHP4, T4 and E2, respectively. Using a proteomic approach, we identified stathmin (STMN1), as a protein that is overproduced in 17NF ovaries. In its phosphorylated state, STMN1 mediates a cell death signal initiated by tumor necrosis factor alpha (TNF). STMN1 is expressed in GCs and excessive NGF increases its abundance as well as that of its forms phosphorylated at serine (Ser) 16, 25 and 38. TNF synthesis is also increased in 17NF ovaries, and this change is abolished by blocking neurotrophic tyrosine kinase (NTRK) receptors. Inhibiting TNF actions in vivo by administering a soluble TNF receptor prevented the increase in total and phosphorylated STMN1 production, as well as GC apoptosis in NGF-overproducing ovaries. These results indicate that an excess of NGF in the ovary promotes steroidogenesis by enhancing the expression of enzyme genes involved in 17-OHP4, T4 and E2 synthesis, and causes GC apoptosis by activating a TNF/STMN1-mediated cell death pathway. PMID:21646391

  17. Identification of the Homeobox Protein Prx1 (MHox, Prrx-1) as a Regulator of Osterix Expression and Mediator of Tumor Necrosis Factor α Action in Osteoblast Differentiation

    PubMed Central

    Lu, Xianghuai; Beck, George R; Gilbert, Linda C; Camalier, Corinne E; Bateman, Nicholas W; Hood, Brian L; Conrads, Thomas P; Kern, Michael J; You, Shaojin; Chen, Hong; Nanes, Mark S

    2011-01-01

    Tumor necrosis factor α (TNF-α) promotes bone loss and inhibits bone formation. Osterix (Osx, SP7) is a transcription factor required for osteoblast (OB) differentiation because deletion results in a cartilaginous skeleton. We previously described a TNF suppressor element in the Osx promoter that was used to isolate nuclear proteins mediating TNF inhibition of OB differentiation. Nuclear extracts from TNF-treated pre-OBs were incubated with the TNF suppressor element for protein pull-down, and tryptic fragments were analyzed by mass spectrometry. Chromatin immunoprecipitation (ChIP) assay confirmed eight bound transcription factors. One protein, the paired related homeobox protein (Prx1), had been shown previously to have a critical role in limb bud formation and skeletal patterning. PCR revealed Prx1 expression in primary stromal cells (MSCs), C3H10T1/2 cells, and MC3T3 preosteoblasts. TNF stimulated a 14-fold increase in mRNA for Prx1, rapid cell accumulation in MC3T3 cells, and expression in periosteal and trabecular lining cells in vivo. Transient expression of Prx inhibited transcription of Osx and RUNX2. Expression of the Prx1b isoform or Prx2 decreased Osx and RUNX2 mRNA and OB differentiation in preosteoblasts. Silencing of Prx1 with siRNA abrogated TNF suppression of Osx mRNA and increased basal Osx expression. Electrophoretic mobility shift revealed Prx1b as the preferred isoform binding the Osx promoter. These results identify the homeobox protein Prx1 as an obligate mediator of TNF inhibition of Osx and differentiation of OB progenitors. Activation of Prx1 by TNF may contribute to reduced bone formation in inflammatory arthritis, menopause, and aging. © 2011 American Society for Bone and Mineral Research. PMID:20683885

  18. Cytotoxic activity of tumor necrosis factor is mediated by early damage of mitochondrial functions. Evidence for the involvement of mitochondrial radical generation.

    PubMed

    Schulze-Osthoff, K; Bakker, A C; Vanhaesebroeck, B; Beyaert, R; Jacob, W A; Fiers, W

    1992-03-15

    Structural mitochondrial damage accompanies the cytotoxic effects of several drugs including tumor necrosis factor (TNF). Using various inhibitors of mitochondrial electron transport we have investigated the mechanism of TNF-mediated cytotoxicity in L929 and WEHI 164 clone 13 mouse fibrosarcoma cells. Inhibitors with different sites of action modulated TNF cytotoxicity, however, with contrasting effects on final cell viability. Inhibition of mitochondrial electron transport at complex III (cytochrome c reductase) by antimycin A resulted in a marked potentiation of TNF-mediated injury. In contrast, when the electron flow to ubiquinone was blocked, either at complex I (NADH-ubiquinone oxidoreductase) with amytal or at complex II (succinate-ubiquinone reductase) with thenoyltrifluoroacetone, cells were markedly protected against TNF cytotoxicity. Neither uncouplers nor inhibitors of oxidative phosphorylation nor complex IV (cytochrome c oxidase) inhibitors significantly interfered with TNF-mediated effects, ruling out the involvement of energy-coupled phenomena. In addition, the toxic effects of TNF were counteracted by the addition of antioxidants and iron chelators. Furthermore, we analyzed the direct effect of TNF on mitochondrial morphology and functions. Treatment of L929 cells with TNF led to an early degeneration of the mitochondrial ultrastructure without any pronounced damage of other cellular organelles. Analysis of the mitochondrial electron flow revealed that TNF treatment led to a rapid inhibition of the mitochondria to oxidize succinate and NADH-linked substrates. The inhibition of electron transport was dose-dependent and became readily detectable 60 min after the start of TNF treatment, thus preceding the onset of cell death by at least 3-6 h. In contrast, only minor effects were observed on complex IV activity. The different effects observed with the mitochondrial respiratory chain inhibitors provide suggestive evidence that mitochondrial production

  19. Interleukin-6 Attenuates Insulin-Mediated Increases in Endothelial Cell Signaling but Augments Skeletal Muscle Insulin Action via Differential Effects on Tumor Necrosis Factor-α Expression

    PubMed Central

    Yuen, Derek Y.C.; Dwyer, Renee M.; Matthews, Vance B.; Zhang, Lei; Drew, Brian G.; Neill, Bronwyn; Kingwell, Bronwyn A.; Clark, Michael G.; Rattigan, Stephen; Febbraio, Mark A.

    2009-01-01

    OBJECTIVE The cytokine interleukin-6 (IL-6) stimulates AMP-activated protein kinase (AMPK) and insulin signaling in skeletal muscle, both of which result in the activation of endothelial nitric oxide synthase (eNOS). We hypothesized that IL-6 promotes endothelial cell signaling and capillary recruitment in vivo, contributing to increased glucose uptake. RESEARCH DESIGN AND METHODS The effect of IL-6 with and without insulin on AMPK, insulin, and eNOS signaling in and nitric oxide (NO) release from human aortic endothelial cells (HAECs) was examined. The physiological significance of these in vitro signaling events was assessed by measuring capillary recruitment in rats during control and euglycemic-hyperinsulinemic clamps with or without IL-6 infusion. RESULTS IL-6 blunted increases in insulin signaling, eNOS phosphorylation (Ser1177), and NO production and reduced phosphorylation of AMPK in HAEC in vitro and capillary recruitment in vivo. In contrast, IL-6 increased Akt phosphorylation (Ser473) in hindlimb skeletal muscle and enhanced whole-body glucose disappearance and glucose uptake during the clamp. The differences in endothelial cell and skeletal muscle signaling were mediated by the cell-specific, additive effects of IL-6 and insulin because this treatment markedly increased tumor necrosis factor (TNF)-α protein expression in HAECs without any effect on TNF-α in skeletal muscle. When HAECs were incubated with a TNF-α–neutralizing antibody, the negative effects of IL-6 on eNOS signaling were abolished. CONCLUSIONS In the presence of insulin, IL-6 contributes to aberrant endothelial cell signaling because of increased TNF-α expression. PMID:19188427

  20. Infliximab ameliorating depression-like behavior through inhibiting the activation of the IDO-HAAO pathway mediated by tumor necrosis factor-α in a rat model.

    PubMed

    Fu, Xiao-Yan; Li, Hai-Yan; Jiang, Qing-Song; Cui, Ting; Jiang, Xin-Hui; Zhou, Qi-Xin; Qiu, Hong-Mei

    2016-09-01

    In recent years, some studies have suggested that the activation of inflammatory system plays a role in the occurrence of depression. Tumor necrosis factor-α (TNF-α), as one of the preinflammatory cytokines, has been reported to be involved in the occurrence of various diseases including depression. Infliximab, an antagonist of TNF-α, is usually used to treat some autoimmune diseases such as Crohn's disease and can perhaps be used to treat other diseases. In this study, the antidepressant effect and a possible mechanism of infliximab were investigated by studying the depression-like behavior and expression of TNF-α, indoleamine 2, 3-dioxygenase (IDO), and 3-hydroxyl amino acid oxygenase (HAAO) from the cortex and hippocampus in rat exposed to chronic unpredicted stress. Forty male Sprague-Dawley rats were divided into a control group (CG), an infliximab-treated control group, a model group (MG), and an infliximab-treated model group (IFXM). Infliximab (5 mg/kg once week) was administered to the infliximab-treated control group and IFXM rats by an intraperitoneal injection, whereas an equivalent volume of vehicle was administered to CG and MG rats. Rat behaviors and the expression of TNF-α, IDO, and HAAO in the cortex and hippocampus were determined. It was found that a significant relief in depression-like behaviors was observed with a downregulation of TNF-α, IDO, and HAAO expression in the IFXM rats compared with MG rats. The results show the antidepressant effect of infliximab and suggest that its mechanism is partly related to inhibition of IDO-HAAO pathway activation mediated by TNF-α in rat brain. PMID:27366867

  1. Human recombinant interleukin-1 beta- and tumor necrosis factor alpha-mediated suppression of heparin-like compounds on cultured porcine aortic endothelial cells

    SciTech Connect

    Kobayashi, M.; Shimada, K.; Ozawa, T. )

    1990-09-01

    Cytokines are known to tip the balance of the coagulant-anticoagulant molecules on the endothelial cell surface toward intravascular coagulation. Their effects on endothelial cell surface-associated heparin-like compounds have not been examined yet. Incorporation of (35S)sulfate into heparan sulfate on cultured porcine aortic endothelial cells was suppressed by human recombinant interleukin-1 beta (rIL-1 beta) or tumor necrosis factor alpha (rTNF alpha) in a dose- and time-dependent manner with little effect on cell number, protein content, and (3H)leucine incorporation of cells. Maximal inhibition was achieved by incubation of cells with 100 ng/ml of rIL-1 beta or 5 ng/ml of rTNF alpha for 12-24 hours, resulting in a reduction of the synthesis of heparan sulfate on the cell surface by approximately 50%. The dose dependency was consistent with that seen in the stimulation of endothelial cell procoagulant activity by each cytokine. The suppression of heparan sulfate synthesis was sustained for at least 48 hours after pretreatment of cells with cytokines and was unchanged after the addition of indomethacin or polymyxin B. The rate of degradation of prelabeled 35S-heparan sulfate on the cell surface was not altered by cytokine treatments. Neither the size, the net negative charge, nor the proportion of the molecule with high affinity for antithrombin III of endothelial cell heparan sulfate was changed by cytokines. Furthermore, specific binding of 125I-labeled antithrombin III to the endothelial cell surface was reduced to 40-60% of control by cytokines. In parallel with reduction in binding, antithrombin III cofactor activity was partially diminished in cytokine-treated endothelial cells. Thus, cytokine-mediated suppression of heparin-like substance on endothelial cells appears to be another cytokine-inducible endothelial effects affecting coagulation.

  2. Phytochemicals of Aristolochia tagala and Curcuma caesia exert anticancer effect by tumor necrosis factor-α-mediated decrease in nuclear factor kappaB binding activity

    PubMed Central

    Hadem, Khetbadei Lysinia Hynniewta; Sharan, Rajeshwar Nath; Kma, Lakhan

    2015-01-01

    Rationale: The active compounds or metabolites of herbal plants exert a definite physiological action on the human body and thus are widely used in human therapy for various diseases including cancer. Previous studies by our group have reported the anticarcinogenic properties of the two herbal plants extracts (HPE) of Aristolochia tagala (AT) Cham. and Curcuma caesia (CC) Roxb. in diethylnitrosamine-induced mouse liver cancer in vivo. The anticarcinogenic properties of these extracts may be due to the active compounds present in them. Objectives: Our objective was to analyze the phytochemical constituents present in AT and CC, to assay their antioxidant properties and to determine their role in a possible intervention on tumor progression. Materials and Methods: Qualitative and quantitative analysis of constituent with anticancer properties present in the crude methanol extract of the two plants CC and AT was carried out following standard methods. Separation of the phytochemical compounds was done by open column chromatography. The extracts were eluted out with gradients of chloroform-methanol solvents. Ultraviolet-visible spectra of individual fractions were recorded, and the fractions were combined based on their λmax. The free radical scavenging activity of crude extracts and fractions obtained was also determined; the radical scavenging activity was expressed as IC50. High-performance thin layer chromatography (HPTLC) analysis of fractionated compounds was carried out to identify partially the phytochemical compounds. The anti-inflammatory and anticancer activity of AT and CC extracts was studied in DEN induced BALB/c mice by analyzing the tumor necrosis factor-α (TNF-α) levels in serum and the nuclear factor kappaB (NF-κB) binding activity in nuclear extracts of the liver. Results: It was observed that both AT and CC contained compounds such as phenolics, tannins, flavonoids, terpenoids, etc., and both extracts exhibited antioxidant capacity. HPTLC

  3. Ketoconazole attenuates radiation-induction of tumor necrosis factor

    SciTech Connect

    Hallahan, D.E.; Virudachalam, S.; Kufe, D.W.; Weichselbaum, R.R.

    1994-07-01

    Previous work has demonstrated that inhibitors of phospholipase A2 attenuate ionizing radiation-induced arachidonic acid production, protein kinase C activation, and prevent subsequent induction of the tumor necrosis factor gene. Because arachidonic acid contributes to radiation-induced tumor necrosis factor expression, the authors analyzed the effects of agents which alter arachidonate metabolism on the regulation of this gene. Phospholipase A2 inhibitors quinicrine, bromphenyl bromide, and pentoxyfylline or the inhibitor of lipoxygenase (ketoconazole) or the inhibitor of cycloxygenase (indomethacine) were added to cell culture 1 h prior to irradiation. Radiation-induced tumor necrosis factor gene expression was attenuated by each of the phospholipase A2 inhibitors (quinicrine, bromphenylbromide, and pentoxyfylline). Furthermore, ketoconazole attenuated X ray induced tumor necrosis factor gene expression. Conversely, indomethacin enhanced tumor necrosis factor expression following irradiation. The finding that radiation-induced tumor necrosis factor gene expression was attenuated by ketoconazole suggests that the lipoxygenase pathway participates in signal transduction preceding tumor necrosis factor induction. Enhancement of tumor necrosis factor expression by indomethacin following irradiation suggests that prostaglandins produced by cyclooxygenase act as negative regulators of tumor necrosis factor expression. Inhibitors of tumor necrosis factor induction ameliorate acute and subacute sequelae of radiotherapy. The authors propose therefore, that ketoconazole may reduce acute radiation sequelae such as mucositis and esophagitis through a reduction in tumor necrosis factor induction or inhibition of phospholipase A2 in addition to its antifungal activity. 25 refs., 2 figs.

  4. A crucial role for tumor necrosis factor receptor 1 in synovial lining cells and the reticuloendothelial system in mediating experimental arthritis

    PubMed Central

    2010-01-01

    Introduction Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that mainly affects synovial joints. Biologics directed against tumor-necrosis-factor (TNF)-α are efficacious in the treatment of RA. However, the role of TNF receptor-1 (TNFR1) in mediating the TNFα effects in RA has not been elucidated and conflicting data exist in experimental arthritis models. The objective is to investigate the role of TNFR1 in the synovial lining cells (SLC) and the reticuloendothelial system (RES) during experimental arthritis. Methods Third generation of adenovirus serotype 5 were either injected locally in the knee joint cavity or systemically by intravenous injection into the retro-orbital venous sinus to specifically target SLC and RES, respectively. Transduction of organs was detected by immunohistochemistry of the eGFP transgene. An adenoviral vector containing a short hairpin (sh) RNA directed against TNFR1 (HpTNFR1) was constructed and functionally evaluated in vitro using a nuclear factor-kappaB (NF-κB) reporter assay and in vivo in streptococcal cell wall-induced arthritis (SCW) and collagen-induced arthritis (CIA). Adenoviruses were administered before onset of CIA, and the effect of TNFR1 targeting on the clinical development of arthritis, histology, quantitative polymerase chain reaction (qPCR), cytokine analyses and T-cell assays was evaluated. Results Systemic delivery of Ad5.CMV-eGFP predominantly transduced the RES in liver and spleen. Local delivery transduced the synovium and not the RES in liver, spleen and draining lymph nodes. In vitro, HpTNFR1 reduced the TNFR1 mRNA expression by three-fold resulting in a 70% reduction of TNFα-induced NF-κB activation. Local treatment with HpTNFR1 markedly reduced mRNA and protein levels of interleukin (IL)-1β and IL-6 in SLC during SCW arthritis and ameliorated CIA. Systemic targeting of TNFR1 in RES of liver and spleen by systemic delivery of Ad5 virus encoding for a small hairpin RNA against TNFR1

  5. Polyinosinic-Polycytidylic Acid Perturbs Ovarian Functions Through Toll-Like Receptor 3-Mediated Tumor Necrosis Factor A Production in Female Mice.

    PubMed

    Yan, Keqin; Cheng, Lijing; Liu, Peng; Liu, Zhenghui; Zhao, Shutao; Zhu, Weiwei; Wang, Qing; Wu, Han; Han, Daishu

    2015-07-01

    Viral infections may perturb ovarian functions and female fertility. Mechanisms underlying viral perturbation of ovarian functions are incompletely understood. This study found that intraperitoneal injection of polyinosinic-polycytidylic acid [poly (I:C)] in female mice inhibits estradiol synthesis and induces ovarian granulosa cell apoptosis. Poly (I:C) is a synthetic viral double-stranded RNA analog, which induces innate antiviral responses mimicking a viral infection through activation of pattern recognition receptors, including toll-like receptor 3 (TLR3), retinoic acid-inducible gene I, and melanoma differentiation-associated gene 5. Injection of poly (I:C) significantly induced granulosa cell apoptosis in antral follicles and reduced antral follicle numbers. These effects were significantly diminished in Tlr3 knockout or tumor necrosis factor-alpha (Tnfa) knockout mice. We demonstrated that poly (I:C) induced TNFA production at a relatively high level in wild-type mice compared with that in Tlr3 knockout mice. Notably, TNFA neutralizing antibody significantly reduced poly (I:C)-induced ovarian dysfunction. In vitro assays confirmed that TNFA inhibits estradiol synthesis and induces granulosa cell apoptosis. Results provide novel insights into the mechanisms by which a mimicked viral infection perturbs ovarian functions in mice. PMID:26040668

  6. Tumor Necrosis Factor-stimulated Gene 6 (TSG-6)-mediated Interactions with the Inter-α-inhibitor Heavy Chain 5 Facilitate Tumor Growth Factor β1 (TGFβ1)-dependent Fibroblast to Myofibroblast Differentiation.

    PubMed

    Martin, John; Midgley, Adam; Meran, Soma; Woods, Emma; Bowen, Timothy; Phillips, Aled O; Steadman, Robert

    2016-06-24

    Fibroblasts are central to wound healing and fibrosis through TGFβ1-triggered differentiation into contractile, α-smooth muscle actin (α-SMA)-positive myofibroblasts. This is mediated by accumulation of a pericellular matrix of hyaluronan (HA) and the HA-dependent co-localization of CD44 with the epidermal growth factor receptor (EGFR). Interactions of HA with hyaladherins, such as inter-α-inhibitor (IαI) and tumor necrosis factor-stimulated gene-6 (TSG-6), are also essential for differentiation. This study investigated the mechanisms involved. TSG-6 and α-SMA had different kinetics of induction by TGFβ1, with TSG-6 peaking before α-SMA Si CD44 or EGFR inhibition prevented differentiation but had no effect on TSG-6 expression. TSG-6 was essential for differentiation, and mAb A38 (preventing IαI heavy chain (HC) transfer), HA-oligosaccharides, cobalt, or Si bikunin prevented TSG-6 activity, preventing differentiation. A38 also prevented the EGFR/CD44 association. This suggested that TSG-6/IαI HC interaction was necessary for the effect of TSG-6 and that HC stabilization of HA initiated the CD44/EGFR association. The newly described HC5 was shown to be the principal HC expressed, and its cell surface expression was prevented by siRNA inhibition of TSG-6 or bikunin. HC5 was released by hyaluronidase treatment, confirming its association with cell surface HA. Finally, HC5 knockdown by siRNA confirmed its role in myofibroblast differentiation. The current study describes a novel mechanism linking the TSG-6 transfer of the newly described HC5 to the HA-dependent control of cell phenotype. The interaction of HC5 with cell surface HA was essential for TGFβ1-dependent differentiation of fibroblasts to myofibroblasts, highlighting its importance as a novel potential therapeutic target. PMID:27143355

  7. Chitinase 3-Like 1 (Chil1) Regulates Survival and Macrophage-Mediated Interleukin-1β and Tumor Necrosis Factor Alpha during Pseudomonas aeruginosa Pneumonia.

    PubMed

    Marion, Chad R; Wang, Jianmiao; Sharma, Lokesh; Losier, Ashley; Lui, Wei; Andrews, Nathaniel; Elias, Jack A; Kazmierczak, Barbara I; Roy, Craig R; Dela Cruz, Charles S

    2016-07-01

    Pseudomonas aeruginosa causes hospital-acquired pneumonia and is associated with high mortality. An effective response to such an infection includes efficient clearance of pathogenic organisms while limiting collateral damage from the host inflammatory response, known as host resistance and host tolerance, respectively. P. aeruginosa expresses a type III secretion system (T3SS) needle complex that induces NLRC4 (NOD-like receptor C4) activation, interleukin-1β (IL-1β) production, and host tissue damage. Chitinase 3-like-1 (Chil1) is expressed during infection and binds to its receptor, IL-13 receptor α2 (IL-13Rα2), to regulate the pathogen-host response during Streptococcus pneumoniae infection, but the role Chil1 plays in balancing the host resistance and host tolerance during P. aeruginosa pneumonia is not known. We conducted experiments using C57BL/6 mice with or without a genetic deficiency of Chil1 and demonstrated that Chil1-deficient mice succumb to P. aeruginosa infection more rapidly than the wild type (WT). The decreased survival time in infected Chil1-deficient mice is associated with more neutrophils recruited to the airways, more lung parenchymal damage, and increased pulmonary consolidation while maintaining equivalent bacterial killing compared to WT mice. Infected Chil1-deficient mice and bone marrow-derived macrophages (BMDMs) from Chil1-deficient mice have increased production of tumor necrosis factor alpha (TNF-α) and IL-1β compared to infected WT mice and macrophages. Infection of Chil1-deficient BMDMs with non-NLRC4-triggering P. aeruginosa, which is deficient in the T3SS needle complex, did not alter the excessive IL-1β production compared to BMDMs from WT mice. The addition of recombinant Chil1 decreases the excessive IL-1β production but only partially rescues stimulated BMDMs from IL-13Rα2-deficient mice. Our data provide mechanistic insights into how Chil1 regulates P. aeruginosa-induced host responses. PMID:27141083

  8. Benzo[a]pyrene and tumor necrosis factor-α coordinately increase genotoxic damage and the production of proinflammatory mediators in alveolar epithelial type II cells.

    PubMed

    Umannová, Lenka; Machala, Miroslav; Topinka, Jan; Schmuczerová, Jana; Krčmář, Pavel; Neča, Jiří; Šujanová, Klára; Kozubík, Alois; Vondráček, Jan

    2011-10-10

    Alveolar type II epithelial (AEII) cells regulate lung inflammatory response and, simultaneously, they are a target of environmental carcinogenic factors. We employed an in vitro model of rat AEII cells, the RLE-6TN cell line, in order to analyze the interactive effects of tumor necrosis factor-α (TNF-α), a cytokine which plays a key role in the initiation of inflammatory responses in the lung, and benzo[a]pyrene (BaP), a highly carcinogenic polycyclic aromatic hydrocarbon. TNF-α strongly augmented the formation of stable BaP diol epoxide-DNA adducts in AEII cells, which was associated with enhanced p53-Ser15 phosphorylation and decreased cell survival. The increased genotoxicity of BaP was associated with altered expression of cytochrome P450 (CYP) enzymes involved in its bioactivation, a simultaneous suppression of CYP1A1 and enhancement of CYP1B1 expression. Importantly, BaP and TNF-α acted synergistically to upregulate key inflammatory regulators in AEII cells, including the expression of inducible NO synthase and cyclooxygenase-2 (COX-2), and enhanced prostaglandin E2 production and expression of proinflammatory cytokines, such as TNF-α, interleukin-1β and interleukin-6. We observed that BaP and TNF-α together strongly activated p38 kinase, a principal regulator of inflammatory response. SB202190, a specific p38 inhibitor, prevented induction of both COX-2 and proinflammatory cytokines, thus confirming that p38 activity was crucial for the observed inflammatory reaction. Taken together, our data demonstrated, for the first time, that a proinflammatory cytokine and an environmental PAH may interact to potentiate both DNA damage and the inflammatory response in AEII cells, which may occur through coordinated upregulation of p38 activity. PMID:21745554

  9. Tumor necrosis factor-alpha antagonists and neuropathy.

    PubMed

    Stübgen, Joerg-Patrick

    2008-03-01

    Tumor necrosis factor (TNF)-alpha plays an important role in many aspects of immune system development, immune-response regulation, and T-cell-mediated tissue injury. The evidence that TNF-alpha, released by autoreactive T cells and macrophages, may contribute to the pathogenesis of immune-mediated demyelinating neuropathies is reviewed. TNF-alpha antagonists (infliximab, etanercept, adalimumab) are indicated for the treatment of advanced inflammatory rheumatic and bowel disease, but these drugs can induce a range of autoimmune diseases that also attack the central and peripheral nervous systems. Case histories and series report on the association between anti-TNF-alpha treatment and various disorders of peripheral nerve such as Guillain-Barré syndrome, Miller Fisher syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy with conduction block, mononeuropathy multiplex, and axonal sensorimotor polyneuropathies. The proposed pathogeneses of TNF-alpha-associated neuropathies include both a T-cell and humoral immune attack against peripheral nerve myelin, vasculitis-induced nerve ischemia, and inhibition of signaling support for axons. Most neuropathies improve over a period of months by withdrawal of the TNF-alpha antagonist, with or without additional immune-modulating treatment. Preliminary observations suggest that TNF-alpha antagonists may be useful as an antigen-nonspecific treatment approach to immune-mediated neuropathies in patients with a poor response to, or intolerance of, standard therapies, but further studies are required. PMID:18041052

  10. TRAIL-induced programmed necrosis as a novel approach to eliminate tumor cells

    PubMed Central

    2014-01-01

    tumor cells, and that this treatment may represent a promising new option for the future development of combination therapies. Our data also suggest that RIPK3 expression may serve as a potential predictive marker for the sensitivity of tumor cells to programmed necrosis and extend the previously established role of ceramide as a key mediator of death receptor-induced programmed necrosis (and thus as a potential target for future therapies) also to the tumor cell lines examined here. PMID:24507727

  11. Smad7 protein induces interferon regulatory factor 1-dependent transcriptional activation of caspase 8 to restore tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis.

    PubMed

    Hong, Suntaek; Kim, Hye-Youn; Kim, Jooyoung; Ha, Huyen Trang; Kim, Young-Mi; Bae, Eunjin; Kim, Tae Hyung; Lee, Kang Choon; Kim, Seong-Jin

    2013-02-01

    Smad7 has been known as a negative regulator for the transforming growth factor-β (TGF-β) signaling pathway through feedback regulation. However, Smad7 has been suspected to have other biological roles through the regulation of gene transcription. By screening differentially regulated genes, we found that the caspase 8 gene was highly up-regulated in Smad7-expressing cells. Smad7 was able to activate the caspase 8 promoter through recruitment of the interferon regulatory factor 1 (IRF1) transcription factor to the interferon-stimulated response element (ISRE) site. Interaction of Smad7 on the caspase 8 promoter was confirmed with electrophoretic mobility shift assay and chromatin immunoprecipitation experiment. Interestingly, Smad7 did not directly interact with the ISRE site, but it increased the binding activity of IRF1 with ISRE. These results support that Smad7 recruits IRF1 protein on the caspase 8 promoter and functions as a transcriptional coactivator. To confirm the biological significance of caspase 8 up-regulation, we tested tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated cell death assay in breast cancer cells. Smad7 in apoptosis-resistant MCF7 cells markedly sensitized the cells to TRAIL-induced cell death by restoring the caspase cascade. Furthermore, restoration of caspase 8-mediated apoptosis pathway repressed the tumor growth in the xenograft model. In conclusion, we suggest a novel role for Smad7 as a transcriptional coactivator for caspase 8 through the interaction with IRF1 in regulation of the cell death pathway. PMID:23255602

  12. Photodynamic therapy with aluminum-chloro-phthalocyanine induces necrosis and vascular damage in mice tongue tumors.

    PubMed

    Longo, João Paulo Figueiró; Lozzi, Silene Paulino; Simioni, Andreza Ribeiro; Morais, Paulo César; Tedesco, Antônio Cláudio; Azevedo, Ricardo Bentes

    2009-02-01

    In this paper we describe the efficacy of the liposomal-AlClPc (aluminum-chloro-phthalocyanine) formulation in PDT study against Ehrlich tumor cells proliferation in immunocompetent swiss mice tongue. Experiments were conduced in sixteen tumor induced mice that were divided in three control groups: (1) tumor without treatment; (2) tumor with 100J/cm(2) laser (670nm) irradiation; and (3) tumor with AlClPc peritumoral injection; and a PDT experimental group when tumors received AlClPc injection followed by tumor irradiation. Control groups present similar macroscopically and histological patterns after treatments, while PDT treatment induced 90% of Ehrlich tumor necrosis after 24h of one single application, showing the efficacy of liposome-AlClPc (aluminum-chloro-phthalocyanine) mediated PDT on the treatment of oral cancer. PMID:19097802

  13. Tumor Necrosis Factor-α-induced Proteolytic Activation of Pro-matrix Metalloproteinase-9 by Human Skin Is Controlled by Down-regulating Tissue Inhibitor of Metalloproteinase-1 and Mediated by Tissue-associated Chymotrypsin-like Proteinase*

    PubMed Central

    Han, Yuan-Ping; Nien, Yih-Dar; Garner, Warren L.

    2008-01-01

    The proteolytic activation of pro-matrix metalloproteinase (MMP)-9 by conversion of the 92-kDa precursor into an 82-kDa active form has been observed in chronic wounds, tumor metastasis, and many inflammation-associated diseases, yet the mechanistic pathway to control this process has not been identified. In this report, we show that the massive expression and activation of MMP-9 in skin tissue from patients with chronically unhealed wounds could be reconstituted in vitro with cultured normal human skin by stimulation with transforming growth factor-β and tumor necrosis factor (TNF)-α. We dissected the mechanistic pathway for TNF-α induced activation of pro-MMP-9 in human skin. We found that proteolytic activation of pro-MMP-9 was mediated by a tissue-associated chymotrypsin-like proteinase, designated here as pro-MMP-9 activator (pM9A). This unidentified activator specifically converted pro-MMP-9 but not pro-MMP-2, another member of the gelatinase family. The tissue-bound pM9A was steadily expressed and not regulated by TNF-α, which indicated that the cytokine-mediated activation of pro-MMP-9 might be regulated at the inhibitor level. Indeed, the skin constantly secreted tissue inhibitor of metalloproteinase-1 at the basal state. TNF-α, but not transforming growth factor-β, down-regulated this inhibitor. The TNF-α-mediated activation of pro-MMP-9 was tightly associated with down-regulation of tissue inhibitor of metalloproteinase-1 in a dose-dependent manner. To establish this linkage, we demonstrate that the recombinant tissue inhibitor of metalloproteinase-1 could block the activation of pro-MMP-9 by either the intact skin or skin fractions. Thus, these studies suggest a novel regulation for the proteolytic activation of MMP-9 in human tissue, which is mediated by tissue-bound activator and controlled by down-regulation of a specific inhibitor. PMID:12004062

  14. HIV-1 Tat Protein Induces PD-L1 (B7-H1) Expression on Dendritic Cells through Tumor Necrosis Factor Alpha- and Toll-Like Receptor 4-Mediated Mechanisms

    PubMed Central

    Planès, Rémi; BenMohamed, Lbachir; Leghmari, Kaoutar; Delobel, Pierre; Izopet, Jacques

    2014-01-01

    ABSTRACT Chronic human immunodeficiency virus type 1 (HIV-1) infection is associated with induction of T-cell coinhibitory pathways. However, the mechanisms by which HIV-1 induces upregulation of coinhibitory molecules remain to be fully elucidated. The aim of the present study was to determine whether and how HIV-1 Tat protein, an immunosuppressive viral factor, induces the PD-1/PD-L1 coinhibitory pathway on human dendritic cells (DCs). We found that treatment of DCs with whole HIV-1 Tat protein significantly upregulated the level of expression of PD-L1. This PD-L1 upregulation was observed in monocyte-derived dendritic cells (MoDCs) obtained from either uninfected or HIV-1-infected patients as well as in primary myeloid DCs from HIV-negative donors. In contrast, no effect on the expression of PD-L2 or PD-1 molecules was detected. The induction of PD-L1 on MoDCs by HIV-1 Tat (i) occurred in dose- and time-dependent manners, (ii) was mediated by the N-terminal 1–45 fragment of Tat, (iii) did not require direct cell-cell contact but appeared rather to be mediated by soluble factor(s), (iv) was abrogated following neutralization of tumor necrosis factor alpha (TNF-α) or blocking of Toll-like receptor 4 (TLR4), (v) was absent in TLR4-knockoout (KO) mice but could be restored following incubation with Tat-conditioned medium from wild-type DCs, (vi) impaired the capacity of MoDCs to functionally stimulate T cells, and (vii) was not reversed functionally following PD-1/PD-L1 pathway blockade, suggesting the implication of other Tat-mediated coinhibitory pathways. Our results demonstrate that HIV-1 Tat protein upregulates PD-L1 expression on MoDCs through TNF-α- and TLR4-mediated mechanisms, functionally compromising the ability of DCs to stimulate T cells. The findings offer a novel potential molecular target for the development of an anti-HIV-1 treatment. IMPORTANCE The objective of this study was to investigate the effect of human immunodeficiency virus type 1 (HIV

  15. Constitutive synthesis of tumor necrosis factor in the thymus.

    PubMed Central

    Giroir, B P; Brown, T; Beutler, B

    1992-01-01

    Although tumor necrosis factor (TNF) is a major mediator of endotoxic shock, the normal function of TNF that has preserved this protein throughout mammalian evolution remains unknown. If the protein serves a role in normal development or homeostasis, it must be produced under physiologic conditions. To determine whether TNF secretion occurs in normal animals, and to define the tissue sources of the protein, we prepared a reporter construct in which the TNF coding sequence and introns are replaced by the chloramphenicol acetyltransferase (CAT) coding sequence. This construct was inserted into the murine genome, yielding 13 transgenic founders. Macrophages harvested from 4 of the transgenic lines expressed CAT activity after stimulation with Escherichia coli lipopolysaccharide in vitro. Each of these 4 transgenic lines also constitutively expressed CAT activity in the thymus but in no other tissue examined. Cultured thymocytes secrete TNF, as demonstrated both by cytotoxicity assays and by immunoprecipitation of radiolabeled thymic culture medium. CAT activity was associated with the thymic lymphocyte population and not with thymic macrophages or dendritic cells. CAT activity was present in thymic lymphocytes irrespective of CD4 or CD8 expression; T cells from the spleen, however, had no detectable CAT activity. The biosynthesis of TNF in the thymus of normal animals implies a role for this protein in the development or regulation of the immune response. Images PMID:1594585

  16. Tumor Necrosis Factor Superfamily in Innate Immunity and Inflammation

    PubMed Central

    Šedý, John; Bekiaris, Vasileios; Ware, Carl F.

    2015-01-01

    The tumor necrosis factor superfamily (TNFSF) and its corresponding receptor superfamily (TNFRSF) form communication pathways required for developmental, homeostatic, and stimulus-responsive processes in vivo. Although this receptor–ligand system operates between many different cell types and organ systems, many of these proteins play specific roles in immune system function. The TNFSF and TNFRSF proteins lymphotoxins, LIGHT (homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for herpes virus entry mediator [HVEM], a receptor expressed by T lymphocytes), lymphotoxin-β receptor (LT-βR), and HVEM are used by embryonic and adult innate lymphocytes to promote the development and homeostasis of lymphoid organs. Lymphotoxin-expressing innate-acting B cells construct microenvironments in lymphoid organs that restrict pathogen spread and initiate interferon defenses. Recent results illustrate how the communication networks formed among these cytokines and the coreceptors B and T lymphocyte attenuator (BTLA) and CD160 both inhibit and activate innate lymphoid cells (ILCs), innate γδ T cells, and natural killer (NK) cells. Understanding the role of TNFSF/TNFRSF and interacting proteins in innate cells will likely reveal avenues for future therapeutics for human disease. PMID:25524549

  17. Tumor necrosis factor superfamily in innate immunity and inflammation.

    PubMed

    Šedý, John; Bekiaris, Vasileios; Ware, Carl F

    2015-04-01

    The tumor necrosis factor superfamily (TNFSF) and its corresponding receptor superfamily (TNFRSF) form communication pathways required for developmental, homeostatic, and stimulus-responsive processes in vivo. Although this receptor-ligand system operates between many different cell types and organ systems, many of these proteins play specific roles in immune system function. The TNFSF and TNFRSF proteins lymphotoxins, LIGHT (homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for herpes virus entry mediator [HVEM], a receptor expressed by T lymphocytes), lymphotoxin-β receptor (LT-βR), and HVEM are used by embryonic and adult innate lymphocytes to promote the development and homeostasis of lymphoid organs. Lymphotoxin-expressing innate-acting B cells construct microenvironments in lymphoid organs that restrict pathogen spread and initiate interferon defenses. Recent results illustrate how the communication networks formed among these cytokines and the coreceptors B and T lymphocyte attenuator (BTLA) and CD160 both inhibit and activate innate lymphoid cells (ILCs), innate γδ T cells, and natural killer (NK) cells. Understanding the role of TNFSF/TNFRSF and interacting proteins in innate cells will likely reveal avenues for future therapeutics for human disease. PMID:25524549

  18. Colchicine prevents tumor necrosis factor-induced toxicity in vivo.

    PubMed Central

    Tiegs, G; Freudenberg, M A; Galanos, C; Wendel, A

    1992-01-01

    Tumor necrosis factor (TNF) toxicity was induced in vivo by intravenous administration of 15 micrograms of recombinant murine TNF-alpha per kg to galactosamine-sensitized mice. Within 8 h, the animals developed a fulminant hepatitis. Intravenous administration of 0.5 mg of colchicine per kg at 19 and 4 h prior to TNF challenge protected the animals against hepatitis. Lipopolysaccharide (LPS)-stimulated, bone marrow-derived macrophages from C3H/HeN mice released significant amounts of TNF in vitro. When such macrophages were intravenously given to LPS-resistant galactosamine-sensitized C3H/HeJ mice, these animals died within 24 h. Preincubation of these transferred macrophages with colchicine did not suppress the LPS-inducible TNF release from these cells. Concordantly, administration of macrophages exposed to colchicine in vitro resulted in full lethality. However, in vivo pretreatment of C3H/HeJ mice with colchicine 19 and 4 h prior to the transfer of LPS-stimulated macrophages prevented lethality. In LPS-responsive NMRI mice which had been protected against galactosamine-LPS-induced hepatitis by pretreatment with colchicine, TNF was still released into the blood. We conclude from our findings that the in vivo protection by colchicine is mediated by blocking TNF action on target cells while the effector cells of LPS toxicity, i.e., the macrophages, remain responsive. PMID:1563785

  19. Low-molecular-weight fractions of Alcalase hydrolyzed egg ovomucin extract exert anti-inflammatory activity in human dermal fibroblasts through the inhibition of tumor necrosis factor-mediated nuclear factor κB pathway.

    PubMed

    Sun, Xiaohong; Chakrabarti, Subhadeep; Fang, Jun; Yin, Yulong; Wu, Jianping

    2016-07-01

    Ovomucin is a mucin-like protein from egg white with a variety of biological functions. We hypothesized that ovomucin-derived peptides might exert anti-inflammatory activity. The specific objectives were to test the anti-inflammatory activities of different ovomucin hydrolysates and its various fractions in human dermal fibroblasts, and to understand the possible molecular mechanisms. Three ovomucin hydrolysates were prepared and desalted; only the desalted Alcalase hydrolysate showed anti-inflammatory activity. Desalting of ovomucin hydrolysate enriched the proportion of low-molecular-weight (MW) peptides. Indeed, ultrafiltration of this hydrolysate displayed comparable anti-inflammatory activity in dermal fibroblasts, indicating the responsible role of low-MW bioactive peptides in exerting the beneficial biological function. The anti-inflammatory activity of low-MW peptides was regulated through the inhibition of tumor necrosis factor-mediated nuclear factor κ-light-chain-enhancer of activated B cells activity. Our study demonstrated that both peptide composition and MW distribution play important roles in anti-inflammatory activity. The low-MW fractions prepared from ovomucin Alcalase hydrolysate may have potential applications for maintenance of dermal health and treatment of skin diseases. PMID:27333955

  20. Blockade of tumor necrosis factor (TNF) receptor type 1-mediated TNF-alpha signaling protected Wistar rats from diet-induced obesity and insulin resistance.

    PubMed

    Liang, Huifang; Yin, Bingjiao; Zhang, Hailong; Zhang, Shu; Zeng, Qingling; Wang, Jing; Jiang, Xiaodan; Yuan, Li; Wang, Cong-Yi; Li, Zhuoya

    2008-06-01

    TNF-alpha plays an important role in the pathogenesis of obesity and insulin resistance in which the effect of TNF-alpha signaling via TNF receptor type 1 (TNFR1) largely remains controversial. To delineate the role of TNFR1-mediated TNF-alpha signaling in the pathogenesis of this disorder, a TNFR1 blocking peptide-Fc fusion protein (TNFR1BP-Fc) was used for the present study. Wistar rats were fed a high-fat/high-sucrose (HFS) diet for 16 wk until obesity and insulin resistance developed. In comparison with increased body weight and fat weight, enlarged adipocytes, and hypertriglyceridemia in the obese state, the subsequent 4-wk treatment with TNFR1BP-Fc resulted in significant weight loss characterized by decreased fat pad weight and adipocyte size and reduced plasma triglycerides. Furthermore, obesity-induced insulin resistance, including hyperinsulinemia, elevated C-peptide, higher degree of hyperglycemia after glucose challenge, and less hypoglycemic response to insulin, was markedly improved, and the compensatory hyperplasia and hypertrophy of pancreatic islets were reduced. Interestingly, treatment with TNFR1BP-Fc markedly suppressed systemic TNF-alpha release and its local expression in pancreatic islets and muscle and adipose tissues. In addition, blockage of TNFR1-mediated TNF-alpha signaling in obese rats significantly enhanced tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) in the muscle and fat tissues. Our results strongly suggest a pivotal role for TNFR1-mediated TNF-alpha signaling in the pathogenesis of obesity and insulin resistance. Thus, TNFR1BP-Fc may be a good candidate for the treatment of this disease. PMID:18339717

  1. Early embryonic and endometrial regulation of tumor necrosis factor and tumor necrosis factor receptor 2 in the cattle uterus.

    PubMed

    Correia-Álvarez, E; Gómez, E; Martín, D; Carrocera, S; Pérez, S; Peynot, N; Giraud-Delville, C; Caamaño, J N; Balseiro, A; Sandra, O; Duranthon, V; Muñoz, M

    2015-04-01

    Tumor necrosis factor (TNF) alpha likely mediates embryomaternal communication in mammals. In bovine, we have previously found that the uterine fluid of heifers that carried early embryos shows downregulation in the TNF and nuclear factor κB system. In this work, we assessed the expression of TNF and its receptor TNFR2 in the bovine endometrium and embryos during blastocyst development. Moreover, to explore the endometrial immune response to early embryos, we analyzed the number of CD45 leukocytes in the bovine endometrium. Day 8 endometrium and blastocyst recovered from animals after transfer of Day 5 embryos showed TNF and TNFR2 mRNA transcription and protein colocalization. The presence of embryos increased endometrial TNF and TNFR2 protein, whereas endometrial leukocytes decreased. Blastocysts exposed to the uterine tract had undetectable levels of TNF and lower levels of TNFR2 mRNA. These results suggest that the endometrium might lower the TNF concentration in the blastocyst by (1) regulating TNF secretion into the uterine fluid and (2) inducing decreased TNF and TNFR2 mRNA transcription in the embryo. Thus, TNF and TNFR2 might participate in early embryomaternal communication. PMID:25589228

  2. Vitamin D Rescues Impaired Mycobacterium tuberculosis-Mediated Tumor Necrosis Factor Release in Macrophages of HIV-Seropositive Individuals through an Enhanced Toll-Like Receptor Signaling Pathway In Vitro

    PubMed Central

    Sinha, Sanjeev; Bole, Medhavi; Sharma, Surendra K.; Kumar, Narendra; Luthra, Kalpana; Li, Xin; Zhou, Xiuqin; Nelson, Benjamin; Han, Xinbing; Tachado, Souvenir D.; Patel, Naimish R.; Koziel, Henry

    2013-01-01

    Mycobacterium tuberculosis disease represents an enormous global health problem, with exceptionally high morbidity and mortality in HIV-seropositive (HIV+) persons. Alveolar macrophages from HIV+ persons demonstrate specific and targeted impairment of critical host cell responses, including impaired M. tuberculosis-mediated tumor necrosis factor (TNF) release and macrophage apoptosis. Vitamin D may promote anti-M. tuberculosis responses through upregulation of macrophage NO, NADPH oxidase, cathelicidin, and autophagy mechanisms, but whether vitamin D promotes anti-M. tuberculosis mechanisms in HIV+ macrophages is not known. In the current study, human macrophages exposed to M. tuberculosis demonstrated robust release of TNF, IκB degradation, and NF-κB nuclear translocation, and these responses were independent of vitamin D pretreatment. In marked contrast, HIV+ U1 human macrophages exposed to M. tuberculosis demonstrated very low TNF release and no significant IκB degradation or NF-κB nuclear translocation, whereas vitamin D pretreatment restored these critical responses. The vitamin D-mediated restored responses were dependent in part on macrophage CD14 expression. Importantly, similar response patterns were observed with clinically relevant human alveolar macrophages from healthy individuals and asymptomatic HIV+ persons at high clinical risk of M. tuberculosis infection. Taken together with the observation that local bronchoalveolar lavage fluid (BALF) levels of vitamin D are severely deficient in HIV+ persons, the data from this study demonstrate that exogenous vitamin D can selectively rescue impaired critical innate immune responses in vitro in alveolar macrophages from HIV+ persons at risk for M. tuberculosis disease, supporting a potential role for exogenous vitamin D as a therapeutic adjuvant in M. tuberculosis infection in HIV+ persons. PMID:23071135

  3. Genes encoding tumor necrosis factor alpha and granzyme A are expressed during development of autoimmune diabetes.

    PubMed Central

    Held, W; MacDonald, H R; Weissman, I L; Hess, M W; Mueller, C

    1990-01-01

    Progressive destruction of the insulin-producing beta cells in nonobese diabetic mice is observed after infiltration of the pancreas with lymphocytes [Makino, S., Kunimoto, K., Muraoka, Y., Mizushima, Y., Katagiri, K. & Tochino, Y. (1980) Exp. Anim. (Tokyo) 29, 1-13]. We show that the genes for tumor necrosis factor alpha and granzyme A, a serine protease associated with cytoplasmic granules of cytotoxic cells, are expressed during the development of spontaneous diabetes mellitus in the nonobese diabetic mouse. Granzyme A-positive cells are found both in and surrounding the islets, implying induction prior to islet infiltration. Tumor necrosis factor alpha expression is exclusively observed in the intra-islet infiltrate, predominantly in lymphocytes adjacent to insulin-producing beta cells, the targets of the autoimmune destruction, implying that tumor necrosis factor alpha expression is induced locally--i.e., in the islet. A considerable portion of cells expressing tumor necrosis factor alpha appear to be CD4+ T cells. This T-cell subset was previously shown to be necessary for development of the disease. Thus, these findings may be important for understanding the pathogenesis of autoimmune diabetes mellitus and potentially also for that of other T-cell-mediated autoimmune diseases. Images PMID:2179951

  4. Mechanisms of tumor necrosis in photodynamic therapy with a chlorine photosensitizer: experimental studies

    NASA Astrophysics Data System (ADS)

    Privalov, Valeriy A.; Lappa, Alexander V.; Bigbov, Elmir N.

    2011-02-01

    A photodynamic therapy experiment on 118 inbred white mice with transplanted Ehrlich's tumor (mouse mammary gland adenocarcinoma) is performed to reveal mechanisms of necrosis formation. In 7-10 days the tumor of 1-1.5 cm diameter is formed under skin at the injection point, and PDT procedure is applied. There were used a chlorine type photosensitizer RadachlorineTM and 662 nm wavelength diode laser. The drug is injected by intravenously at the dose of 40 mg/kg; the irradiation is executed in 2-2.5 hours at the surface dose of about 200 J/cm2. Each of the mice had a photochemical reaction in form of destructive changes at the irradiation region with subsequent development of dry coagulation necrosis. After rejection of the necrosis there occurred epithelization of defect tissues in a tumor place. Histological investigations were conducted in different follow-up periods, in 5 and 30 min, 1, 3, 6, and 12 hours, 1, 3, 7 and 28 days after irradiation. They included optical microscopy, immune marker analysis, morphometry with measurements of volume density of epithelium, tumor stroma and necroses, vascular bed. The investigations showed that an important role in damaging mechanisms of photodynamic action belongs to hypoxic injuries of tumor mediated by micro vascular disorders and blood circulatory disturbances. The injuries are formed in a few stages: microcirculation angiospasm causing vessel paresis, irreversible stases in capillaries, diapedetic hemorrhages, thromboses, and thrombovasculitis. It is marked mucoid swelling and fibrinoid necrosis of vascular tissue. Progressive vasculitises result in total vessel obliteration and tumor necrosis.

  5. Tumor necrosis factor induces glomerular damage in the rabbit.

    PubMed Central

    Bertani, T.; Abbate, M.; Zoja, C.; Corna, D.; Perico, N.; Ghezzi, P.; Remuzzi, G.

    1989-01-01

    Tumor necrosis factor (TNF) is a polypeptide hormone produced by activated macrophages detectable in the circulation of experimental animals given endotoxin. Recent evidence strongly suggests that many of the deleterious effects of endotoxin in experimental animals are mediated by TNF. Because endotoxemia in experimental animals and humans is associated with glomerular damage the present investigation was designed to establish whether TNF directly induces glomerular functional and structural changes. Twenty-three rabbits were given human recombinant TNF at the doses of 0.08, 0.8, and 8.0 micrograms/kg/h as a continuous 5-hour intravenous infusion. Animals were killed at the end of the infusion. All rabbits given 0.8 and 8.0 micrograms/kg/h TNF developed anemia (Ht value decrease at 5 hours: 0.8 microgram/kg/h, 15%; 8.0 micrograms/kg/h, 16%); leukopenia (leukocyte count decrease at 5 hours: 0.8 micrograms/kg/h, 47%; 8.0 micrograms/kg/h, 59%); thrombocytopenia (platelet count decrease at 5 hours; 0.8 micrograms/kg/h, 45%; 8.0 micrograms/kg/h, 57%). Rabbits given 8.0 micrograms/kg/h also had renal failure (serum creatinine from 1.02 +/- 0.15 to 1.64 +/- 0.34 mg/dl). By light microscopy only occasional polymorphonuclear leukocytes in the glomerular capillaries were detectable in rabbits infused with 0.08 micrograms/kg/h TNF, whereas with 0.8 micrograms/kg/h TNF the presence of inflammatory cells in the glomerular capillaries was the prominent finding. With 8.0 micrograms/kg/h TNF beside leukocyte accumulation, fibrin was detected in the glomerular capillary lumens of two of eight animals. Electron microscopy found dose-dependent glomerular endothelial cell damage in animals given TNF with fibrinlike material in the capillary lumens. Glomerular changes induced by TNF were remarkably similar to those previously found in animals given endotoxin. Thus, TNF is likely to be the mediator of endotoxin-induced glomerular damage and can be regarded as a new mediator of

  6. Toll-Like Receptor 2- and 6-Mediated Stimulation by Macrophage-Activating Lipopeptide 2 Induces Lipopolysaccharide (LPS) Cross Tolerance in Mice, Which Results in Protection from Tumor Necrosis Factor Alpha but in Only Partial Protection from Lethal LPS Doses

    PubMed Central

    Deiters, Ursula; Gumenscheimer, Marina; Galanos, Chris; Mühlradt, Peter F.

    2003-01-01

    Patients or experimental animals previously exposed to lipopolysaccharide (LPS) become tolerant to further LPS challenge. We investigated the potential of the macrophage-activating lipopeptide 2 (MALP-2) to induce in vivo cross tolerance to tumor necrosis factor alpha (TNF-α) and LPS. MALP-2-induced tolerance could be of practical interest, as MALP-2 proved much less pyrogenic in rabbits than LPS. Whereas LPS signals via Toll-like receptor 4 (TLR4), MALP-2 uses TLR2 and TLR6. LPS-mediated cytokine release was studied in mice pretreated with intraperitoneal injections of MALP-2. No biologically active TNF-α could be detected in the serum of MALP-2-treated animals when challenged with LPS 24 or 72 h later, whereas suppression of LPS-dependent interleukin (IL)-6 lasted for only 24 h. Protection from lethal TNF-α shock was studied in galactosamine-treated mice. Dose dependently, MALP-2 prevented death from lethal TNF-α doses in TLR4−/− but not in TLR2−/− mice, with protection lasting from 5 to 24 h. To assay protection from LPS, mice were pretreated with MALP-2 doses of up to 10 μg. Five and 24 h later, the animals were simultaneously sensitized and challenged by intravenous coinjection of galactosamine and a lethal dose of 50 ng of LPS. There was only limited protection (four of seven mice survived) when mice were challenged 5 h after MALP-2 pretreatment, and no protection when mice were challenged at later times. The high effectiveness of MALP-2 in suppressing TNF-α, the known ways of biological inactivation, and low pyrogenicity make MALP-2 a potential candidate for clinical use. PMID:12874325

  7. Interferon-gamma and tumor necrosis factor-alpha mediate the upregulation of indoleamine 2,3-dioxygenase and the induction of depressive-like behavior in mice in response to bacillus Calmette-Guerin.

    PubMed

    O'Connor, Jason C; André, Caroline; Wang, Yunxia; Lawson, Marcus A; Szegedi, Sandra S; Lestage, Jacques; Castanon, Nathalie; Kelley, Keith W; Dantzer, Robert

    2009-04-01

    Although the tryptophan-degrading enzyme, indoleamine 2,3-dioxygenase (IDO), is a pivotal mediator of inflammation-induced depression, its mechanism of regulation has not yet been investigated in this context. Here, we demonstrate an essential role for interferon (IFN)gamma and tumor necrosis factor (TNF)alpha in the induction of IDO and depressive-like behaviors in response to chronic immune activation. Wild-type (WT) control mice and IFNgammaR(-/-) mice were inoculated with an attenuated form of Mycobacterium bovis, bacille Calmette-Guérin (BCG). Infection with BCG induced an acute episode of sickness that was similar in WT and IFNgammaR(-/-) mice. Increased immobility during the forced swim and tail suspension tests occurred in WT mice 7 d after BCG inoculation but was entirely absent in IFNgammaR(-/-) mice. In WT mice, these indices of depressive-like behavior were associated with chronic upregulation of IFNgamma, interleukin(IL)-1beta, TNFalpha, and IDO. Proinflammatory cytokine expression was elevated in BCG-infected IFNgammaR(-/-) mice as well, but upregulation of lung and brain IDO mRNA was completely abolished. This was accompanied by an attenuation of BCG-induced TNFalpha mRNA and the lack of an increase in plasma kynurenine/tryptophan ratio in the BCG-inoculated IFNgammaR(-/-) mice compared with WT controls. Pretreatment of mice with the TNFalpha antagonist, etanercept, partially blunted BCG-induced IDO activation and depressive-like behavior. In accordance with these in vivo data, IFNgamma and TNFalpha synergized to induce IDO in primary microglia. Together, these data demonstrate that IFNgamma, with TNFalpha, is necessary for induction of IDO and depressive-like behavior in mice after BCG infection. PMID:19339614

  8. Correlation of MRI Biomarkers with Tumor Necrosis in Hras5 Tumor Xenograft in Athymic Rats

    PubMed Central

    Bradley, Daniel P; Tessier, Jean J; Ashton, Susan E; Waterton, John C; Wilson, Zena; Worthington, Philip L; Ryan, Anderson J

    2007-01-01

    Magnetic resonance imaging (MRI) can measure the effects of therapies targeting the tumor vasculature and has demonstrated that vascular-damaging agents (VDA) induce acute vascular shutdown in tumors in human and animal models. However, at subtherapeutic doses, blood flow may recover before the induction of significant levels of necrosis. We present the relationship between changes in MRI biomarkers and tumor necrosis. Multiple MRI measurements were taken at 4.7 T in athymic rats (n = 24) bearing 1.94 ± 0.2-cm3 subcutaneous Hras5 tumors (ATCC 41000) before and 24 hours after clinically relevant doses of the VDA, ZD6126 (0–10 mg/kg, i.v.). We measured effective transverse relaxation rate (R2*), initial area under the gadolinium concentration-time curve (IAUGC60/150), equivalent enhancing fractions (EHF60/150), time constant (Ktrans), proportion of hypoperfused voxels as estimated from fit failures in Ktrans analysis, and signal intensity (SI) in T2-weighted MRI (T2W). ZD6126 treatment induced > 90% dose-dependent tumor necrosis at 10 mg/kg; correspondingly, SI changes were evident from T2W MRI. Although R2* did not correlate, other MRI biomarkers significantly correlated with necrosis at doses of ≥ 5 mg/kg ZD6126. These data on Hras5 tumors suggest that the quantification of hypoperfused voxels might provide a useful biomarker of tumor necrosis. PMID:17534443

  9. Tumor Necrosis Factor Receptor 2: Its Contribution to Acute Cellular Rejection and Clear Cell Renal Carcinoma

    PubMed Central

    Wang, Jun; Al-Lamki, Rafia S.

    2013-01-01

    Tumor necrosis factor receptor 2 (TNFR2) is a type I transmembrane glycoprotein and one of the two receptors that orchestrate the complex biological functions of tumor necrosis factor (TNF, also designed TNF-α). Accumulating experimental evidence suggests that TNFR2 plays an important role in renal disorders associated with acute cellular rejection and clear cell renal carcinoma but its exact role in these settings is still not completely understood. This papers reviews the factors that may mediate TNFR2 induction in acute cellular rejection and clear cell renal carcinoma and its contribution to these conditions and discusses its therapeutic implications. A greater understanding of the function of TNFR2 may lead to the development of new anti-TNF drugs. PMID:24350291

  10. Tumor necrosis factor inhibitors – state of knowledge

    PubMed Central

    Lis, Krzysztof; Kuzawińska, Olga

    2014-01-01

    Tumor necrosis factor (TNF) is considered a major proinflammatory cytokine, affecting various aspects of the immune reaction. All five TNF inhibitors currently available on the market (i.e., etanercept, infliximab, adalimumab, certolizumab and golimumab) are top sellers, although indicated only in autoimmune diseases, including rheumatoid arthritis, Crohn's disease and psoriasis. This article briefly discusses the background and place for TNF inhibitors in modern therapy. The main safety aspects of TNF inhibitor administration are described in particular, with special consideration of the available meta-analyses. Finally, perspectives on the next-generation TNF inhibitors and their use in the clinic are given. PMID:25624856

  11. Ketamine inhibits tumor necrosis factor-{alpha} and interleukin-6 gene expressions in lipopolysaccharide-stimulated macrophages through suppression of toll-like receptor 4-mediated c-Jun N-terminal kinase phosphorylation and activator protein-1 activation

    SciTech Connect

    Wu, G.-J.; Chen, T.-L.; Ueng, Y.-F.; Chen, R.-M.

    2008-04-01

    Our previous study showed that ketamine, an intravenous anesthetic agent, has anti-inflammatory effects. In this study, we further evaluated the effects of ketamine on the regulation of tumor necrosis factor-{alpha} (TNF-{alpha}) and interlukin-6 (IL-6) gene expressions and its possible signal-transducing mechanisms in lipopolysaccharide (LPS)-activated macrophages. Exposure of macrophages to 1, 10, and 100 {mu}M ketamine, 100 ng/ml LPS, or a combination of ketamine and LPS for 1, 6, and 24 h was not cytotoxic to macrophages. A concentration of 1000 {mu}M of ketamine alone or in combined treatment with LPS caused significant cell death. Administration of LPS increased cellular TNF-{alpha} and IL-6 protein levels in concentration- and time-dependent manners. Meanwhile, treatment with ketamine concentration- and time-dependently alleviated the enhanced effects. LPS induced TNF-{alpha} and IL-6 mRNA syntheses. Administration of ketamine at a therapeutic concentration (100 {mu}M) significantly inhibited LPS-induced TNF-{alpha} and IL-6 mRNA expressions. Application of toll-like receptor 4 (TLR4) small interfering (si)RNA into macrophages decreased cellular TLR4 levels. Co-treatment of macrophages with ketamine and TLR4 siRNA decreased the LPS-induced TNF-{alpha} and IL-6 productions more than alone administration of TLR4 siRNA. LPS stimulated phosphorylation of c-Jun N-terminal kinase and translocation of c-Jun and c-Fos from the cytoplasm to nuclei. However, administration of ketamine significantly decreased LPS-induced activation of c-Jun N-terminal kinase and translocation of c-Jun and c-Fos. LPS increased the binding of nuclear extracts to activator protein-1 consensus DNA oligonucleotides. Administration of ketamine significantly ameliorated LPS-induced DNA binding activity of activator protein-1. Therefore, a clinically relevant concentration of ketamine can inhibit TNF-{alpha} and IL-6 gene expressions in LPS-activated macrophages. The suppressive mechanisms

  12. Necrosis and apoptosis in Trichinella spiralis-mediated tumour reduction

    PubMed Central

    Vasilev, Sasa; Ilic, Natasa; Gruden-Movsesijan, Alisa; Vasilijic, Sasa; Bosic, Martina

    2015-01-01

    It is known that infection with different pathogens, including helminths, can alter the progression of malignant or other diseases. We studied the effect of chronic Trichinella spiralis infection or muscle larvae excretory-secretory (ES L1) antigens on the malignant tumour growth in the mouse melanoma model system in vivo and in vitro. Our results confirmed that chronic infection with T. spiralis possesses the capacity to slow down the progression of tumour growth, resulting in an impressive reduction in tumour size. We found that the phenomenon could, at least partially, be related to a lower level of tumour necrosis compared to necrosis present in control animals with progressive malignancy course. An increased apoptotic potential among the low percentage of cells within the total tumour cell number in vivo was also observed. ES L1 antigen, as a parasitic product that is released during the chronic phase of infection, reduced the survival and slightly, but significantly increased the apoptosis level of melanoma cells in vitro. Our results imply that powerful Trichinella anti-malignance capacity does not rely only on necrosis and apoptosis but other mechanisms through which infection or parasite products manipulate the tumor establishment and expansion should be considered. PMID:26155183

  13. Tumor necrosis factor and cancer, buddies or foes?*

    PubMed Central

    WANG, Xia; LIN, Yong

    2008-01-01

    Tumor necrosis factor (TNF) is a multifunctional cytokine that plays important roles in diverse cellular events such as cell survival, proliferation, differentiation, and death. As a pro-inflammatory cytokine, TNF is secreted by inflammatory cells, which may be involved in inflammation-associated carcinogenesis. TNF exerts its biological functions through activating distinct signaling pathways such as nuclear factor κB (NF-κB) and c-Jun N-terminal kinase (JNK). NF-κB is a major cell survival signal that is anti-apoptotic while sustained JNK activation contributes to cell death. The crosstalk between the NF-κB and JNK is involved in determining cellular outcomes in response to TNF. In regard to cancer, TNF is a double-dealer. On one hand, TNF could be an endogenous tumor promoter, because TNF stimulates cancer cells’ growth, proliferation, invasion and metastasis, and tumor angiogenesis. On the other hand, TNF could be a cancer killer. The property of TNF in inducing cancer cell death renders it a potential cancer therapeutic, although much work is needed to reduce its toxicity for systematic TNF administration. Recent studies have focused on sensitizing cancer cells to TNF-induced apoptosis through inhibiting survival signals such as NF-κB, by combined therapy. In this article we provide an overview of the roles of TNF-induced signaling pathways in cancer biology with specific emphasis on carcinogenesis and cancer therapy. PMID:18954521

  14. Role of Tumor Necrosis Factor Superfamily in Neuroinflammation and Autoimmunity

    PubMed Central

    Sonar, Sandip; Lal, Girdhari

    2015-01-01

    Tumor necrosis factor superfamily (TNFSF) molecules play an important role in the activation, proliferation, differentiation, and migration of immune cells into the central nervous system (CNS). Several TNF superfamily molecules are known to control alloimmunity, autoimmunity, and immunity. Development of transgenic and gene knockout animals, and monoclonal antibodies against TNFSF molecules have increased our understanding of individual receptor–ligand interactions, and their intracellular signaling during homeostasis and neuroinflammation. A strong clinical association has been observed between TNFSF members and CNS autoimmunity such as multiple sclerosis and also in its animal model experimental autoimmune encephalomyelitis. Therefore, they are promising targets for alternative therapeutic options to control autoimmunity. Although, TNFSF ligands are widely distributed and have diverse functions, we have restricted the discussions in this review to TNFSF receptor–ligand interactions and their role in the pathogenesis of neuroinflammation and CNS autoimmunity. PMID:26257732

  15. Anti-tumor necrosis factor-α therapy in uveitis.

    PubMed

    Cordero-Coma, Miguel; Sobrin, Lucia

    2015-01-01

    Since the first reported use in 2001 of an anti-tumor necrosis factor-alpha (TNF-α) agent, infliximab, for the treatment of uveitis, several new anti-TNF-α agents have emerged for the treatment of refractory noninfectious uveitides, although their use remains off-label in the US. These agents have demonstrated remarkable clinical antiinflammatory efficacy and a potential immunoregulatory role in selected uveitis patients, but it is currently unclear whether they can modify the natural history of disease. We review the rationale and clinical indications for this therapy, the differences between agents, how to manage dosing and intervals, and how to screen for and identify potential side effects. We also present a summary of the science behind the use of anti-TNF-α agents in ocular inflammation and the evidence for their efficacy. PMID:26164735

  16. Tumor necrosis factor alpha polymorphism in heart failure/cardiomyopathy.

    PubMed

    Vadlamani, Lou; Iyengar, Srinivas

    2004-01-01

    Tumor necrosis factor a (TNF-alpha) is a proinflammatory cytokine that is produced by activated macrophages. It has been shown to stimulate the release of endothelial cytokines and NO, increase vascular permeability, decrease contractility, and induce a prothrombotic state. The most studied TNF-a gene mutation in heart disease is a gamma to alpha substitution, which occurs when 308 nucleotides move upstream from the transcription initiation site in the TNF promoter and has been associated with elevated levels of TNF-alpha. The TNF1 allele (wild type) contains gamma at this site, while the TNF2 allele has an alpha substitution at the site. The TNF2 allele is a more powerful transcriptional activator, therefore leading to higher TNF-alpha levels. Most of the studies to date have failed to conclusively show any link between the polymorphism and heart disease, both coronary artery disease and cardiomyopathy/heart failure. PMID:15591843

  17. Targeted Cancer Therapy with Tumor Necrosis Factor-Alpha

    PubMed Central

    Cai, Weibo; Kerner, Zachary J.; Hong, Hao; Sun, Jiangtao

    2013-01-01

    Tumor necrosis factor-alpha (TNF-α), a member of the TNF superfamily, was the first cytokine to be evaluated for cancer biotherapy. However, the clinical use of TNF-α is severely limited by its toxicity. Currently, TNF-α is administered only through locoregional drug delivery systems such as isolated limb perfusion and isolated hepatic perfusion. To reduce the systemic toxicity of TNF-α, various strategies have been explored over the last several decades. This review summarizes current state-of-the-art targeted cancer therapy using TNF-α. Passive targeting, cell-based therapy, gene therapy with inducible or tissue-specific promoters, targeted polymer-DNA complexes, tumor pre-targeting, antibody-TNF-α conjugate, scFv/TNF-α fusion proteins, and peptide/TNF-α fusion proteins have all been investigated to combat cancer. Many of these agents are already in advanced clinical trials. Molecular imaging, which can significantly speed up the drug development process, and nanomedicine, which can integrate both imaging and therapeutic components, has the potential to revolutionize future cancer patient management. Cooperative efforts from scientists within multiple disciplines, as well as close partnerships among many organizations/entities, are needed to quickly translate novel TNF-α-based therapeutics into clinical investigation. PMID:24115841

  18. Accuracy of magnetic resonance spectroscopy in distinction between radiation necrosis and recurrence of brain tumors

    PubMed Central

    Anbarloui, Mousa Reza; Ghodsi, Seyed Mohammad; Khoshnevisan, Alireza; Khadivi, Masoud; Abdollahzadeh, Sina; Aoude, Ahmad; Naderi, Soheil; Najafi, Zeynab; Faghih-Jouibari, Morteza

    2015-01-01

    Background: Distinction between radiation necrosis and recurrence of intraparenchymal tumors is necessary to select the appropriate treatment, but it is often difficult based on imaging features alone. We developed an algorithm for analyzing magnetic resonance spectroscopy (MRS) findings and studied its accuracy in differentiation between radiation necrosis and tumor recurrence. Methods: Thirty-three patients with a history of intraparenchymal brain tumor resection and radiotherapy, which had developed new enhancing lesion were evaluated by MRS and subsequently underwent reoperation. Lesions with Choline (Cho)/N-acetyl aspartate (NAA) > 1.8 or Cho/Lipid > 1 were considered as tumor recurrence and the remaining as radiation necrosis. Finally, pre-perative MRS diagnoses were compared with histopathological report. Results: The histological diagnosis was recurrence in 25 patients and necrosis in 8 patients. Mean Cho/NAA in recurrent tumors was 2.72, but it was 1.46 in radiation necrosis (P < 0.01). Furthermore, Cho/Lipid was significantly higher in recurrent tumors (P < 0.01) with the mean of 2.78 in recurrent tumors and 0.6 in radiation necrosis. Sensitivity, specificity, and diagnostic accuracy of the algorithm for detecting tumor recurrence were 84%, 75% and 81%, respectively. Conclusion: MRS is a safe and informative tool for differentiating between tumor recurrence and radiation necrosis. PMID:25874054

  19. Inverse regulation of human ERBB2 and epidermal growth factor receptors by tumor necrosis factor alpha.

    PubMed Central

    Kalthoff, H; Roeder, C; Gieseking, J; Humburg, I; Schmiegel, W

    1993-01-01

    Recombinant human tumor necrosis factor (TNF) alpha decreased the expression of ERBB2 mRNA by stimulating p55 TNF receptors of pancreatic tumor cells. This decrease contrasts with an increase in epidermal growth factor receptor (EGFR) mRNA. Both effects were selectively achieved by TNF-alpha or -beta, whereas interferon alpha or gamma or transforming growth factor beta showed no such effects. The inverse regulatory effects of TNF on ERBB2 and EGFR mRNA levels were evoked by different signaling pathways of p55 TNF receptors. The TNF-mediated ERBB2 mRNA decrease was followed by a reduction in protein. Four of five pancreatic tumor cell lines exhibited this down-regulation. This decrease of ERBB2 is a singular example of a modulation of this growth factor receptor by TNF. Overexpression of ERBB2 has been reported to cause resistance to TNF and other cytotoxic cytokines. In our study we show that the TNF-mediated down-regulation of ERBB2 in pancreatic tumor cells is accompanied by an increase in growth inhibition at low doses of TNF. The simultaneous alteration of the ERBB2/EGFR balance by TNF represents a striking model of cytokine receptor transregulation in the growth control of malignant pancreatic epithelial cells. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 PMID:8105469

  20. Cathepsins mediate tumor metastasis

    PubMed Central

    Tan, Gong-Jun; Peng, Zheng-Ke; Lu, Jin-Ping; Tang, Fa-Qing

    2013-01-01

    Cathepsins are highly expressed in various human cancers, associated with tumor metastasis. It is superfamily, concluding A, B, C, D, E, F, G, H, L, K, O, S, V, and W family members. As a group of lysosomal proteinases or endopeptidases, each member has a different function, playing different roles in distinct tumorigenic processes such as proliferation, angiogenesis, metastasis, and invasion. Cathepsins belong to a diverse number of enzyme subtypes, including cysteine proteases, serine proteases and aspartic proteases. The contribution of cathepsins to invasion in human cancers is well documented, although the precise mechanisms by which cathepsins exert their effects are still not clear. In the present review, the role of cathepsin family members in cancer is discussed. PMID:24340132

  1. Expression of Tumor Necrosis Factor in Human Acute Cardiac Rejection

    PubMed Central

    Arbustini, Eloisa; Grasso, Maurizia; Diegoli, Marta; Bramerio, Manuela; Foglieni, Andrea Scotti; Albertario, Marco; Martinelli, Luigi; Gavazzi, Antonello; Goggi, Claudio; Campana, Carlo; Vigano, Mario

    1991-01-01

    The authors performed an immunohistochemical study on expression of tumor necrosis factor alpha (TNFα) in endomyocardial biopsies from human cardiac allografts. TNFα immunoreactivity was found in 45% biopsies with mild acute rejection, in 83% biopsies with focal moderate rejection, in 80% biopsies with diffuse moderate rejection. Biopsies with absent rejection did not show immunoreactive cells. In mild rejection, positive cells were few and scanty monocytes and macrophages (MAC-387 and LN5 positive cells) and T lymphocytes (UCHL-1/CD45 RO positive cells) (up to 20% of all infiltrating cells). Expression of major histocompatibility complex (MHC) class II antigens on infiltrating and endothelial cells occurred earlier and independent of TNFα reactivity. Number of immunoreactive cells increased in moderate rejection (up to 50%). Immunoreactivity was also present in nonpigmented macrophages in part of the biopsies with resolving rejection (45%). The authors conclude that TNFα is expressed in acute cardiac rejection by immunologically activated inflammatory cells. Immunoreactive cells increase in number with increasing severity of the reaction. ImagesFigure 1Figure 2Figure 3Figure 4 PMID:1928295

  2. Tumor necrosis factor induced stimulation of granulopoiesis and radioprotection.

    PubMed

    Urbaschek, R; Männel, D N; Urbaschek, B

    1987-01-01

    Human recombinant tumor necrosis factor, TNF, was used to assess its ability to stimulate granulopoiesis and to protect mice against lethal irradiation, effects known to be inducable with TNF-rich postendotoxin serum from BCG infected mice (BCG/ET serum). Although the endotoxin contamination of this TNF preparation is extremely low its effects were compared in endotoxin low responder C3H/HeJ mice and susceptible NMRI mice. TNF is a potent inducer of serum colony stimulating activity, CSA, in both mouse strains. In peripheral blood a marked granulocytosis with a concomitant decrease in lymphocytes and monocytopenia occurs at 2 hours after injection of TNF. Moreover, TNF induces an increase in the number of splenic myelopoietic committed stem cells (GM-CFC, granulocyte-macrophage colony forming cells) determined five days after injection. The lethality rate, registered over 30 days after exposure to 660 cGy whole body X-irradiation is reduced to 40% in C3H/HeJ mice as compared to 75% in control animals. The reduction in lethality is observed both, when TNF was injected 24 hours before or after irradiation. In vitro, TNF significantly increases the number of colonies in the presence of CSA in bone marrow cultures. TNF per se does not effect colony growth. The studies reported here demonstrate that TNF is a myelopoiesis stimulating factor in mice which may be related to the reduction in lethality following whole body irradiation. PMID:3306175

  3. Tumor necrosis factor drives increased splenic monopoiesis in old mice.

    PubMed

    Loukov, Dessi; Naidoo, Avee; Puchta, Alicja; Marin, Jorge L Arredondo; Bowdish, Dawn M E

    2016-07-01

    Aging is accompanied by changes in hematopoiesis and consequently in leukocyte phenotype and function. Although age-related changes in bone marrow hematopoiesis are fairly well documented, changes in extramedullary hematopoiesis are less well described. We observed that 18-22-mo-old mice had larger spleens than young controls and found that the enlargement was caused by increased monopoiesis. Because extramedullary hematopoiesis is often driven by inflammation, we hypothesized that the chronic, low-level inflammation that occurs with age is a causal agent in splenomegaly. To test this theory, we compared the number of monocytes in 18-mo-old tumor necrosis factor-knockout mice, which are protected from age-associated inflammation, and found that they did not have increased extramedullary monopoiesis. To determine whether increased splenic monopoiesis is caused by intrinsic changes in the myeloid precursors that occur with age or by the aging microenvironment, we created heterochronic bone marrow chimeras. Increased splenic monopoiesis occurred in old recipient mice, regardless of the age of the donor mouse, but not in young recipient mice, demonstrating that these cells respond to signals from the microenvironment. These data suggest that decreasing the inflammatory microenvironment with age would be an effective strategy for reducing inflammatory diseases propagated by cells of myeloid lineage, which increase in number with age. PMID:27037197

  4. Trovafloxacin-induced Replication Stress Sensitizes HepG2 Cells to Tumor Necrosis Factor-alpha-induced Cytotoxicity Mediated by Extracellular Signal-regulated Kinase and Ataxia Telangiectasia and Rad3-related

    PubMed Central

    Beggs, Kevin M.; Maiuri, Ashley R.; Fullerton, Aaron M.; Poulsen, Kyle L.; Breier, Anna B.; Ganey, Patricia E.; Roth, Robert A.

    2015-01-01

    Use of the fluoroquinolone antibiotic trovafloxacin (TVX) was restricted due to idiosyncratic, drug-induced liver injury (IDILI). Previous studies demonstrated that tumor necrosis factor-alpha (TNF) and TVX interact to cause death of hepatocytes in vitro that was associated with prolonged activation of c-Jun N-terminal kinase (JNK), activation of caspases 9 and 3, and DNA damage. The purpose of this study was to explore further the mechanism by which TVX interacts with TNF to cause cytotoxicity. Treatment with TVX caused cell cycle arrest, enhanced expression of p21 and impaired proliferation, but cell death only occurred after cotreatment with TVX and TNF. Cell death involved activation of extracellular signal-related kinase (ERK), which in turn activated caspase 3 and ataxia telangiectasia and Rad3-related (ATR), both of which contributed to cytotoxicity. Cotreatment of HepG2 cells with TVX and TNF caused double-strand breaks in DNA, and ERK contributed to this effect. Inhibition of caspase activity abolished the DNA strand breaks. The data suggest a complex interaction of TVX and TNF in which TVX causes replication stress, and the downstream effects are exacerbated by TNF, leading to hepatocellular death. These results raise the possibility that IDILI from TVX results from MAPK and ATR activation in hepatocytes initiated by interaction of cytokine signaling with drug-induced replication stress. PMID:25748550

  5. Percentage tumor necrosis following chemotherapy in neuroblastoma correlates with MYCN status but not survival.

    PubMed

    Bomken, Simon; Davies, Beverley; Chong, Leeai; Cole, Michael; Wood, Katrina M; McDermott, Michael; Tweddle, Deborah A

    2011-03-01

    The percentage of chemotherapy-induced necrosis in primary tumors corresponds with outcome in several childhood malignancies, including high-risk metastatic diseases. In this retrospective pilot study, the authors assessed the importance of postchemotherapy necrosis in high-risk neuroblastoma with a histological and case notes review of surgically resected specimens. The authors reviewed all available histology of 31 high-risk neuroblastoma cases treated with COJEC (dose intensive etoposide and vincristine with either cyclophosphamide, cisplatin or carboplatin) or OPEC/OJEC (etoposide, vincristine and cyclophosphamide with alternating cisplatin [OPEC] or carboplatin [OJEC]) induction chemotherapy in 2 Children's Cancer & Leukaemia Group (CCLG) pediatric oncology centers. The percentage of postchemotherapy necrosis was assessed and compared with MYCN amplification status and overall survival. The median percentage of postchemotherapy tumor necrosis was 60%. MYCN status was available for 28 cases, of which 12 were amplified (43%). Survival in cases with ≥ 60% necrosis or ≥ 90% necrosis was not better than those with less necrosis, nor was percentage necrosis associated with survival using Cox regression. However, MYCN-amplified tumors showed a higher percentage of necrosis than non-MYCN-amplified tumors, 71.3% versus 37.2% (P = .006). This effect was not related to prechemotherapy necrosis and did not confer improved overall survival. Postchemotherapy tumor necrosis is higher in patients with MYCN amplification. In this study, postchemotherapy necrosis did not correlate with overall survival and should not lead to modification of postoperative treatment. However, these findings need to be confirmed in a larger prospective study of children with high-risk neuroblastoma. PMID:21214410

  6. Hepatocellular carcinoma: IVIM diffusion quantification for prediction of tumor necrosis compared to enhancement ratios

    PubMed Central

    Kakite, Suguru; Dyvorne, Hadrien A.; Lee, Karen M.; Jajamovich, Guido H.; Knight-Greenfield, Ashley; Taouli, Bachir

    2015-01-01

    Purpose To correlate intra voxel incoherent motion (IVIM) diffusion parameters of liver parenchyma and hepatocellular carcinoma (HCC) with degree of liver/tumor enhancement and necrosis; and to assess the diagnostic performance of diffusion parameters vs. enhancement ratios (ER) for prediction of complete tumor necrosis. Patients and methods In this IRB approved HIPAA compliant study, we included 46 patients with HCC who underwent IVIM diffusion-weighted (DW) MRI in addition to routine sequences at 3.0 T. True diffusion coefficient (D), pseudo-diffusion coefficient (D*), perfusion fraction (PF) and apparent diffusion coefficient (ADC) were quantified in tumors and liver parenchyma. Tumor ER were calculated using contrast-enhanced imaging, and degree of tumor necrosis was assessed using post-contrast image subtraction. IVIM parameters and ER were compared between HCC and background liver and between necrotic and viable tumor components. ROC analysis for prediction of complete tumor necrosis was performed. Results 79 HCCs were assessed (mean size 2.5 cm). D, PF and ADC were significantly higher in HCC vs. liver (p < 0.0001). There were weak significant negative/positive correlations between D/PF and ER, and significant correlations between D/PF/ADC and tumor necrosis (for D, r 0.452, p < 0.001). Among diffusion parameters, D had the highest area under the curve (AUC 0.811) for predicting complete tumor necrosis. ER outperformed diffusion parameters for prediction of complete tumor necrosis (AUC > 0.95, p < 0.002). Conclusion D has a reasonable diagnostic performance for predicting complete tumor necrosis, however lower than that of contrast-enhanced imaging. PMID:27069971

  7. Interleukin 1 and Tumor Necrosis Factor Inhibit Cardiac Myocyte β -adrenergic Responsiveness

    NASA Astrophysics Data System (ADS)

    Gulick, Tod; Chung, Mina K.; Pieper, Stephen J.; Lange, Louis G.; Schreiner, George F.

    1989-09-01

    Reversible congestive heart failure can accompany cardiac allograft rejection and inflammatory myocarditis, conditions associated with an immune cell infiltrate of the myocardium. To determine whether immune cell secretory products alter cardiac muscle metabolism without cytotoxicity, we cultured cardiac myocytes in the presence of culture supernatants from activated immune cells. We observed that these culture supernatants inhibit β -adrenergic agonist-mediated increases in cultured cardiac myocyte contractility and intracellular cAMP accumulation. The myocyte contractile response to increased extracellular Ca2+ concentration is unaltered by prior exposure to these culture supernatants, as is the increase in myocyte intracellular cAMP concentration in response to stimulation with forskolin, a direct adenyl cyclase activator. Inhibition occurs in the absence of alteration in β -adrenergic receptor density or ligand binding affinity. Suppressive activity is attributable to the macrophage-derived cytokines interleukin 1 and tumor necrosis factor. Thus, these observations describe a role for defined cytokines in regulating the hormonal responsiveness and function of contractile cells. The effects of interleukin 1 and tumor necrosis factor on intracellular cAMP accumulation may be a model for immune modulation of other cellular functions dependent upon cyclic nucleotide metabolism. The uncoupling of agonist-occupied receptors from adenyl cyclase suggests that β -receptor or guanine nucleotide binding protein function is altered by the direct or indirect action of cytokines on cardiac muscle cells.

  8. Effects of tumor necrosis factor α-857C/T polymorphism on the expression of tumor necrosis factor α.

    PubMed

    Kimura, Koji; Takayanagi, Risa; Yokoyama, Haruko; Yamada, Yasuhiko

    2016-08-01

    It was reported that homozygosity for a lymphotoxin α (LTA) 1-1-1-1 haplotype (LTA NcoI-TNFc-aa13L-aa26) may identify subgroups with a poor response to infliximab in Crohn's disease patients. Previously, we found a genetic polymorphism that linked with the LTA 1-1-1-1 haplotype and noted that it was a tumor necrosis factor (TNF) α-857 T allele. To investigate the effects of the -857C/T (rs1799724) polymorphism on the expression of TNFα, we compared levels of transcriptional activity of the gene, mRNA, and protein of the TNFα. The change in transcriptional activity of the -857T allele was higher than that of the -857C allele. Furthermore, the accumulated transcriptional activity of the -857T allele was 1.3-fold higher than that of the -857C allele up to 48 h. The levels of mRNA and protein of the TNFα after stimulation were also shown to be significantly higher in -857C/T as compared to the -857C/C genotype. Our results suggested that TNFα promoter -857T is higher than -857C in the levels of transcriptional activity of the gene, mRNA, and protein of the TNFα. The differences in therapeutic effect of TNF inhibitors among individuals can be explained in part by the induction ability of TNFα via the -857C/T polymorphism. PMID:27307133

  9. Tumor necrosis factor-alpha gene is not associated with obsessive-compulsive disorder.

    PubMed

    Zai, Gwyneth; Arnold, Paul D; Burroughs, Eliza; Richter, Margaret A; Kennedy, James L

    2006-02-01

    Dysregulation of the immune system has been suggested to play a role in the complex etiology of obsessive-compulsive disorder. In this context, tumor necrosis factor-alpha is considered an interesting candidate for genetic studies as overproduction of tumor necrosis factor-alpha, which may be genetically modulated, can exert neurotoxic effects and influence neural cell growth and proliferation. Moreover, the tumor necrosis factor-alpha gene is located on chromosome 6p21.3, a region that has been found to be weakly associated with obsessive-compulsive disorder in linkage studies. One functional polymorphism, G-308A, has been found within the gene. PMID:16395130

  10. Regulation of bitter taste responses by tumor necrosis factor.

    PubMed

    Feng, Pu; Jyotaki, Masafumi; Kim, Agnes; Chai, Jinghua; Simon, Nirvine; Zhou, Minliang; Bachmanov, Alexander A; Huang, Liquan; Wang, Hong

    2015-10-01

    Inflammatory cytokines are important regulators of metabolism and food intake. Over production of inflammatory cytokines during bacterial and viral infections leads to anorexia and reduced food intake. However, it remains unclear whether any inflammatory cytokines are involved in the regulation of taste reception, the sensory mechanism governing food intake. Previously, we showed that tumor necrosis factor (TNF), a potent proinflammatory cytokine, is preferentially expressed in a subset of taste bud cells. The level of TNF in taste cells can be further induced by inflammatory stimuli. To investigate whether TNF plays a role in regulating taste responses, in this study, we performed taste behavioral tests and gustatory nerve recordings in TNF knockout mice. Behavioral tests showed that TNF-deficient mice are significantly less sensitive to the bitter compound quinine than wild-type mice, while their responses to sweet, umami, salty, and sour compounds are comparable to those of wild-type controls. Furthermore, nerve recording experiments showed that the chorda tympani nerve in TNF knockout mice is much less responsive to bitter compounds than that in wild-type mice. Chorda tympani nerve responses to sweet, umami, salty, and sour compounds are similar between TNF knockout and wild-type mice, consistent with the results from behavioral tests. We further showed that taste bud cells express the two known TNF receptors TNFR1 and TNFR2 and, therefore, are potential targets of TNF. Together, our results suggest that TNF signaling preferentially modulates bitter taste responses. This mechanism may contribute to taste dysfunction, particularly taste distortion, associated with infections and some chronic inflammatory diseases. PMID:25911043

  11. Tumor necrosis factor-beta in human pregnancy and labor.

    PubMed

    Laham, N; Van Dunné, F; Abraham, L J; Farrugia, W; Bendtzen, K; Brennecke, S P; Rice, G E

    1997-04-01

    The aims of this study were to determine tumor necrosis factor-beta (TNF-beta) concentration profiles in peripheral venous plasma and amniotic fluid during pregnancy and at the time of labor and to characterise TNF-beta mRNA expression and TNF-beta release from human gestational tissues. In addition, we investigated the expression of TNF-beta binding protein, lymphotoxin-beta (LT-beta), in human gestational tissues. The mean (+/-S.E.M.) TNF-beta concentrations in maternal plasma (TIL, 78 +/- 12 pg/ml, n = 7 vs. TNIL, 304 +/- 88 pg/ml, n = 7) and amniotic fluid (TIL, 8 +/- 5 pg/ml, n = 6 vs. TNIL, 73 +/- 20 pg/ml, n = 20) were significantly (P < 0.05) decreased in association with term labor-onset (TIL) compared to term not-in-labor (TNIL). TNF-beta concentration in maternal plasma and amniotic fluid did not change significantly either with preterm labor (PIL), or during pregnancy. Group-matched comparison of maternal plasma and amniotic fluid TNF-beta concentrations demonstrated that amniotic fluid TNF-beta concentrations were 6-8 fold lower than maternal plasma TNF-beta concentrations. Furthermore, no detectable TNF-beta was secreted from cultured human amniotic, choriodecidual and placental explants. Although, TNF-beta mRNA was detected in amnion, choriodecidual and placenta, LT-beta was similarly expressed in these tissues, suggesting that TNF-beta may be cell membrane bound. These data demonstrate that TNF-beta is present at low levels within the intrauterine environment and may suggest that TNF-beta is specifically inhibited at the maternal-fetal interface. PMID:9185077

  12. A third distinct tumor necrosis factor receptor of orthopoxviruses.

    PubMed

    Loparev, V N; Parsons, J M; Knight, J C; Panus, J F; Ray, C A; Buller, R M; Pickup, D J; Esposito, J J

    1998-03-31

    Cowpox virus Brighton red strain (CPV) contains a gene, crmD, which encodes a 320-aa tumor necrosis factor receptor (TNFR) of 44% and 22% identity, respectively, to the CPV TNFR-like proteins, cytokine response modifiers (crm) CrmB and CrmC. The crmD gene was interrupted in three other cowpox strains examined and absent in various other orthopoxviruses; however, four strains of ectromelia virus (ECT) examined contained an intact crmD (97% identity to CPV crmD) and lacked cognates of crmB and crmC. The protein, CrmD, contains a transport signal; a 151-aa cysteine-rich region with 21 cysteines that align with human TNFRII ligand-binding region cysteines; and C-terminal region sequences that are highly diverged from cellular TNFR C-terminal region sequences involved in signal transduction. Bacterial maltose-binding proteins containing the CPV or ECT CrmD cysteine-rich region bound TNF and lymphotoxin-alpha (LTalpha) and blocked their in vitro cytolytic activity. Secreted viral CrmD bound TNF and LTalpha and was detectable after the early stage of replication, using nonreducing conditions, as 60- to 70-kDa predominant and 90- to 250-kDa minor disulfide-linked complexes that were able to be reduced to a 46-kDa form and deglycosylated to a 38-kDa protein. Cells infected with CPV produced extremely low amounts of CrmD compared with ECT. Possessing up to three TNFRs, including CrmD, which is secreted as disulfide-linked complexes in varied amounts by CPV and ECT, likely enhances the dynamics of the immune modulating mechanisms of orthopoxviruses. PMID:9520445

  13. EARLY DIVERSIFICATION OF THE TUMOR NECROSIS SUPERFAMILY IN TELEOSTS: GENOMIC CHARACTERIZATION AND EXPRESSION ANALYSIS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Members of the tumor necrosis factor superfamily (TNFSF) are cytokines involved in diverse immunological and developmental pathways. Little is known about their evolution or expression in lower vertebrate species. Bioinformatic searches of available teleost databases including Zebrafish, Tetroadon...

  14. Tumor necrosis factor and stroke: role of the blood-brain barrier

    PubMed Central

    Pan, Weihong; Kastin, Abba J.

    2008-01-01

    The progression and outcome of stroke is affected by the intricate relationship between the blood-brain barrier (BBB) and tumor necrosis factor α (TNFα). TNFα crosses the intact BBB by a receptor-mediated transport system that is upregulated by CNS trauma and inflammation. In this review, we discuss intracellular trafficking and transcytosis of TNFα, regulation of TNFα transport after stroke, and the effects of TNFα on stroke preconditioning. TNFα can activate cytoprotective pathways by pretreatment or persistent exposure to low doses. This explains the paradoxical observation that transport of this proinflammatory cytokine improves the survival and function of hypoxic cells and of mice with stroke. The dual effects of TNFα may be related to differential regulation of TNFα trafficking downstream to TNFR1 and TNFR2 receptors. As we better understand how peripheral TNFα affects its own transport and modulates neuroregeneration, we may be in a better position to pharmacologically manipulate its regulatory transport system to treat stroke. PMID:17913328

  15. The effect of Escherichia coli lipopolysaccharide and Tumor Necrosis Factor alpha on ovarian function

    PubMed Central

    Williams, Erin J.; Sibley, Kelly; Miller, Aleisha N.; Lane, Elizabeth A.; Fishwick, John; Nash, Deborah M.; Herath, Shan; England, Gary CW; Dobson, Hilary; Sheldon, I. Martin

    2009-01-01

    Problem Pelvic inflammatory disease and metritis are important causes of infertility in humans and domestic animals. Uterine infection with Escherichia coli in cattle is associated with reduced ovarian follicle growth and decreased estradiol secretion. We hypothesized that this effect could be mediated by the bacterial lipopolysaccharide (LPS) or cytokines such as tumor necrosis factor alpha (TNFα). Method of study In vitro, bovine ovarian theca and granulosa cells were treated with LPS or TNFα and steroid secretion measured. In vivo, the effect of LPS or TNFα intrauterine infusion was determined by ovarian ultrasonography and measurement of hormones in cattle. Results LPS reduced granulosa cell estradiol secretion, whilst TNFα decreased theca and granulosa cell androstenedione and estradiol production, respectively. In vivo, fewer animals ovulated following intrauterine infusion with LPS or TNFα. Conclusion LPS and TNFα suppress ovarian cell function, supporting the concept that pelvic inflammatory disease and metritis are detrimental for bovine ovarian health. PMID:19238751

  16. Phosphorylation of tumor necrosis factor receptor 1 (p55) protects macrophages from silica-induced apoptosis.

    PubMed

    Gambelli, Federica; Di, Peter; Niu, Xiaomei; Friedman, Mitchell; Hammond, Timothy; Riches, David W H; Ortiz, Luis A

    2004-01-16

    Macrophages play a fundamental role in silicosis in part by removing silica particles and producing inflammatory mediators in response to silica. Tumor necrosis factor alpha (TNFalpha) is a prominent mediator in silicosis. Silica induction of apoptosis in macrophages might be mediated by TNFalpha. However, TNFalpha also activates signal transduction pathways (NF-kappaB and AP-1) that rescue cells from apoptosis. Therefore, we studied the TNFalpha-mediated mechanisms that confer macrophage protection against the pro-apoptotic effects of silica. We will show that exposure to silica induced TNFalpha production by RAW 264.7 cells, but not by IC-21. Silica-induced activation of NF-kappaB and AP-1 was only observed in RAW 264.7 macrophages. ERK activation in response to silica exposure was only observed in RAW 264.7 macrophages, whereas activation of p38 phosphorylation was predominantly observed in IC-21 macrophages. No changes in JNK activity were observed in either cell line in response to silica exposure. Silica induced apoptosis in both macrophage cell lines, but the induction of apoptosis was significantly larger in IC-21 cells. Protection against apoptosis in RAW 264.7 cells in response to silica was mediated by enhanced NF-kappaB activation and ERK-mediated phosphorylation of the p55 TNFalpha receptor. Inhibition of these two protective mechanisms by specific pharmacological inhibitors or transfection of dominant negative mutants that inhibit IkappaBalpha or ERK phosphorylation significantly increased silica-induced apoptosis in RAW 264.7 macrophages. These data suggest that NF-kappaB activation and ERK-mediated phosphorylation of the p55 TNF receptor are important cell survival mechanisms in the macrophage response to silica exposure. PMID:14570868

  17. Correlation of Doxorubicin Delivery and Tumor Necrosis after Drug-eluting Bead Transarterial Chemoembolization of Rabbit VX2 Liver Tumors.

    PubMed

    Gaba, Ron C; Emmadi, Rajyasree; Parvinian, Ahmad; Casadaban, Leigh C

    2016-09-01

    Purpose To quantify the correlation between doxorubicin (DOX) delivery and tumor necrosis after drug-eluting bead (DEB) transarterial chemoembolization (TACE). Materials and Methods In this animal care committee-approved study, New Zealand white rabbit VX2 liver tumors were treated transarterially with DOX-loaded 70-150-μm DEBs in five treatment groups with varying drug doses: sham (saline), 0 mg, 12.5 mg, 25 mg, and 37.5 mg. DEB TACE was followed by 3- and 7-day sacrifice, tumor harvest, and sectioning. Drug delivery was assessed by using fluorescence imaging, and tumor necrosis was quantified by means of histologic analysis. Statistical correlation of DOX delivery and tumor necrosis was performed by using the Spearman rank correlation coefficient (ρ). Results Thirty-six VX2 tumors (median diameter, 1.3 cm) in 20 rabbits (median weight, 2.8 kg) underwent successful DEB TACE. Treatment groups included eight, seven, eight, five, and eight tumors of similar size (P > .05). Tumors showed progressively greater DOX extent (sham, 0%; 0 mg, 0%; 12.5 mg, 3%; 25 mg, 20%; and 37.5 mg, 27%) and intensity (sham, 0.4; 0 mg, 1.9; 12.5 mg, 8.5; 25 mg, 9.6; and 37.5 mg, 18.3) and higher median percentage necrosis (sham, 68%; 0 mg, 64%; 12.5 mg, 76%; 25 mg, 78%; and 37.5 mg, 83%) across DOX treatment groups. Correlation of DOX extent (ρ = 0.975, P = .005) and intensity (ρ = 0.900, P = .037) with percentage tumor necrosis was statistically significant. Conclusion Incremental increases in DOX correlate with greater necrosis in rabbit VX2 liver tumors after DEB TACE. This result indicates an essential role for chemotherapy-induced cytotoxicity in TACE effectiveness and supports the use of chemotherapeutic drugs in transarterial therapy. (©) RSNA, 2016 Online supplemental material is available for this article. PMID:26967144

  18. Testicular Seminoma With Pseudocyst and Coagulation Necrosis Like Burned-out Tumor: A Case Report.

    PubMed

    Hoshii, Tatsuhiko; Hasegawa, Go; Ikeda, Yohei; Nishiyama, Tsutomu

    2016-07-01

    Testicular seminoma is a relatively common testicular cancer; however, testicular seminoma with pseudocyst is an extremely rare. The 'burned-out' phenomenon in germ cell tumors refers to a germ cell tumor in extra-gonadal tissues with spontaneous regression of an intra-gonadal tumor. We present a case of the testicular seminoma with pseudocyst and coagulation necrosis like burned-out tumor without metastasis. PMID:27335779

  19. CCL11-induced eosinophils inhibit the formation of blood vessels and cause tumor necrosis.

    PubMed

    Xing, Yanjiang; Tian, Yijun; Kurosawa, Takamasa; Matsui, Sayaka; Touma, Maki; Yanai, Takanori; Wu, Qiong; Sugimoto, Kenkichi

    2016-06-01

    We previously demonstrated that IL-18 and CCL11 were highly expressed in an NFSA tumor cell line that showed limited angiogenesis and severe necrosis. However, IL-18 was not responsible for the immune cell accumulation and necrosis. Here, we attempted to clarify the relevance of CCL11 in angiogenesis and tumor formation. We established CCL11-overexpressing MS-K cell clones (MS-K-CCL11) to assess the role of CCL11 in immune cell accumulation and angiogenesis. The MS-K-CCL11 cells did not form tumors in mice. MS-K-CCL11-conditioned medium (CM) and recombinant CCL11 induced macrophage and eosinophil differentiation from bone marrow cells. The MS-K-CCL11-CM effectively recruited the differentiated eosinophils. Furthermore, the eosinophils damaged the MS-K, NFSA and endothelial cells in a dose-dependent manner. Administration of an antagonist of CCR3, a CCL11 receptor, to NFSA tumor-bearing mice restored the blood vessel formation and blocked the eosinophil infiltration into the NFSA tumors. Furthermore, other CCL11-overexpressing LM8 clones were established, and their tumor formation ability was reduced compared to the parental LM8 cells, accompanied by increased eosinophil infiltration, blockade of angiogenesis and necrosis. These results indicate that CCL11 was responsible for the limited angiogenesis and necrosis by inducing and attracting eosinophils in the tumors. PMID:27169545

  20. Enhancement of tumor necrosis factor-induced endothelial cell injury by cycloheximide

    SciTech Connect

    Nolop, K.B.; Ryan, U.S. )

    1990-08-01

    Tumor necrosis factor (TNF), a potent polypeptide mediator released by activated monocytes and macrophages, has a number of proinflammatory effects on endothelial cells. TNF is cytotoxic to tumor cells in vivo and in vitro, but TNF-induced toxicity to endothelial cells is less well established. We now report that cycloheximide (CHX), an inhibitor of protein synthesis, renders endothelial cells highly susceptible to TNF-induced lysis. TNF alone did not change the overall rate of protein synthesis by endothelial cells, whereas the addition of CHX completely abolished protein synthesis. Endothelial cells incubated in TNF alone in high concentrations (up to 1,000 U/ml) showed minimal rounding up and release of 51Cr. Likewise, CHX alone (5 micrograms/ml) had no significant effect on endothelial cell morphology and release of 51Cr. However, incubation of endothelial cells in both CHX and TNF caused injury in a dose-dependent manner. Morphological evidence of cell retraction, rounding, and detachment began within 2 h, but specific 51Cr release did not begin to rise until after 4 h. These changes were not observed when endothelial cells were incubated with TNF/CHX at 4 degrees C. The combination of TNF/CHX was lethal to all endothelial cells tested (bovine pulmonary artery, human umbilical vein, and human aorta), with human aortic cells showing the most pronounced changes. We conclude that healthy endothelial cells are resistant to TNF-induced lysis, but inhibition of their ability to make protein renders them highly susceptible.

  1. Involvement of specific matrix metalloproteinases during tumor necrosis factor/IFNgamma-based cancer therapy in mice.

    PubMed

    Van Roy, Maarten; Van Lint, Philippe; Van Laere, Ineke; Wielockx, Ben; Wilson, Carole; López-Otin, Carlos; Shapiro, Stephen; Libert, Claude

    2007-09-01

    The potent antitumor activity of tumor necrosis factor (TNF) in combination with IFN-gamma can only be applied in local regimens due to their strong proinflammatory properties. It has been shown that the broad-spectrum matrix metalloproteinase (MMP) inhibitor BB-94 protects against TNF/IFNgamma-induced toxicity without blocking the antitumor effect. Here, we tried to explain this protective role of BB-94 and sought to assign roles to specific MMPs in TNF/IFNgamma-induced toxicity. By studying the expression of MMP genes in different organs and in the tumor, we observed that the expression levels of MMP-7, MMP-8, MMP-9, and MMP-12 and tissue inhibitor of metalloproteinase-4 are clearly up-regulated in the liver during therapy. MMP-8 and MMP-9 are also up-regulated in the lung and kidney, respectively. In the tumor, most MMP genes are expressed, but only MMP-3 is up-regulated during TNF/IFNgamma treatment. Using MMP-deficient or double-deficient mice, we have shown a mediating role for MMP-3 during TNF/IFNgamma treatment in tumor-free and B16BL6 melanoma-bearing mice. By contrast, MMP-12 seemed to have some protective role in both models. However, because most phenotypes were not extremely outspoken, we have to conclude, based on the set of MMP-deficient mice we have studied, that inhibition of a single MMP will probably not increase the therapeutic value of TNF/IFNgamma, but that rather, broad-spectrum MMP inhibitors will be required. PMID:17876053

  2. Downregulation of tumor necrosis factor and other proinflammatory biomarkers by polyphenols.

    PubMed

    Gupta, Subash C; Tyagi, Amit K; Deshmukh-Taskar, Priya; Hinojosa, Myriam; Prasad, Sahdeo; Aggarwal, Bharat B

    2014-10-01

    Human tumor necrosis factor (TNF), first isolated by our group as an anticancer agent, has been now shown to be a primary mediator of inflammation. Till today 19 different members of the TNF superfamily which interact with 29 different receptors, have been identified. Most members of this family exhibit pro-inflammatory activities, in part through the activation of the transcription factor, nuclear factor-kappaB (NF-κB). Thus TNF and the related pro-inflammatory cytokines have been shown to play a key role in most chronic diseases such as cancer, rheumatoid arthritis, cardiovascular diseases, psoriasis, neurologic diseases, Crohn's disease, and metabolic diseases. Therefore, agents that can modulate the TNF-mediated inflammatory pathways may have potential against these pro-inflammatory diseases. Although blockers of TNF-α, such as infliximab (antibody against TNF-α), adalimumab (humanized antibody against TNF-α), and etanercept (soluble form of TNFR2) have been approved for human use, these blockers exhibit numerous side effects. In this review, we describe various plant-derived polyphenols that can suppress TNF-α activated inflammatory pathways both in vitro and in vivo. These polyphenols include curcumin, resveratrol, genistein, epigallocatechin gallate, flavopiridol, silymarin, emodin, morin isoliquiritigenin, naringenin, ellagic acid, apigenin, kaempferol, catechins, myricetin, xanthohumol, fisetin, vitexin, escin, mangostin and others. Thus these polyphenols are likely to have potential against various pro-inflammatory diseases. PMID:24946050

  3. Are circulating cytokines interleukin-6 and tumor necrosis factor alpha involved in chlorpyrifos-induced fever?

    PubMed

    Gordon, C J; Rowsey, P J

    1999-05-01

    Oral exposure to chlorpyrifos (CHP) in the rat results in an initial hypothermic response followed by a delayed fever. Fever from infection is mediated by the release of cytokines, including interleukin-6 (IL-6) and tumor necrosis factor (TNF alpha). This study determined if the CHP-induced fever involves cytokine-mediated mechanisms similar to that of infectious fevers. Long-Evans rats were gavaged with the corn oil vehicle or CHP (10-50 mg/kg). The rats were euthanized and blood collected at various times that corresponded with the hypothermic and febrile effects of CHP. Plasma IL-6, TNF alpha, cholinesterase activity (ChE), total iron, unsaturated iron binding capacity (UIBC), and zinc were measured. ChE activity was reduced by approximately 50% 4 h after CHP. There was no effect of CHP on IL-6 when measured during the period of CHP-induced hypothermia or fever. TNF alpha levels nearly doubled in female rats 48 h after 25 mg/kg CHP. The changes in plasma cytokine levels following CHP were relatively small when compared to > 1000-fold increase in IL-6 and > 10-fold rise in TNF alpha following lipopolysaccharide (E. coli; 50 microg/kg; i.p.)-induced fever. This does not preclude a role of cytokines in CHP-induced fever. Nonetheless, the data suggest that the delayed fever from CHP is unique, involving mechanisms other than TNF alpha and IL-6 release into the circulation characteristic of infectious fevers. PMID:10413184

  4. [Brain MR perfusion and MR spectroscopy in differentiation of radiation necrosis from tumor recurrence (case report)].

    PubMed

    Tekşam, Mehmet; Kayahan, Esra Meltem; Yerli, Hasan; Ağildere, A Muhteşem

    2004-12-01

    It is not always possible to differentiate tumor recurrence from radiation necrosis using conventional MR images. In this report we present a case of pathologically proven radiation necrosis which appeared as nodular contrast enhancement on conventional MR images in a patient who was surgically treated for grade II astrocytoma 5 years ago. There were decreased choline, creatine and N-acetyl aspartate peaks and significantly increased lipid peak on multivoxel H1-MR spectroscopy while there was no significant perfusion increase on MR perfusion. These findings suggested changes secondary to radiation necrosis. PMID:15611913

  5. Use of tumor necrosis factor (TNF) inhibitors in patients with HIV/AIDS.

    PubMed

    Gallitano, Stephanie M; McDermott, Laura; Brar, Kanwaljit; Lowenstein, Eve

    2016-05-01

    Patients with HIV and AIDS are living longer because of advancements in antiretroviral therapy. These patients are often susceptible to debilitating inflammatory disorders that are refractory to standard treatment. We discuss the relationship of tumor necrosis factor-alpha and HIV and then review 27 published cases of patients with HIV being treated with tumor necrosis factor-alpha inhibitors. This review is limited because no randomized controlled trials have been performed with this patient population. Regardless, we propose that reliable seropositive patients, who are adherent to medication regimens and frequent monitoring and have failed other treatment modalities, should be considered for treatment with tumor necrosis factor-alpha inhibitors. PMID:26774690

  6. Enhancement of glioblastoma radioresponse by a selective COX-2 inhibitor celecoxib: Inhibition of tumor angiogenesis with extensive tumor necrosis

    SciTech Connect

    Kang, Khong Bee . E-mail: dmskkb@nccs.com.sg; Wang, Ting Ting; Woon, Chow Thai; Cheah, Elizabeth S.; Moore, Xiao Lei; Zhu Congju; Wong, Meng Cheong

    2007-03-01

    Purpose: Toward improved glioblastoma multiforme treatment, we determined whether celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, could enhance glioblastoma radiosensitivity by inducing tumor necrosis and inhibiting tumor angiogenesis. Methods and Materials: U-87MG cells treated with celecoxib, irradiation, or both were assayed for clonogenic survival and angiogenic factor protein analysis (angiopoietin-1, angiopoietin-2, and vascular endothelial growth factor [VEGF]). In vivo, survival of mice intracranially implanted with U-87MG cells and treated with celecoxib and/or irradiation was monitored. Isolated tumors were assessed for tumor necrosis and tumor microvascular density by von Williebrand's factor (vWF) immunohistochemical staining. Results: Celecoxib (4 and 30 {mu}M; 24, 48, and 72 h) enhanced U-87MG cell radiosensitivity by significantly reducing clonogenic survival of irradiated cells. Angiopoietin-1 and VEGF proteins were decreased, whereas angiopoietin-2 expression increased after 72 h of celecoxib alone and when combined with irradiation. In vivo, median survival of control mice intracranially implanted with U-87MG cells was 18 days. Celecoxib (100 mg/kg/day, 2 weeks) significantly extended median survival of irradiated mice (24 Gy total) from 34 to 41 days, with extensive tumor necrosis [24.5 {+-} 8.6% of tumor region, compared with irradiation alone (2.7 {+-} 1.8%)]. Tumor microvascular density was significantly reduced in combined celecoxib and irradiated tumors (52.5 {+-} 2.9 microvessels per mm{sup 2} tumor region), compared with irradiated tumors alone (65.4 {+-} 4.0 microvessels per mm{sup 2}). Conclusion: Celecoxib significantly enhanced glioblastoma radiosensitivity, reduced clonogenic survival, and prolonged survival of glioblastoma-implanted mice by inhibition of tumor angiogenesis with extensive tumor necr0010os.

  7. Unilamellar liposomes modulate secretion of tumor necrosis factor by lipopolysaccharide-stimulated macrophages.

    PubMed Central

    Brisseau, G F; Kresta, A; Schouten, D; Bohnen, J M; Shek, P N; Fok, E; Rotstein, O D

    1994-01-01

    Liposomal encapsulation of antimicrobial agents has been used to improve drug delivery, particularly against intracellular pathogens. The effect of unilamellar liposomes on macrophage activation in response to Escherichia coli lipopolysaccharide was examined. Liposomes caused a dose- and time-dependent inhibition of tumor necrosis factor release by lipopolysaccharide-treated cells. The accumulation of tumor necrosis factor mRNA transcripts was unaffected, suggesting a posttranscriptional mechanism for this effect. However, induction of macrophage procoagulant activity was unaffected by liposomes, indicating a selective rather than a global inhibition. These data suggest that liposomes used for drug delivery may modulate the host response to infection. Images PMID:7872768

  8. Dissecting Cellulitis of the Scalp Responding to Intravenous Tumor Necrosis Factor-alpha Antagonist.

    PubMed

    Wollina, Uwe; Gemmeke, Astrid; Koch, André

    2012-04-01

    The authors present the case of a 30-year-old male patient with a severe and long-standing dissecting cellulitis of the scalp. The disease did not respond to conventional treatment, including oral antibiotics, isotretinoin, and prednisolone. Quality of life was significantly impaired. After introduction of anti-tumor necrosis factor-alpha treatment (infliximab), the malodorous discharge stopped, inflammation was reduced significantly, nodules became flat, and pain decreased. The treatment was well tolerated although he developed a temporary psoriasiform rash after the second intravenous infusion. In conclusion, anti-tumor necrosis factor-alpha treatment is a new therapeutic option in this severe and recalcitrant disorder. PMID:22708007

  9. Until Death Do Us Part: Necrosis and Oxidation Promote the Tumor Microenvironment

    PubMed Central

    Lotfi, Ramin; Kaltenmeier, Christof; Lotze, Michael T.; Bergmann, Christoph

    2016-01-01

    Summary Tumor proliferation is concomitant with autophagy, limited apoptosis, and resultant necrosis. Necrosis is associated with the release of damage-associated molecular pattern molecules (DAMPs), which act as ‘danger signals’, recruiting inflammatory cells, inducing immune responses, and promoting wound healing. Most of the current treatment strategies for cancer (chemotherapy, radiation therapy, hormonal therapy) promote DAMP release following therapy-induced tumor death by necroptosis and necrosis. Myeloid cells (monocytes, dendritic cells (DCs), and granulocytes), as well as mesenchymal stromal cells (MSCs) belong to the early immigrants in response to unscheduled cell death, initiating and modulating the subsequent inflammatory response. Responding to DAMPs, MSCs, and DCs promote an immunosuppressive milieu, while eosinophils induce oxidative conditions limiting the biologic activity of DAMPs over time and distance. Regulatory T cells are strongly affected by pattern recognition receptor signaling in the tumor microenvironment and limit immune reactivity coordinately with myeloid-derived suppressor cells. Means to ‘aerobically’ oxidize DAMPs provide a novel strategy for limiting tumor progression. The present article summarizes our current understanding of the impact of necrosis on the tumor microenvironment and the influence of oxidative conditions found within this setting. PMID:27226794

  10. Estimation of salivary tumor necrosis factor-alpha in chronic and aggressive periodontitis patients

    PubMed Central

    Varghese, Sheeja S.; Thomas, Hima; Jayakumar, N. D.; Sankari, M.; Lakshmanan, Reema

    2015-01-01

    Introduction: Periodontitis is a chronic bacterial infection characterized by persistent inflammation, connective tissue breakdown and alveolar bone destruction mediated by pro-inflammatory mediators. Tumor necrosis factor-alpha (TNF-α) is an important pro-inflammatory mediator that produced causes destruction of periodontal tissues. Objective: The aim of the study is to estimate the salivary TNF-α in chronic and aggressive periodontitis and control participants and further correlate the levels with clinical parameter such as gingival index (GI), plaque index (PI), probing pocket depth (PPD) and clinical attachment loss. Materials and Methods: The study population consisted of 75 subjects age ranging from 25 to 55 years attending the outpatient section of Department of Periodontics, Saveetha Dental College and Hospital. The study groups included Groups 1, 2, and 3 with participants with healthy periodontium (n = 25), generalized chronic periodontitis (n = 25) and generalized aggressive periodontitis (n = 25), respectively. Salivary samples from the participants were used to assess the TNF-α levels using enzyme-linked immunosorbent assay. Results: GI and PI were found to be significantly higher in chronic and aggressive periodontitis compared to the controls. The mean TNF-α value in chronic periodontitis patients (12.92 ± 17.21 pg/ml) was significantly higher than in control subjects (2.15 ± 3.60 pg/ml). Whereas, in aggressive periodontitis patients the mean TNF-α (7.23 ± 7.67) were not significantly different from chronic periodontitis or healthy subjects. Among periodontitis participants, aggressive periodontitis subjects exhibited a significant positive correlation between the salivary TNF-α and PPD. Conclusion: Salivary TNF-α levels are significantly higher in chronic periodontitis than in healthy subjects, but there was no significant correlation with the clinical parameters. PMID:26604566

  11. Synergistic activation of NF-kappaB by nontypeable Haemophilus influenzae and tumor necrosis factor alpha.

    PubMed

    Watanabe, Takahiro; Jono, Hirofumi; Han, Jiahuai; Lim, David J; Li, Jian-Dong

    2004-03-01

    Nontypeable Haemophilus influenzae (NTHi) is an important human pathogen causing otitis media in children and exacerbation of chronic obstructive pulmonary disease in adults. Like most other bacterial infections, NTHi infections are also characterized by inflammation, which is mainly mediated by cytokines and chemokines such as tumor necrosis factor alpha (TNF-alpha). Among a variety of transcription regulators, NF-kappaB has been shown to play a critical role in regulating the expression of large numbers of genes encoding inflammatory mediators. In review of the current studies on NF-kappaB regulation, most of them have focused on investigating how NF-kappaB is activated by a single inducer at a time. However, in bacteria-induced inflammation in vivo, multiple inducers including both exogenous and endogenous mediators are present simultaneously. A key issue that has yet to be addressed is whether the exogenous inducers such as NTHi and the endogenous factors such as TNF-alpha activate NF-kappaB in a synergistic manner. We show that NTHi and TNF-alpha, when present together, synergistically induce NF-kappaB activation via two distinct signaling pathways: NF-kappaB translocation-dependent and -independent pathways. The NF-kappaB translocation-dependent pathway involves NF-kappaB-inducing kinase-IkappaB kinase beta/gamma-dependent phosphorylation and degradation of IkappaBalpha, whereas the NF-kappaB translocation-independent pathway involves mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase kinase kinase 1-dependent activation of MAPK kinase 3/6-p38 MAPK pathway. In addition, the same signaling pathways are also involved in synergistic induction of TNF-alpha, IL-1beta, and IL-8. These studies should deepen our understanding of the molecular mechanisms underlying the combinatorial regulation of inflammation and lead to development of therapeutic strategies for NTHi-induced infections. PMID:14993593

  12. Tumor necrosis factor-alpha induced enhancement of cryosurgery

    NASA Astrophysics Data System (ADS)

    Goel, Raghav; Paciotti, Guilio F.; Bischof, John C.

    2008-02-01

    Local recurrence of cancer after cryosurgery is related to the inability to monitor and predict destruction of cancer (temperatures > -40°C) within an iceball. We previously reported that a cytokine adjuvant TNF-α could be used to achieve complete cancer destruction at the periphery of an iceball (0 to -40°C). This study is a further development of that work in which cryosurgery was performed using cryoprobes operating at temperatures > -40°C. LNCaP Pro 5 tumor grown in a dorsal skin fold chamber (DSFC) was frozen at -6°C after TNF-α incubation for 4 or 24 hours. Tumors grown in the hind limb were frozen with a probe tip temperature of -40°C, 4 or 24 hours after systemic injection with TNF-α. Both cryosurgery alone or TNF-α treatment alone caused only a minimal damage to the tumor tissue at the conditions used in the study. The combination of TNF-α and cryosurgery produced a significant damage to the tumor tissue in both the DSFC and the hind limb model system. This augmentation in cryoinjury was found to be time-dependent with 4-hour time period between the two treatments being more effective than 24-hour. These results suggests the possibility of cryotreatment at temperatures > -40°C with the administration of TNF-α.

  13. Brefeldin A reduces tumor necrosis factor-α-stimulated production of inflammatory mediators by suppressing the Akt, mTOR, and NF-κB pathways in human keratinocytes.

    PubMed

    Nam, Yoon Jeong; Lee, Chung Soo

    2016-09-01

    Keratinocytes may play an important role in the pathogenesis of inflammatory skin diseases. Brefeldin A has been shown to attenuate the production and secretion of chemical mediators involved in inflammation and immune responses. However, the effect of brefeldin A on the TNF-α-stimulated production of inflammatory mediators in keratinocytes has not been studied. We investigated the effect of brefeldin A on the TNF-α-stimulated production of inflammatory mediators using HaCaT cells and primary keratinocytes in relation to the Akt, mTOR, and NF-κB pathways, which regulates the transcription genes involved in immune and inflammatory responses. Brefeldin A, Akt inhibitor, Bay 11-7085 (an inhibitor of NF-κB activation), and rapamycin (mTOR inhibitor) inhibited the TNF-α-stimulated productions of inflammatory mediators, and activations of Akt, mTOR, and NF-κB in keratinocytes. The results show that brefeldin A appears to attenuate TNF-α-stimulated inflammatory mediator production in keratinocytes by suppressing the activation of the Akt, mTOR, and NF-κB pathways. PMID:27198515

  14. Bone necrosis and tumor induction following experimental intraoperative irradiation.

    PubMed

    Powers, B E; Gillette, E L; McChesney, S L; LeCouteur, R A; Withrow, S J

    1989-09-01

    The bone of the lumbar vertebrae of 153 dogs was examined 2 and 5 years after intraoperative irradiation (IORT), fractionated external beam irradiation (EBRT), or the combination. Groups of dogs received 15 to 55 Gy IORT only, 10 to 47.5 Gy IORT combined with 50 Gy EBRT in 2 Gy fractions or 60 to 80 Gy EBRT in 30 fractions. Six MeV electrons were used for IORT, and EBRT was done using photons from a 6 MV linear accelerator. The paraaortic region was irradiated and the ventral part of the lumbar vertebrae was in the 90% isodose level. Two years after irradiation, the dose causing significant bone necrosis as determined by at least 50% empty lacunae in the vertebral cortex was 38.2 Gy IORT alone and 32.5 Gy IORT combined with EBRT. Five years after irradiation, the dose causing 50% empty lacunae was 28.5 Gy IORT only and 14.4 Gy IORT combined with EBRT. The ED50 for lesions of the ventral vertebral artery was 21.7 Gy IORT only and 20.1 Gy IORT combined with 50 Gy EBRT 2 years after irradiation and 27.0 Gy IORT only and 20.0 Gy IORT combined with 50 Gy EBRT 5 years after irradiation. All lesions after EBRT only were mild. Eight dogs developed osteosarcomas 4 to 5 years after irradiation, one at 47.5 Gy IORT only and the remainder at 25.0 Gy IORT and above combined with 50 Gy EBRT. In conclusion, the extent of empty lacunae, indicating bone necrosis, was more severe 5 years after irradiation than after 2 years. The effect of 50 Gy EBRT in 2 Gy fractions was equivalent to about 6 Gy IORT 2 years after irradiation and to about 14 Gy 5 years after irradiation. Based on these estimates, IORT doses of 10 to 15 Gy have an effect 5 times or greater than the amount given in 2 Gy fractions. Osteosarcomas occurred in 21% of dogs which received doses greater than 25 Gy IORT. Doses of 15 to 20 Gy IORT in combination with 50 Gy EBRT in 2 Gy fractions may be near the tolerance level for late developing bone injury. PMID:2506159

  15. Genetics Home Reference: tumor necrosis factor receptor-associated periodic syndrome

    MedlinePlus

    ... Tumor necrosis factor receptor-associated periodic syndrome (TRAPS): definition, semiology, prognosis, pathogenesis, treatment, and place relative to other periodic joint diseases. Joint Bone Spine. 2004 Jul;71(4):284-90. Review. Citation on PubMed Pettersson T, Kantonen J, Matikainen S, ...

  16. Functional Characterization of Tumor Necrosis Factor Superfamily 15(TNFSF15) Induced by Lipopolysaccharides and Eimeria Infection

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A full-length cDNA encoding chicken tumor necrosis factor superfamily 15 (TNFSF15) was isolated and its functional role was investigated. TNFSF15 transcripts were primarily expressed in spleen, liver, intestinal intraepithelial lymphocytes (IEL), peripheral blood lymphocytes and bursa. In vitro inf...

  17. Tumor necrosis a regulation of adipokine gene expression in neonatal adipose tissue

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The neonatal period is also a time of significant stress and susceptibility to infection, conditions which favor the secretion of tumor necrosis a. The present study was designed to determine if TNFa can alter adipokine gene expression within the adipose tissue of neonatal swine. Primary stromal v...

  18. Vertical Transmission of Histoplasmosis Associated With Anti-Tumor Necrosis Factor Therapy.

    PubMed

    Carlucci, James G; Halasa, Natasha; Creech, C Buddy; Dulek, Daniel E; Gómez-Duarte, Oscar G; Nelson, George E; Talbot, H Keipp; Scalise, Melissa L; Scott, Patricia L; Mahadevan, Uma; Beaulieu, Dawn B

    2016-06-01

    Therapeutics blocking the activity of tumor necrosis factor (anti-TNF) are a risk factor for invasive fungal infections; however, infectious risks to infants born to mothers receiving anti-TNF therapy are not well defined. We report a case of vertical transmission of disseminated histoplasmosis in a mother-infant pair exposed to anti-TNF therapy. PMID:27012275

  19. Structural Biology of Tumor Necrosis Factor Demonstrated for Undergraduates Instruction by Computer Simulation

    ERIC Educational Resources Information Center

    Roy, Urmi

    2016-01-01

    This work presents a three-dimensional (3D) modeling exercise for undergraduate students in chemistry and health sciences disciplines, focusing on a protein-group linked to immune system regulation. Specifically, the exercise involves molecular modeling and structural analysis of tumor necrosis factor (TNF) proteins, both wild type and mutant. The…

  20. Role of tumor necrosis factor-alpha in lipopolysaccharide-induced pathologic alterations.

    PubMed Central

    Remick, D. G.; Strieter, R. M.; Eskandari, M. K.; Nguyen, D. T.; Genord, M. A.; Raiford, C. L.; Kunkel, S. L.

    1990-01-01

    Tumor necrosis factor-alpha (TNF) has been implicated strongly as a principal mediator in the pathogenesis of septic shock. The authors investigated the in vivo production of TNF in CBA/J and CD-1 mice that had been primed by an intraperitoneal injection of complete Freund's adjuvant followed 2 weeks later by an intraperitoneal injection of lipopolysaccharide (LPS). TNF bioactivity peaked in both the ascites and plasma one hour after challenge, and TNF mRNA expression in the ascites cells peaked 30 minutes after LPS. After the induction of bioactivity, an interstitial pulmonary neutrophilic infiltrate occurred that was quantitated both morphometrically and by a myeloperoxidase (MPO) assay. Peripheral blood neutrophilia and lymphopenia developed after the LPS injection (PMNs: control, 46 +/- 2%; LPS, 65 +/- 3%; Lymphs control, 53 +/- 2%; LPS, 37 +/- 3%). Treatment with dexamethasone (Dex) completely inhibited the pulmonary neutrophilic infiltrate as measured by the (MPO) assay. Because Dex will inhibit the production of several cytokines, anti-TNF antiserum was given to mice at the same time as the LPS challenge to assess specifically the role of TNF in inducing these changes. This antiserum partially blocked the pulmonary neutrophil infiltrate, and completely blocked the peripheral blood changes at one hour after LPS. These data demonstrate that TNF plays an important role in the early pathophysiologic alterations that occur after systemic exposure to LPS. Images Figure 3 Figure 4 Figure 6 Figure 11 PMID:2297050

  1. Perirenal fat promotes renal arterial endothelial dysfunction in obese swine through tumor necrosis factor-α

    PubMed Central

    Ma, Shuangtao; Zhu, Xiang-Yang; Eirin, Alfonso; Woollard, John R.; Jordan, Kyra L.; Tang, Hui; Lerman, Amir; Lerman, Lilach O.

    2015-01-01

    Purpose Perirenal fat is associated with poor blood pressure control and chronic kidney disease, but the underlying mechanisms remain elusive. We tested the hypothesis that perirenal fat impairs renal arterial endothelial function in pigs with obesity-metabolic derangements (ObM). Material and Methods Fourteen domestic pigs were studied after 16 weeks of a high-fat/high-fructose diet (ObM) or standard chow (Lean). Renal blood flow (RBF), glomerular filtration rate (GFR), and visceral fat volumes were studied in-vivo with CT. Renal arterial endothelial function was also studied ex-vivo in the organ bath. Results ObM pigs demonstrated increased body weight, blood pressure, cholesterol, and intra-abdominal fat compared to lean pigs, and perirenal fat volume was significantly larger. RBF and GFR were markedly elevated, while urinary protein level was preserved. Ex-vivo acetylcholine-induced endothelium-dependent vasodilation of renal artery rings was substantially impaired in ObM compared to Lean. Endothelial function was further blunted in both ObM and Lean arterial rings by incubation with perirenal fat harvested from ObM, but not from Lean pigs, and was restored by inhibition of tumor necrosis factor (TNF)-α. ObM perirenal fat also showed increased pro-inflammatory macrophage infiltration and TNF-α expression. Conclusions ObM perirenal fat directly causes renal artery endothelial dysfunction, partly mediated by TNF-α. PMID:26417644

  2. Tumor Necrosis Factor-α-Induced Ototoxicity in Mouse Cochlear Organotypic Culture

    PubMed Central

    Wu, Qian; Wang, Guo-Peng; Xie, Jing; Guo, Jing-Ying; Gong, Shu-Sheng

    2015-01-01

    Tumor necrosis factor (TNF)-α is a cytokine involved in acute inflammatory phase reactions, and is the primary upstream mediator in the cochlear inflammatory response. Treatment of the organ of Corti with TNF-α can induce hair cell damage. However, the resulting morphological changes have not been systematically examined. In the present study, cochlear organotypic cultures from neonatal mice were treated with various concentrations and durations of TNF-α to induce inflammatory responses. Confocal microscopy was used to evaluate the condition of hair cells and supporting cells following immunohistochemical staining. In addition, the ultrastructure of the stereocilia bundle, hair cells, and supporting cells were examined by scanning and transmission electron microscopy. TNF-α treatment resulted in a fusion and loss of stereocilia bundles in hair cells, swelling of mitochondria, and vacuolation and degranulation of the endoplasmic reticulum. Disruption of tight junctions between hair cells and supporting cells was also observed at high concentrations. Hair cell loss was preceded by apoptosis of Deiters’ and pillar cells. Taken together, these findings detail the morphological changes in the organ of Corti after TNF-α treatment, and provide an in vitro model of inflammatory-induced ototoxicity. PMID:26000970

  3. Production of tumor necrosis factor alpha in human leukocytes stimulated by Cryptococcus neoformans.

    PubMed Central

    Levitz, S M; Tabuni, A; Kornfeld, H; Reardon, C C; Golenbock, D T

    1994-01-01

    Tumor necrosis factor alpha (TNF-alpha) is a key mediator of inflammation and may promote human immunodeficiency virus replication in latently infected cells. Since cryptococcosis often is associated with aberrations in the host inflammatory response and occurs preferentially in persons with AIDS, we defined the conditions under which human leukocytes produce TNF-alpha when stimulated by Cryptococcus neoformans. Peripheral blood mononuclear cells (PBMC) produced comparable amounts of TNF-alpha following stimulation with C. neoformans and lipopolysaccharide. Detectable TNF-alpha release in response to C. neoformans occurred only when fungi with small-sized capsules were used and complement-sufficient serum was added. Fractionation of PBMC established that monocytes were the predominant source of TNF-alpha. TNF-alpha gene expression and release occurred significantly later in PBMC stimulated with C. neoformans than in PBMC stimulated with LPS. C. neoformans was also a potent inducer of TNF-alpha from freshly isolated bronchoalveolar macrophages (BAM). Upon in vitro culture, BAM and monocytes bound greater numbers of fungal cells, yet their capacity to produce TNF-alpha following cryptococcal stimulation declined by 74 to 100%. However, this decline was reversed if the BAM and monocytes were cultured with gamma interferon. These data establish that C. neoformans can potently stimulate TNF-alpha release from human leukocytes. However, several variables profoundly affected the amount of TNF-alpha released, including the type of leukocyte and its state of activation, the size of the cryptococcal capsule, and the availability of opsonins. PMID:8168965

  4. Erythropoietin protects myocardin-expressing cardiac stem cells against cytotoxicity of tumor necrosis factor-{alpha}

    SciTech Connect

    Madonna, Rosalinda; Shelat, Harnath; Xue, Qun; Willerson, James T.; De Caterina, Raffaele; Geng, Yong-Jian

    2009-10-15

    Cardiac stem cells are vulnerable to inflammation caused by infarction or ischemic injury. The growth factor, erythropoietin (Epo), ameliorates the inflammatory response of the myocardium to ischemic injury. This study was designed to assess the role of Epo in regulation of expression and activation of the cell death-associated intracellular signaling components in cardiac myoblasts stimulated with the proinflammatory cytokine tumor necrosis factor (TNF)-{alpha}. Cardiac myoblasts isolated from canine embryonic hearts characterized by expression of myocardin A, a promyogenic transcription factor for cardiovascular muscle development were pretreated with Epo and then exposed to TNF-{alpha}. Compared to untreated cells, the Epo-treated cardiac myoblasts exhibited better morphology and viability. Immunoblotting revealed lower levels of active caspase-3 and reductions in iNOS expression and NO production in Epo-treated cells. Furthermore, Epo pretreatment reduced nuclear translocation of NF-{kappa}B and inhibited phosphorylation of inhibitor of kappa B (I{kappa}B) in TNF-{alpha}-stimulated cardiac myoblasts. Thus, Epo protects cardiac myocyte progenitors or myoblasts against the cytotoxic effects of TNF-{alpha} by inhibiting NF-{kappa}B-mediated iNOS expression and NO production and by preventing caspase-3 activation.

  5. Tumor necrosis factor inhibition increases the revascularization of ischemic hind-limbs in diabetic mice.

    PubMed

    Assiri, Adel M A; El-Baz, Hatim A; Amin, Ali H

    2015-10-01

    Tumor necrosis factor (TNF) is first identified as a mediator of lethal endotoxin poisoning. The anti-TNF therapy in the treatment of rheumatoid arthritis is based on the recognition of the role of TNF as the master regulator. Type II diabetes is characterized with altered stem cells and reduced vasculogenesis. Therefore, we aimed to determine if TNF inhibitor would improve vasculogenesis in ischemic hind-limbs of diabetic mice. Fifty male type 2 diabetic and their control (8-10 weeks old mice) were used, and ischemia was induced in the hind-limbs of all mice for 28 days. Vessel density was assessed by high-definition microangiography at the end of the treatment period. After 4 weeks, vessel density displayed no difference between the ischemic and the non-ischemic legs in control mice. However, in diabetic mice, the ischemic hind-limb vessel density was significantly decreased. Interestingly, diabetic mice displayed a significant improved vasculogenesis when treated with TNF inhibitor. Moreover, this data was confirmed by capillary density determined by immunostaining. TNF inhibitors are able to improve the formation of microvessels in response to ischemia in type 2 diabetes. PMID:26026701

  6. Inhibition of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) reverses experimental pulmonary hypertension.

    PubMed

    Hameed, Abdul G; Arnold, Nadine D; Chamberlain, Janet; Pickworth, Josephine A; Paiva, Claudia; Dawson, Sarah; Cross, Simon; Long, Lu; Zhao, Lan; Morrell, Nicholas W; Crossman, David C; Newman, Christopher M H; Kiely, David G; Francis, Sheila E; Lawrie, Allan

    2012-10-22

    Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by the progressive narrowing and occlusion of small pulmonary arteries. Current therapies fail to fully reverse this vascular remodeling. Identifying key pathways in disease pathogenesis is therefore required for the development of new-targeted therapeutics. We have previously reported tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) immunoreactivity within pulmonary vascular lesions from patients with idiopathic PAH and animal models. Because TRAIL can induce both endothelial cell apoptosis and smooth muscle cell proliferation in the systemic circulation, we hypothesized that TRAIL is an important mediator in the pathogenesis of PAH. We demonstrate for the first time that TRAIL is a potent stimulus for pulmonary vascular remodeling in human cells and rodent models. Furthermore, antibody blockade or genetic deletion of TRAIL prevents the development of PAH in three independent rodent models. Finally, anti-TRAIL antibody treatment of rodents with established PAH reverses pulmonary vascular remodeling by reducing proliferation and inducing apoptosis, improves hemodynamic indices, and significantly increases survival. These preclinical investigations are the first to demonstrate the importance of TRAIL in PAH pathogenesis and highlight its potential as a novel therapeutic target to direct future translational therapies. PMID:23071256

  7. Inhibition of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) reverses experimental pulmonary hypertension

    PubMed Central

    Hameed, Abdul G.; Arnold, Nadine D.; Chamberlain, Janet; Pickworth, Josephine A.; Paiva, Claudia; Dawson, Sarah; Cross, Simon; Long, Lu; Zhao, Lan; Morrell, Nicholas W.; Crossman, David C.; Newman, Christopher M.H.; Kiely, David G.; Francis, Sheila E.

    2012-01-01

    Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by the progressive narrowing and occlusion of small pulmonary arteries. Current therapies fail to fully reverse this vascular remodeling. Identifying key pathways in disease pathogenesis is therefore required for the development of new-targeted therapeutics. We have previously reported tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) immunoreactivity within pulmonary vascular lesions from patients with idiopathic PAH and animal models. Because TRAIL can induce both endothelial cell apoptosis and smooth muscle cell proliferation in the systemic circulation, we hypothesized that TRAIL is an important mediator in the pathogenesis of PAH. We demonstrate for the first time that TRAIL is a potent stimulus for pulmonary vascular remodeling in human cells and rodent models. Furthermore, antibody blockade or genetic deletion of TRAIL prevents the development of PAH in three independent rodent models. Finally, anti-TRAIL antibody treatment of rodents with established PAH reverses pulmonary vascular remodeling by reducing proliferation and inducing apoptosis, improves hemodynamic indices, and significantly increases survival. These preclinical investigations are the first to demonstrate the importance of TRAIL in PAH pathogenesis and highlight its potential as a novel therapeutic target to direct future translational therapies. PMID:23071256

  8. Tumor Necrosis Factor-alpha Converting Enzyme: Implications for Ocular Inflammatory Diseases

    PubMed Central

    Ramana, Kota V

    2010-01-01

    Tumor necrosis factor-alpha (TNF-α) –converting enzyme (TACE), a member of the family of metalloproteinase disintegrin proteins, is responsible for the conversion of inactive TNF-α precursor from to active mature form. TNF-α is a pleiotropic cytokine that contributes to cellular immunity and inflammatory response in wide range of inflammatory pathologies. Although a large number of studies indicate the use of TACE inhibitors, which prevents processing of TNF-α as potential therapeutic drugs for the treatment of inflammatory diseases including rheumatoid arthritis, Crohn’s disease and cancer, very few studies indicate its use in ocular pathologies. It is still not clearly understood how the TACE-mediated shedding of cytokines and growth factors in various ocular tissues plays a critical role in the cytotoxic signals causing tissue dysfunction and damage leading to blindness. Regulation of TACE activity is likely to have wide implications for ocular immunology and inflammatory diseases. Specifically, since anti-TNF-α therapies have been used to prevent ocular inflammatory complications, the use of TACE inhibitors could be a novel therapeutic approach for ocular inflammatory diseases especially uveitis. PMID:20303413

  9. Role of Reactive Oxygen Species in Tumor Necrosis Factor-alpha Induced Endothelial Dysfunction

    PubMed Central

    Chen, Xiuping; Andresen1, Bradley T.; Hill, Michael; Zhang, Jing; Booth, Frank; Zhang, Cuihua

    2010-01-01

    Endothelial cell injury and dysfunction are the major triggers of pathophysiological processes leading to cardiovascular disease. Endothelial dysfunction (ED) has been implicated in atherosclerosis, hypertension, coronary artery disease, vascular complications of diabetes, chronic renal failure, insulin resistance and hypercholesterolemia. Although now recognized as a class of physiological second messengers, reactive oxygen species (ROS) are important mediators in cellular injury, specifically, as a factor in endothelial cell damage. Uncontrolled ROS production and/or decreased antioxidant activity results in a deleterious state referred to as ‘oxidative stress’. A candidate factor in causing ROS production in endothelial cells is tumor necrosis factor alpha (TNF-α), a pleiotropic inflammatory cytokine. TNF-α has been shown to both be secreted by endothelial cells and to induce intracellular ROS formation. These observations provide a potential mechanism by which TNF-α may activate and injure endothelial cells resulting in ED. In this review, we focus on the relationship between intracellular ROS formation and ED in endothelial cells or blood vessels exposed to TNF-α to provide insight into the role of this important cytokine in cardiovascular disease. PMID:20559453

  10. Receptor-interacting protein kinase 3-mediated programmed cell necrosis in rats subjected to focal cerebral ischemia-reperfusion injury

    PubMed Central

    DONG, YANRU; BAO, CUIFEN; YU, JINGWEI; LIU, XIA

    2016-01-01

    In the current study, the activation of tumor necrosis factor-α receptor 1 (TNFR1) and receptor-interacting protein kinase 3 (RIP3) were investigated following cerebral ischemia-reperfusion injury (CIRI). Healthy SD rats were randomly divided into 3 groups: Sham operation group, model group and inhibitor group. The model group and inhibitor group were further divided into 4 subgroups of 6, 12, 24 and 72 h following CIRI. Using right middle cerebral artery embolization, the CIRI model was generated. To confirm that the CIRI model was established, neurological scores, TTC staining and brain water content measurements were conducted. Immunohistochemistry and western blotting were conducted to investigate the expression of TNFR1 and RIP3 in the cerebral cortex. It was observed that nerve cell necrosis occurred following 6 h of CIRI. The appearance of necrotic cells was gradually increased with increasing CIRI duration. TNFR1 and RIP3 were positively expressed following 6 h of CIRI. With increasing durations of CIRI, the protein expression levels of TNFR1 and RIP3 were significantly increased. Pre-administration with Z-VAD-FMK (zVAD) significantly increased the protein level of RIP3, however, had no effect on the levels of TNFR1, and was accompanied by a reduction in necrosis. In conclusion, RIP3-mediated cell necrosis was enhanced by caspase blockade zVAD and the function of zVAD was independent of TNFR1 signaling following IR. PMID:27220678

  11. Monocyte Tumor Necrosis Factor-α–Converting Enzyme Catalytic Activity and Substrate Shedding in Sepsis and Noninfectious Systemic Inflammation*

    PubMed Central

    O’Callaghan, David J. P.; O’Dea, Kieran P.; Scott, Alasdair J.; Takata, Masao

    2015-01-01

    Objectives: To determine the effect of severe sepsis on monocyte tumor necrosis factor-α–converting enzyme baseline and inducible activity profiles. Design: Observational clinical study. Setting: Mixed surgical/medical teaching hospital ICU. Patients: Sixteen patients with severe sepsis, 15 healthy volunteers, and eight critically ill patients with noninfectious systemic inflammatory response syndrome. Interventions: None. Measurements and Main Results: Monocyte expression of human leukocyte antigen-D-related peptide, sol-tumor necrosis factor production, tumor necrosis factor-α–converting enzyme expression and catalytic activity, tumor necrosis factor receptor 1 and 2 expression, and shedding at 48-hour intervals from day 0 to day 4, as well as p38-mitogen activated protein kinase expression. Compared with healthy volunteers, both sepsis and systemic inflammatory response syndrome patients’ monocytes expressed reduced levels of human leukocyte antigen-D-related peptide and released less sol-tumor necrosis factor on in vitro lipopolysaccharide stimulation, consistent with the term monocyte deactivation. However, patients with sepsis had substantially elevated levels of basal tumor necrosis factor-α–converting enzyme activity that were refractory to lipopolysaccharide stimulation and this was accompanied by similar changes in p38-mitogen activated protein kinase signaling. In patients with systemic inflammatory response syndrome, monocyte basal tumor necrosis factor-α–converting enzyme, and its induction by lipopolysaccharide, appeared similar to healthy controls. Changes in basal tumor necrosis factor-α–converting enzyme activity at day 0 for sepsis patients correlated with Acute Physiology and Chronic Health Evaluation II score and the attenuated tumor necrosis factor-α–converting enzyme response to lipopolysaccharide was associated with increased mortality. Similar changes in monocyte tumor necrosis factor-α–converting enzyme activity could

  12. Fraxetin inhibits the induction of anti-Fas IgM, tumor necrosis factor-alpha and interleukin-1beta-mediated apoptosis by Fas pathway inhibition in human osteoblastic cell line MG-63.

    PubMed

    Kuo, Po-Lin; Huang, Yu-Ting; Chang, Cheng-Hsiung; Chang, Jiunn-Kae

    2006-07-01

    The survival of osteoblast cells is one of the determinants of the development of osteoporosis in patients with inflamed synovium, such as in rheumatoid arthritis (RA). By means of alkaline phosphatase (ALP) activity and osteocalcin ELISA assay, we have shown that fraxetin exhibits a significant induction of differentiation in the human osteoblast-like cell line MG-63. In addition, we also assessed whether fraxetin affects inflammatory cytokine-mediated apoptosis in osteoblast cells. TNF-alpha or IL-1beta enhance apoptotic DNA fragmentation in anti-Fas IgM-treated MG-63 cells by increasing Fas receptor expression. However, TNF-alpha or IL-1beta treatment alone does not induce apoptosis. Treatment of MG-63 cells with fraxetin not only inhibited anti-Fas IgM-induced apoptosis, but also blocked the synergetic effect of anti-Fas IgM with TNF-alpha or IL-1beta on cell death. The apoptotic inhibition of fraxetin is associated with inhibition of TNF-alpha and IL-1beta-mediated Fas expression and enhancement of FLIP expression, resulting in a decrease of caspase-8 and caspase-3 activation. These results indicate a potential use of fraxetin in preventing osteoporosis by inhibiting inflammatory cytokine-mediated apoptosis in osteoblast cells. PMID:16714221

  13. Regulatory mechanisms underlying sepsis progression in patients with tumor necrosis factor-α genetic variations

    PubMed Central

    LIU, YANGZHOU; HAN, NING; LI, QINCHUAN; LI, ZENGCHUN

    2016-01-01

    The present study aimed to investigate the regulatory mechanisms underlying sepsis progression in patients with tumor necrosis factor (TNF)-α genetic variations. The GSE5760 expression profile data, which was downloaded from the Gene Expression Omnibus database, contained 30 wild-type (WT) and 28 mutation (MUT) samples. Differentially expressed genes (DEGs) between the two types of samples were identified using the Student's t-test, and the corresponding microRNAs (miRNAs) were screened using WebGestalt software. An integrated miRNA-DEG network was constructed using the Cytoscape software, based on the interactions between the DEGs, as identified using the Search Tool for the Retrieval of Interacting Genes/Proteins database, and the correlation between miRNAs and their target genes. Furthermore, Gene Ontology and pathway enrichment analyses were conducted for the DEGs using the Database for Annotation, Visualization and Integrated Discovery and the KEGG Orthology Based Annotation System, respectively. A total of 390 DEGS between the WT and MUT samples, along with 11 -associated miRNAs, were identified. The integrated miRNA-DEG network consisted of 38 DEGs and 11 miRNAs. Within this network, COPS2 was found to be associated with transcriptional functions, while FUS was found to be involved in mRNA metabolic processes. Other DEGs, including FBXW7 and CUL3, were enriched in the ubiquitin-mediated proteolysis pathway. In addition, miR-15 was predicted to target COPS2 and CUL3. The results of the present study suggested that COPS2, FUS, FBXW7 and CUL3 may be associated with sepsis in patients with TNF-α genetic variations. In the progression of sepsis, FBXW7 and CUL3 may participate in the ubiquitin-mediated proteolysis pathway, whereas COPS2 may regulate the phosphorylation and ubiquitination of the FUS protein. Furthermore, COPS2 and CUL3 may be novel targets of miR-15. PMID:27347057

  14. Attenuation of tumor necrosis factor-induced endothelial cell cytotoxicity and neutrophil chemiluminescence

    SciTech Connect

    Zheng, H.; Crowley, J.J.; Chan, J.C.; Hoffmann, H.; Hatherill, J.R.; Ishizaka, A.; Raffin, T.A. )

    1990-11-01

    Our laboratory has previously shown that the administration of tumor necrosis factor (TNF), a cytokine produced by activated mononuclear cells, to guinea pigs produces a syndrome similar to gram-negative sepsis or ARDS. Pentoxifylline (PTX), a methylxanthine, protects against TNF-induced and sepsis-induced acute lung injury in vivo. We now report on in vitro cellular studies of PMN-mediated cellular injury and its attenuation. We studied TNF-induced bovine pulmonary artery endothelial cell (EC) cytotoxicity both with and without PMN. A 51Cr release assay was used to measure EC damage. Further, we investigated PMN function in response to TNF by measuring chemiluminescence. Agents that attenuate EC damage and PMN activation were evaluated in the above assays. Results revealed that TNF causes EC injury (p less than 0.05) and PMN increase TNF-induced EC injury. Furthermore, PTX, aminophylline (AMPH), caffeine, and forskolin attenuate TNF-induced EC cytotoxicity only in the presence of PMN (p less than 0.05). Of interest, dibutyryl cAMP (DBcAMP) protects EC from TNF-induced injury both with and without PMN. Agents that may increase cAMP levels in PMN (PTX, DBcAMP, forskolin, isobutyl methylxanthine, and terbutaline) significantly attenuate TNF-induced PMN chemiluminescence (p less than 0.05). We conclude that TNF causes EC damage and PMN increase this damage. Furthermore, PTX, AMPH, caffeine, and forskolin can attenuate TNF-induced EC injury in the presence of PMN, whereas DBcAMP attenuates TNF-induced EC injury with and without PMN. In addition, agents that may increase intracellular cAMP levels in PMN can attenuate TNF-induced PMN chemiluminescence. Thus, these agents likely attenuate TNF-induced PMN-mediated EC injury through their inhibitory effects on PMN.

  15. Glucocorticoid-induced tumor necrosis factor receptor-related protein co-stimulation facilitates tumor regression by inducing IL-9-producing helper T cells.

    PubMed

    Kim, Il-Kyu; Kim, Byung-Seok; Koh, Choong-Hyun; Seok, Jae-Won; Park, Jun-Seok; Shin, Kwang-Soo; Bae, Eun-Ah; Lee, Ga-Eun; Jeon, Hyewon; Cho, Jaebeom; Jung, Yujin; Han, Daehee; Kwon, Byoung S; Lee, Ho-Young; Chung, Yeonseok; Kang, Chang-Yuil

    2015-09-01

    T cell stimulation via glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) elicits antitumor activity in various tumor models; however, the underlying mechanism of action remains unclear. Here we demonstrate a crucial role for interleukin (IL)-9 in antitumor immunity generated by the GITR agonistic antibody DTA-1. IL-4 receptor knockout (Il4ra(-/-)) mice, which have reduced expression of IL-9, were resistant to tumor growth inhibition by DTA-1. Notably, neutralization of IL-9 considerably impaired tumor rejection induced by DTA-1. In particular, DTA-1-induced IL-9 promoted tumor-specific cytotoxic T lymphocyte (CTL) responses by enhancing the function of dendritic cells in vivo. Furthermore, GITR signaling enhanced the differentiation of IL-9-producing CD4(+) T-helper (TH9) cells in a TNFR-associated factor 6 (TRAF6)- and NF-κB-dependent manner and inhibited the generation of induced regulatory T cells in vitro. Our findings demonstrate that GITR co-stimulation mediates antitumor immunity by promoting TH9 cell differentiation and enhancing CTL responses and thus provide a mechanism of action for GITR agonist-mediated cancer immunotherapies. PMID:26280119

  16. Tumor necrosis factor receptor associated factor 6 (TRAF6) regulation of development, function, and homeostasis of the immune system

    PubMed Central

    Walsh, Matthew C.; Lee, JangEun; Choi, Yongwon

    2016-01-01

    Summary Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) is an adaptor protein that mediates a wide array of protein-protein interactions via its TRAF domain and a RING finger domain that possesses non-conventional E3 ubiquitin ligase activity. First identified nearly two decades ago as a mediator of IL-1 receptor (IL-1R)-mediated activation of NFκB, TRAF6 has since been identified as an actor downstream of multiple receptor families with immunoregulatory functions, including members of the TNFR superfamily, the toll-like receptor (TLR) family, tumor growth factor-β receptors (TGFβR), and T cell receptor (TCR). In addition to NFκB, TRAF6 may also direct activation of mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), and interferon regulatory factor (IRF) pathways. In the context of the immune system, TRAF6-mediated signals have proven critical for the development, homeostasis, and/or activation of B cells, T cells, and myeloid cells, including macrophages, dendritic cells, and osteoclasts, as well as for organogenesis of thymic and secondary lymphoid tissues. In multiple cellular contexts, TRAF6 function is essential not only for proper activation of the immune system, but also for maintaining immune tolerance, and more recent works have begun to identify mechanisms of contextual specificity for TRAF6, involving both regulatory protein interactions, and messenger RNA regulation by microRNAs. PMID:26085208

  17. Peroxisome Proliferator-activated Receptor α Positively Regulates Complement C3 Expression but Inhibits Tumor Necrosis Factor α-mediated Activation of C3 Gene in Mammalian Hepatic-derived Cells*

    PubMed Central

    Mogilenko, Denis A.; Kudriavtsev, Igor V.; Shavva, Vladimir S.; Dizhe, Ella B.; Vilenskaya, Ekaterina G.; Efremov, Alexander M.; Perevozchikov, Andrej P.; Orlov, Sergey V.

    2013-01-01

    Complement C3 is a pivotal component of three cascades of complement activation. The liver is the main source of C3 in circulation and expression and secretion of C3 by hepatocytes is increased during acute inflammation. However, the mechanism of the regulation of the C3 gene in hepatocytes is not well elucidated. We showed that the C3 gene is the direct target for peroxisome proliferator-activated receptor α (PPARα) in human hepatoma HepG2 cells and mouse liver. Using PPARα siRNA and synthetic PPARα agonist WY-14643 and antagonist MK886 we showed that activation of PPARα results in up-regulation of C3 gene expression and protein secretion by HepG2 cells. The PPAR response element (PPRE), which is able to bind PPARα in vitro and in vivo, was found in the human C3 promoter. PPRE is conserved between human and mouse, and WY-14643 stimulates mouse C3 expression in the liver. TNFα increases C3 gene via NF-κB and, to a lesser extent, MEK1/2 signaling pathways, whereas TNFα-mediated stimulation of C3 protein secretion depends on activation of MEK1/2, p38, and JNK in HepG2 cells. Activation of PPARα abolishes TNFα-mediated up-regulation of C3 gene expression and protein secretion due to interference with NF-κB via PPRE-dependent mechanism in HepG2 cells. TNFα decreases PPARα protein content via NF-κB and MEK1/2 signaling pathways and inhibits PPARα binding with the human C3 promoter in HepG2 cells. These results suggest novel mechanism controlling C3 expression in hepatocytes during acute phase inflammation and demonstrate a crosstalk between PPARα and TNFα in the regulation of complement system. PMID:23168409

  18. The Mitogenic Potential of Heparin-Binding Epidermal Growth Factor in the Human Endometrium Is Mediated by the Epidermal Growth Factor Receptor and Is Modulated by Tumor Necrosis Factor-α

    PubMed Central

    CHOBOTOVA, KATYA; MUCHMORE, MARY-ELIZABETH; CARVER, JANET; YOO, HYUNG-J; MANEK, SANJIV; GULLICK, WILLIAM J.; BARLOW, DAVID H.; MARDON, HELEN J.

    2006-01-01

    Heparin-binding epidermal growth factor (HB-EGF), a member of the epidermal growth factor (EGF) family, is implicated in a variety of biological processes, including reproduction. Previous studies describe increased levels of HB-EGF in the human endometrium during the midsecretory stage of the menstrual cycle, suggesting a function for HB-EGF in implantation of the human blastocyst. Here we have investigated the expression and function of the soluble and transmembrane forms of HB-EGF in the human endometrium. We show that the expression of the transmembrane form of HB-EGF in the human endometrium is modulated according to the stage of the menstrual cycle. We present data demonstrating that both the soluble and transmembrane forms of HB-EGF induce DNA synthesis in human endometrial stromal cells. Furthermore, TNFα has a cooperative effect on HB-EGF, EGF, TGFα, and betacellulin-induced DNA synthesis in stromal cells, suggesting roles for the EGF family and TNFα in regeneration and maturation of human endometrium. Induction of DNA synthesis by HB-EGF and its modulation by TNFα in endometrial stromal cells are mediated by the EGF receptor and not the HB-EGF receptor ErbB4. Our data suggest key functions for HB-EGF, TNFα, and the EGF receptor in endometrial maturation, via autocrine/paracrine and juxtacrine pathways, in preparation for embryo implantation. PMID:12466384

  19. Strain-induced Differentiation of Fetal Type II Epithelial Cells Is Mediated via the Integrin α6β1-ADAM17/Tumor Necrosis Factor-α-converting Enzyme (TACE) Signaling Pathway*

    PubMed Central

    Wang, Yulian; Huang, Zheping; Nayak, Pritha S.; Matthews, Benjamin D.; Warburton, David; Shi, Wei; Sanchez-Esteban, Juan

    2013-01-01

    Mechanical forces are critical for normal fetal lung development. However, the mechanisms regulating this process are not well-characterized. We hypothesized that strain-induced release of HB-EGF and TGF-α is mediated via integrin-ADAM17/TACE interactions. Employing an in vitro system to simulate mechanical forces in fetal lung development, we showed that mechanical strain of fetal epithelial cells actives TACE, releases HB-EGF and TGF-α, and promotes differentiation. In contrast, in samples incubated with the TACE inhibitor IC-3 or in cells isolated from TACE knock-out mice, mechanical strain did not release ligands or promote cell differentiation, which were both rescued after transfection of ADAM17. Cell adhesion assay and co-immunoprecipitation experiments in wild-type and TACE knock-out cells using several TACE constructs demonstrated not only that integrins α6 and β1 bind to TACE via the disintegrin domain but also that mechanical strain enhances these interactions. Furthermore, force applied to these integrin receptors by magnetic beads activated TACE and shed HB-EGF and TGF-α. The contribution of integrins α6 and β1 to differentiation of fetal epithelial cells by strain was demonstrated by blocking their binding site with specific antibodies and by culturing the cells on membranes coated with anti-integrin α6 and β1 antibodies. In conclusion, mechanical strain releases HB-EGF and TGF-α and promotes fetal type II cell differentiation via α6β1 integrin-ADAM17/TACE signaling pathway. These investigations provide novel mechanistic information on how mechanical forces promote fetal lung development and specifically differentiation of epithelial cells. This information could be also relevant to other tissues exposed to mechanical forces. PMID:23888051

  20. Release of tumor necrosis factor alpha by human peritoneal macrophages in response to toxic shock syndrome toxin-1.

    PubMed

    Buyalos, R P; Rutanen, E M; Tsui, E; Halme, J

    1991-08-01

    We examined the release in vitro of tumor necrosis factor-alpha (TNF-alpha) by peritoneal macrophages and peripheral blood monocytes following incubation with toxic shock syndrome toxin-1 (TSST-1). We obtained peritoneal macrophages from 22 women at laparoscopy and peripheral blood monocytes from four healthy women during both the midfollicular and midluteal phases of the menstrual cycle. The samples were incubated for 24 hours at 37 C with 10(-2)-10(4) ng/mL of TSST-1 or 10(4) ng/mL of bacterial endotoxin. Tumor necrosis factor-alpha activity was determined with a bioassay using an actinomycin D-sensitized WEHI-164 murine fibrosarcoma cell line. Twenty-four-hour incubation with TSST-1 resulted in a dose-dependent release of TNF-alpha by both peritoneal macrophages (maximal response 554 +/- 97 U of activity) and peripheral blood monocytes (maximal response 478 +/- 81 U of activity). We observed enhanced TNF-alpha release by peritoneal macrophages from women with endometriosis, compared with those without endometriosis, at a concentration of 10(4) ng/mL of TSST-1 (704 +/- 134 versus 354 +/- 103 U of activity; P less than .05). These data support the theory that the metabolic and physiologic derangements of perimenstrual toxic shock syndrome may be partially mediated by TNF-alpha released by peritoneal macrophages as a result of exposure to TSST-1. PMID:2067760

  1. Regulation of human lung fibroblast glycosaminoglycan production by recombinant interferons, tumor necrosis factor, and lymphotoxin.

    PubMed Central

    Elias, J A; Krol, R C; Freundlich, B; Sampson, P M

    1988-01-01

    Mononuclear cells may be important regulators of fibroblast glycosaminoglycan (GAG) biosynthesis. However, the soluble factors mediating these effects, the importance of intercytokine interactions in this regulation and the mechanisms of these alterations remain poorly understood. We analyzed the effect of recombinant (r) tumor necrosis factor (TNF), lymphotoxin (LT), and gamma, alpha, and beta 1 interferons (INF-gamma, -alpha and -beta 1), alone and in combination, on GAG production by normal human lung fibroblasts. rTNF, rLT, and rINF-gamma each stimulated fibroblast GAG production. In addition, rIFN-gamma synergized with rTNF and rLT to further augment GAG biosynthesis. In contrast, IFN-alpha A, -alpha D, and -beta 1 neither stimulated fibroblast GAG production nor interacted with rTNF or rLT to regulate GAG biosynthesis. The effects of the stimulatory cytokines and cytokine combinations were dose dependent and were abrogated by the respective monoclonal antibodies. In addition, these cytokines did not cause an alteration in the distribution of GAG between the fibroblast cell layer and supernatant. However, the stimulation was at least partially specific for particular GAG moieties with hyaluronic acid biosynthesis being markedly augmented without a comparable increase in the production of sulfated GAGs. Fibroblast prostaglandin production did not mediate these alterations since indomethacin did not decrease the stimulatory effects of the cytokines. In contrast, protein and mRNA synthesis appeared to play a role since the stimulatory effects of the cytokines were abrogated by cyclohexamide and actinomycin D, respectively. In addition, the cytokines and cytokine combinations increased cellular hyaluronate synthetase activity in proportion to their effects on hyaluronic acid suggesting that induction of this enzyme(s) is important in this stimulatory process. These studies demonstrate that IFN-gamma, TNF, and LT are important stimulators of fibroblast GAG

  2. Key facts and hot spots on tumor necrosis factor receptor-associated periodic syndrome.

    PubMed

    Rigante, Donato; Lopalco, Giuseppe; Vitale, Antonio; Lucherini, Orso Maria; De Clemente, Caterina; Caso, Francesco; Emmi, Giacomo; Costa, Luisa; Silvestri, Elena; Andreozzi, Laura; Iannone, Florenzo; Galeazzi, Mauro; Cantarini, Luca

    2014-09-01

    Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), formerly known as familial Hibernian fever, is the most common autosomal dominant autoinflammatory disease, resulting from mutations in the TNFRSF1A gene, encoding the 55-kD tumor necrosis factor receptor. The pathophysiologic mechanism of TRAPS remains ambiguous and only partially explained. The onset age of the syndrome is variable and the clinical scenery is characterized by recurrent episodes of high-grade fever that typically lasts 1-3 weeks, associated with migrating myalgia, pseudocellulitis, diffuse abdominal pain, appendicitis-like findings, ocular inflammatory signs, and risk of long-term amyloidosis. Fever episodes are responsive to high-dose corticosteroids, but different classes of drugs have been reported to be ineffective. The use of etanercept is unable to control systemic inflammation, while interleukin-1 blockade has been shown as effective in the control of disease activity in many patients reported so far. PMID:24935411

  3. Tumor necrosis factor alpha gene expression in human monocytic THP-1 cells exposed to beryllium.

    PubMed

    Galbraith, G M; Pandey, J P; Schmidt, M G; Arnaud, P; Goust, J M

    1996-01-01

    Chronic beryllium disease, which results from occupational exposure to particulate beryllium, is characterized by the development of lung granulomas and progressive pulmonary fibrosis. Increased production of proinflammatory cytokines (e.g., tumor necrosis factor alpha and interleukin-1 beta) by pulmonary alveolar macrophages occurs in many chronic fibrotic lung diseases and is thought to contribute to the disease process. The purpose of the present study was to investigate cytokine production by human monocytic cells exposed to beryllium in vitro. The results indicated that such cells respond to beryllium ions in the presence of fluoride by accumulation of messenger ribonucleic acid for both tumor necrosis factor alpha and interleukin-1 beta. These findings suggest that inhaled beryllium may directly stimulate the production of these cytokines by alveolar macrophages in vitro. PMID:8629860

  4. Advances in the diagnosis and treatment of tumor necrosis factor receptor-associated periodic syndrome.

    PubMed

    Aguado-Gil, L; Irarrazaval-Armendáriz, I; Pretel-Irazabal, M

    2013-09-01

    Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a rare autosomal dominant disease included in the group of autoinflammatory syndromes. It is characterized by recurrent episodes of fever and inflammation in different regions of the body. The main clinical manifestations are myalgia, migratory erythematous rash, periorbital edema, and abdominal pain. The diagnosis is reached using gene analysis and prognosis depends on the appearance of amyloidosis secondary to the recurrent episodes of inflammation. Tumor necrosis factor inhibitors and corticosteroids are the most widely used treatments. In recent years, significant advances have been made in the diagnosis and treatment of TRAPS, thanks to a better understanding of its pathogenesis. Dermatologists must be aware that the skin manifestations of TRAPS are particularly important, as they are often diagnostic. PMID:23891452

  5. Structural biology of tumor necrosis factor demonstrated for undergraduates instruction by computer simulation.

    PubMed

    Roy, Urmi

    2016-05-01

    This work presents a three-dimensional (3D) modeling exercise for undergraduate students in chemistry and health sciences disciplines, focusing on a protein-group linked to immune system regulation. Specifically, the exercise involves molecular modeling and structural analysis of tumor necrosis factor (TNF) proteins, both wild type and mutant. The structure of the tumor necrosis factor type 1 receptor (TNF-R1) is also briefly explored. TNF and TNF-R1 play major roles in maintaining human immune-system homeostasis. Upon binding with TNFR-1, the TNF can activate the nuclear factor kappa B (NF-κB), eventually resulting in apoptosis or cell death. These essential features of the clinically relevant TNF family is explored within the frame work of a readily adaptable tutorial. © 2015 by The International Union of Biochemistry and Molecular Biology, 44:246-255, 2016. PMID:26638199

  6. Gene transfer into experimental brain tumors mediated by adenovirus, herpes simplex virus, and retrovirus vectors.

    PubMed

    Boviatsis, E J; Chase, M; Wei, M X; Tamiya, T; Hurford, R K; Kowall, N W; Tepper, R I; Breakefield, X O; Chiocca, E A

    1994-02-01

    Three vectors derived from retrovirus, herpes simplex virus type 1 (HSV), and adenovirus were compared in cultured rat 9L gliosarcoma cells for gene transfer efficiency and in a 9L rat brain tumor model for histologic pattern and distribution of foreign gene delivery, as well as for associated tumor necrosis and inflammation. At a multiplicity of infection of 1, in vitro transfer of a foreign gene (lacZ from Escherichia coli) into cells was more efficient with either the replication-defective retrovirus vector or the replication-conditional thymidine kinase (TK)-deficient HSV vector than with the replication-defective adenovirus vector. In vivo, stereotactic injections of each vector into rat brain tumors revealed three main histopathologic findings: (i) retrovirus and HSV vector-mediated gene transfer was relatively selective for cells within the tumor, whereas adenovirus vector-mediated gene transfer occurred into several types of endogenous neural cells, as well as into cells within the tumor; (ii) gene transfer to multiple infiltrating tumor deposits without apparent gene transfer to intervening normal brain tissue occurred uniquely in one animal inoculated with the HSV vector, and (iii) extensive necrosis and selective inflammation in the tumor were evident with the HSV vector, whereas there was minimal evidence of tumor necrosis and inflammation with either the retrovirus or adenovirus vectors. PMID:8186298

  7. Tumor necrosis factor-induced contraction of cultured rat mesangial cells: interaction with angiotensin II.

    PubMed

    Medina, J; Baud, L; Garcia Escribano, C; Gila, J A; Rodriguez Puyol, D; Rodriguez Puyol, M

    1993-08-01

    The role of tumor necrosis factor alpha in the regulation of renal function, particularly glomerular filtration rate, has not been completely defined. This study was designed to assess the intrinsic role of this cytokine on glomerular filtration rate by analyzing its short-term effect on the degree of contraction in cultured rat mesangial cells, not only directly but also in the presence of angiotensin II. Contraction was evaluated both morphologically--by measuring planar cell surface area of cultured rat mesangial cells and glomerular cross-sectional area of isolated rat glomeruli--and biochemically--by analyzing myosin light-chain phosphorylation in cells. Tumor necrosis factor alpha significantly decreased planar cell surface area in a dose-dependent and time-dependent manner, an effect completely abolished by preincubation of the cells with platelet-activating factor receptor antagonists BN 52021 and alprazolam. This effect was also observed in the presence of angiotensin II, whether tumor necrosis factor alpha was added before or after angiotensin II, increasing the reduction in planar cell surface area induced by angiotensin II in both cases. Changes in planar cell surface area were evident not only when the absolute values of this parameter were considered but also when the percentage of contracted cells (cells with a planar cell surface area reduction > 10%) was analyzed. Tumor necrosis factor alpha also induced a significant reduction of glomerular cross-sectional area in isolated rat glomeruli. The results of the morphologic studies were supported by myosin light-chain phosphorylation experiments.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8340701

  8. Gemella morbillorum Bacteremia after Anti-Tumor Necrosis Factor Alpha as Acne Inversa Therapy

    PubMed Central

    Vossen, Matthias G.; Gattringer, Klaus B.; Khalifeh, Neda; Koreny, Maria; Spertini, Verena; Mallouhi, Ammar; Willeit, Markus; Volc-Platzer, Beatrix; Asboth, Friederike; Graninger, Wolfgang; Thalhammer, Florian

    2012-01-01

    We present a case of fever, brain abscesses, and Gemella morbillorum bacteremia after anti-tumor necrosis factor alpha (TNF-α) therapy in a 21-year-old acne inversa patient currently taking long-term dapsone. To the best of our knowledge, this is the first report describing such a case. During antimicrobial therapy, the patient developed systemic varicella infection with severe thrombocytopenia. PMID:22189120

  9. Comparative Biochemical and Functional Analysis of Viral and Human Secreted Tumor Necrosis Factor (TNF) Decoy Receptors.

    PubMed

    Pontejo, Sergio M; Alejo, Ali; Alcami, Antonio

    2015-06-26

    The blockade of tumor necrosis factor (TNF) by etanercept, a soluble version of the human TNF receptor 2 (hTNFR2), is a well established strategy to inhibit adverse TNF-mediated inflammatory responses in the clinic. A similar strategy is employed by poxviruses, encoding four viral TNF decoy receptor homologues (vTNFRs) named cytokine response modifier B (CrmB), CrmC, CrmD, and CrmE. These vTNFRs are differentially expressed by poxviral species, suggesting distinct immunomodulatory properties. Whereas the human variola virus and mouse ectromelia virus encode one vTNFR, the broad host range cowpox virus encodes all vTNFRs. We report the first comprehensive study of the functional and binding properties of these four vTNFRs, providing an explanation for their expression profile among different poxviruses. In addition, the vTNFRs activities were compared with the hTNFR2 used in the clinic. Interestingly, CrmB from variola virus, the causative agent of smallpox, is the most potent TNFR of those tested here including hTNFR2. Furthermore, we demonstrate a new immunomodulatory activity of vTNFRs, showing that CrmB and CrmD also inhibit the activity of lymphotoxin β. Similarly, we report for the first time that the hTNFR2 blocks the biological activity of lymphotoxin β. The characterization of vTNFRs optimized during virus-host evolution to modulate the host immune response provides relevant information about their potential role in pathogenesis and may be used to improve anti-inflammatory therapies based on soluble decoy TNFRs. PMID:25940088

  10. Targeting Tumor Necrosis Factor-α with Adalimumab: Effects on Endothelial Activation and Monocyte Adhesion

    PubMed Central

    Oberoi, Raghav; Schuett, Jutta; Schuett, Harald; Koch, Ann-Kathrin; Luchtefeld, Maren

    2016-01-01

    Objective It is well known that atherosclerotic inflammatory vascular disease is critically driven by oxidized lipids and cytokines. In this regard, tumor necrosis factor (TNF)-α is known as a crucial mediator of early pro-atherosclerotic events. Epidemiologic data suggest that blockade of TNF-α has beneficial effects on vascular outcomes in patients with rheumatoid arthritis, however, detailed mechanistic studies are still lacking. This study aims to elucidate effects of TNF-α blockade by adalimumab–which is approved for several inflammatory disorders–on endothelial activation and monocyte adhesion under pro-atherosclerotic conditions. Methods and Results Phorbol myristate acetate (PMA) differentiated THP-1 macrophages were stimulated with oxidized low density lipoprotein and subsequent analysis of this conditioned media (oxLDL CM) revealed a strong release of TNF-α. The TNF-α rich supernatant led to activation of human umbilical vein endothelial cells (HUVEC) as shown by enhanced expression of major adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin which was suppressed by the TNF-α inhibitor adalimumab. Accordingly, adalimumab effectively prevented THP-1 monocyte adhesion to endothelial cells under static as well as under flow conditions. Furthermore, adalimumab suppressed endothelial leakage as shown by Evan's blue diffusion across a confluent endothelial monolayer. Of note, after intraperitoneal injection we detected abundant deposition of fluorophore-labelled adalimumab in atherosclerotic plaques of hypercholesterolemic mice. Conclusion Our results show that adalimumab prevents major inflammatory effects of TNF-α on endothelial activation, endothelial monocyte adhesion, endothelial leakage and therefore extends the therapeutic options of adalimumab to limit vascular inflammation. PMID:27467817

  11. Histamine receptor antagonists, cyclooxygenase blockade, and tumor necrosis factor during acute septic insult.

    PubMed

    Leeper-Woodford, S K; Carey, D; Byrne, K; Walsh, C; Fisher, B; Sugerman, H J; Fowler, A A

    1998-02-01

    Tumor necrosis factor (TNF) may be a major endogenous mediator of sepsis-induced acute organ injury. We proposed that treatment of septic pigs with the combined agents ibuprofen, a cyclooxygenase inhibitor, and histamine receptor antagonists, cimetidine (H2 antagonist) and diphenhydramine (H1 antagonist) would result in lower circulating levels of TNF and decreased parameters of sepsis-induced injury in these animals. To test this, plasma TNF activity, cardiac index, systemic and pulmonary arterial pressures, arterial PO2 and bronchoalveolar lavage protein content were monitored for 300 min in four groups of anesthetized pigs: saline-infused control pigs (n = 4); pigs infused for 60 min with Pseudomonas aeruginosa (5 x 10(8) organisms/mL, .3 mL/20 kg/min) (n = 5) and pigs infused for 60 min with P. aeruginosa plus ibuprofen (12.5 mg/kg) alone (n = 4) or ibuprofen plus cimetidine (150 mg) and diphenhydramine (30 mg/kg) at 0 and 120 min (CID, n = 4). Within 60 min, pigs infused with P. aeruginosa exhibited increased plasma TNF activity (>8-fold increase in ng/mL TNF; L929 cytolysis assay) and showed alterations in all hemodynamic and pulmonary parameters. Ibuprofen or CID administration in the septic pigs decreased peak TNF activity by 4.6 and 10.2 ng/mL, respectively, and CID treatment was correlated with better attenuation of certain sepsis-induced alterations. These results show that CID treatment attenuates sepsis-induced injury and that this is correlated with reduced plasma TNF activity in a porcine model of sepsis-induced acute organ injury. PMID:9488252

  12. Pharmacologic reduction in tumor necrosis factor activity of pulmonary alveolar macrophages.

    PubMed

    Leeper-Woodford, S K; Fisher, B J; Sugerman, H J; Fowler, A A

    1993-02-01

    Tumor necrosis factor-alpha (TNF), an inflammatory cytokine released by macrophages, may be a mediator of lung injury during septicemia. We previously reported that the cyclooxygenase inhibitor ibuprofen and histamine receptor antagonists cimetidine (H2 antagonist) and diphenhydramine (H1 antagonist) attenuate lung injury and reduce circulating TNF surges during porcine sepsis. Since pulmonary alveolar macrophages (PAM) may participate in early sepsis by producing TNF, we hypothesized that the TNF activity of PAM is reduced by ibuprofen, cimetidine, and diphenhydramine. To test this, we examined changes in PAM-derived TNF bioactivity and cell viability of freshly isolated porcine PAM during exposure to bacterial endotoxin (LPS), ibuprofen, cimetidine, and diphenhydramine. The TNF activity (% L929 cytotoxicity of PAM conditioned medium) was elevated in LPS-stimulated PAM cultures (15 to 25% increase at 1 to 6 h and 40 to 43% increase at 6 to 48 h, compared with non-LPS-stimulated cultures), and ibuprofen (150 micrograms/ml) added with LPS decreased the TNF activity for 24 h (20 to 28% reduction at 1 to 24 h). Ibuprofen added 1 h after LPS was less effective in reducing the PAM-derived TNF activity (20 to 22% reduction at 2 to 6 h). Cimetidine (112 micrograms/ml) reduced the TNF activity of LPS-stimulated PAM cultures during the first 4 h of LPS exposure (15 to 24% decrease at 1 to 4 h). Diphenhydramine (150 micrograms/ml) attenuated the PAM-derived TNF activity but also decreased viability of PAM, indicating a toxic effect of this agent on PAM.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8093999

  13. Trypanosoma cruzi Infection in Tumor Necrosis Factor Receptor p55-Deficient Mice

    PubMed Central

    Castaños-Velez, Esmeralda; Maerlan, Stephanie; Osorio, Lyda M.; Åberg, Frederik; Biberfeld, Peter; Örn, Anders; Rottenberg, Martín E.

    1998-01-01

    Tumor necrosis factor receptor p55 (TNFRp55) mediates host resistance to several pathogens by allowing microbicidal activities of phagocytes. In the studies reported here, TNFRp55−/− mice infected with the intracellular parasite Trypanosoma cruzi showed clearly higher parasitemia and cumulative mortality than wild-type (WT) controls did. However, gamma interferon (IFN-γ)-activated macrophages from TNFRp55−/− mice produced control levels of nitric oxide and killed the parasite efficiently in vitro. Trypanocidal mechanisms of nonphagocytic cells (myocardial fibroblasts) from both TNFRp55−/− and WT mice were also activated by IFN-γ in a dose-dependent way. However, IFN-γ-activated TNFRp55−/− nonphagocytes showed less effective killing of T. cruzi than WT control nonphagocytes, even when interleukin 1β (IL-1β) was added as a costimulator. In vivo, T. cruzi-infected TNFRp55−/− mice and WT mice released similar levels of NO and showed similar levels of IFN-γ mRNA and inducible nitric oxide synthase mRNA in their tissues. Instead, increased susceptibility to T. cruzi of TNFRp55−/− mice was associated with reduced levels of parasite-specific immunoglobulin G (IgG) (but not IgM) antibodies during infection, which is probably linked to abnormal B-cell differentiation in secondary lymphoid tissues of the mutant mice. Surprisingly, T. cruzi-infected TNFRp55−/− mice showed increased inflammatory and necrotic lesions in several tissues, especially in skeletal muscles, indicating that TNFRp55 plays an important role in controlling the inflammatory process. Accordingly, levels of Mn2+ superoxide dismutase mRNA, a TNF-induced enzyme which protects the cell from the toxic effects of superoxide, were lower in mutant than in WT infected mice. PMID:9596773

  14. Ultrasound-targeted antisense oligonucleotide attenuates ischemia/reperfusion-induced myocardial tumor necrosis factor-alpha.

    PubMed

    Erikson, John M; Freeman, Gregory L; Chandrasekar, Bysani

    2003-01-01

    Ultrasound contrast agents are now emerging as effective vehicles for delivering therapeutic agents to target tissues. In the present study, we used ultrasound-targeted, contrast-bound antisense oligonucleotides to inhibit the expression of tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine with negative inotropic effects. We compared the efficacy of left ventricular vs. intravenous administration and determined the optimal time for delivery. WKY rats were treated with perfluorocarbon-exposed sonicated dextrose albumin (PESDA) microspheres incubated with 100 microg of antisense oligonucleotide directed against TNF-alpha. Contrast was infused into either the superior vena cava or the left ventricular cavity along with simultaneous application of ultrasound. Twenty-four hours later, the animals underwent 15 min of ischemia and 2 h reperfusion. Control animals underwent sham operation only, ischemia/reperfusion only, or received PESDA only. A second group received treatment just prior to, or immediately after the onset of ischemia. At the end of the experimental period, hearts were removed and analyzed for TNF-alpha by northern and western blotting. While no TNF-alpha expression was detected in sham-operated animals, robust expression of TNF-alpha mRNA and protein was seen in controls treated with ultrasound and PESDA alone. In contrast, intravenous or left ventricular administration of antisense oligonucleotides significantly inhibited ischemia/reperfusion-induced TNF-alpha expression. Direct delivery into the left ventricular cavity was more effective than intravenous administration, and delivery just prior to ischemia was most effective in attenuating TNF-alpha expression. Furthermore, attenuation of TNF-alpha expression also significantly inhibited other post-ischemic inflammatory mediators including IL-1beta and intercellular adhesion molecule-1 (ICAM-1). Thus, ultrasound-targeted antisense oligonucleotides can effectively attenuate post

  15. Model-Based Radiation Dose Correction for Yttrium-90 Microsphere Treatment of Liver Tumors With Central Necrosis

    SciTech Connect

    Liu, Ching-Sheng; Lin, Ko-Han; Lee, Rheun-Chuan; Tseng, Hsiou-Shan; Wang, Ling-Wei; Huang, Pin-I; Chao, Liung-Sheau; Chang, Cheng-Yen; Yen, Sang-Hue; Tung, Chuan-Jong; Wang, Syh-Jen; Oliver Wong, Ching-yee

    2011-11-01

    Purpose: The objectives of this study were to model and calculate the absorbed fraction {phi} of energy emitted from yttrium-90 ({sup 90}Y) microsphere treatment of necrotic liver tumors. Methods and Materials: The tumor necrosis model was proposed for the calculation of {phi} over the spherical shell region. Two approaches, the semianalytic method and the probabilistic method, were adopted. In the former method, the range--energy relationship and the sampling of electron paths were applied to calculate the energy deposition within the target region, using the straight-ahead and continuous-slowing-down approximation (CSDA) method. In the latter method, the Monte Carlo PENELOPE code was used to verify results from the first method. Results: The fraction of energy, {phi}, absorbed from {sup 90}Y by 1-cm thickness of tumor shell from microsphere distribution by CSDA with complete beta spectrum was 0.832 {+-} 0.001 and 0.833 {+-} 0.001 for smaller (r{sub T} = 5 cm) and larger (r{sub T} = 10 cm) tumors (where r is the radii of the tumor [T] and necrosis [N]). The fraction absorbed depended mainly on the thickness of the tumor necrosis configuration, rather than on tumor necrosis size. The maximal absorbed fraction {phi} that occurred in tumors without central necrosis for each size of tumor was different: 0.950 {+-} 0.000, and 0.975 {+-} 0.000 for smaller (r{sub T} = 5 cm) and larger (r{sub T} = 10 cm) tumors, respectively (p < 0.0001). Conclusions: The tumor necrosis model was developed for dose calculation of {sup 90}Y microsphere treatment of hepatic tumors with central necrosis. With this model, important information is provided regarding the absorbed fraction applicable to clinical {sup 90}Y microsphere treatment.

  16. Does the Degree of Hepatocellular Carcinoma Tumor Necrosis following Transarterial Chemoembolization Impact Patient Survival?

    PubMed Central

    Haywood, Nathan; Gennaro, Kyle; Obert, John; Sauer, Paul F.; Redden, David T.; Zarzour, Jessica; Smith, J. Kevin; Bolus, David; Saddekni, Souheil; Aal, Ahmed Kamel Abdel; Gray, Stephen; White, Jared; Eckhoff, Devin E.; DuBay, Derek A.

    2016-01-01

    Purpose. The association between transarterial chemoembolization- (TACE-) induced HCC tumor necrosis measured by the modified Response Evaluation Criteria In Solid Tumors (mRECIST) and patient survival is poorly defined. We hypothesize that survival will be superior in HCC patients with increased TACE-induced tumor necrosis. Materials and Methods. TACE interventions were retrospectively reviewed. Tumor response was quantified via dichotomized (responders and nonresponders) and the four defined mRECIST categories. Results. Median survival following TACE was significantly greater in responders compared to nonresponders (20.8 months versus 14.9 months, p = 0.011). Survival outcomes also significantly varied among the four mRECIST categories (p = 0.0003): complete, 21.4 months; partial, 20.8; stable, 16.8; and progressive, 7.73. Only progressive disease demonstrated significantly worse survival when compared to complete response. Multivariable analysis showed that progressive disease, increasing total tumor diameter, and non-Child-Pugh class A were independent predictors of post-TACE mortality. Conclusions. Both dichotomized (responders and nonresponders) and the four defined mRECIST responses to TACE in patients with HCC were predictive of survival. The main driver of the survival analysis was poor survival in the progressive disease group. Surprisingly, there was small nonsignificant survival benefit between complete, partial, and stable disease groups. These findings may inform HCC treatment decisions following first TACE. PMID:26949394

  17. Purification and characterization of an inhibitor (soluble tumor necrosis factor receptor) for tumor necrosis factor and lymphotoxin obtained from the serum ultrafiltrates of human cancer patients

    SciTech Connect

    Gatanaga, Tetsuya; Whang, Chenduen; Cappuccini, F.; Lucci, J.A. III; Jeffes, E.W.B. ); Kohr, W. ); Lentz, R. ); Tomich, J. ); Yamamoto, R.S. ); Granger, G.A. Memorial Cancer Inst., Long Beach, CA )

    1990-11-01

    Serum ultrafiltrates (SUF) from human patients with different types of cancer contain a blocking factor (BF) that inhibits the cytolytic activity of human tumor necrosis factor {alpha} (TNF-{alpha}) in vitro. BF is a protein with a molecular mass of 28kDa on reducing sodium dodecyl sulfate/polyacrylamide gel electrophoresis (SDS/PAGE). The active material was purified to homogeneity by a combination of affinity chromatography, PAGE, and high-pressure liquid chromatography. Amino acid sequence analysis revealed that BF is derived from the membrane TNF receptor. Purified BF blocks the lytic activity of recombinant human and mouse TNF-{alpha} and recombinant human lymphotoxin activity of TNF-{alpha} and recombinant human lymphotoxin on murine L929 cells in vitro. However, BF inhibits the lytic activity of TNF-{alpha} more effectively than it does that of lymphotoxin. The BF also inhibits the necrotizing activity of recombinant human TNF-{alpha} when coinjected into established cutaneous Meth A tumors in BALB/c mice. The BF may have an important role in (i) the regulation and control of TNF-{alpha} and lymphotoxin activity in cancer patients, (ii) interaction between the tumor and the host antitumor mechanisms, and (iii) use of systemically administered TNF-{alpha} in clinical trials with human cancer patients.

  18. Tumor necrosis is associated with increased alphavbeta3 integrin expression and poor prognosis in nodular cutaneous melanomas

    PubMed Central

    Bachmann, Ingeborg M; Ladstein, Rita G; Straume, Oddbjørn; Naumov, George N; Akslen, Lars A

    2008-01-01

    Background Tumor necrosis and apoptotic activity are considered important in cancer progression, but these features have not been much studied in melanomas. Our hypothesis was that rapid growth in cutaneous melanomas of the vertical growth phase might lead to tissue hypoxia, alterations in apoptotic activity and tumor necrosis. We proposed that these tumor characteristics might be associated with changes in expression of cell adhesion proteins leading to increased invasive capacity and reduced patient survival. Methods A well characterized series of nodular melanoma (originally 202 cases) and other benign and malignant melanocytic tumors (109 cases) were examined for the presence of necrosis, apoptotic activity (TUNEL assay), immunohistochemical expression of hypoxia markers (HIF-1 α, CAIX, TNF-α, Apaf-1) and cell adhesion proteins (αvβ3 integrin, CD44/HCAM and osteopontin). We hypothesized that tumor hypoxia and necrosis might be associated with increased invasiveness in melanoma through alterations of tumor cell adhesion proteins. Results Necrosis was present in 29% of nodular melanomas and was associated with increased tumor thickness, tumor ulceration, vascular invasion, higher tumor proliferation and apoptotic index, increased expression of αvβ3 integrin and poor patient outcome by multivariate analysis. Tumor cell apoptosis did also correlate with reduced patient survival. Expression of TNF-α and Apaf-1 was significantly associated with tumor thickness, and osteopontin expression correlated with increased tumor cell proliferation (Ki-67). Conclusion Tumor necrosis and apoptotic activity are important features of melanoma progression and prognosis, at least partly through alterations in cell adhesion molecules such as increased αvβ3 integrin expression, revealing potentially important targets for new therapeutic approaches to be further explored. PMID:19061491

  19. Iron-independent induction of ferritin H chain by tumor necrosis factor.

    PubMed Central

    Miller, L L; Miller, S C; Torti, S V; Tsuji, Y; Torti, F M

    1991-01-01

    Iron increases the synthesis of the iron-storage protein, ferritin, largely by promoting translation of preexisting mRNAs for both the H and L ferritin isoforms (H, heavy, heart, acidic; L, light, liver, basic). We have recently cloned and sequenced a full-length cDNA to murine ferritin H and identified ferritin H as a gene induced by tumor necrosis factor alpha (TNF-alpha, cachectin). Using primary human myoblasts, we have now examined the relationship between TNF-alpha and iron in regulating ferritin. Four lines of evidence suggest that TNF-alpha regulates ferritin independently of iron. First, evaluation of mRNA showed that TNF-alpha increased ferritin H chain specifically, provoking no change in steady-state levels of ferritin L mRNA; iron, in contrast, increased the mRNA of both isoforms. Second, the increase in ferritin H protein synthesis observed during TNF-alpha treatment was dependent on an increase in ferritin H mRNA: actinomycin D blocked the TNF-alpha-induced changes in ferritin H but did not inhibit the translational induction of ferritin seen with iron treatment. Third, equal ferritin mRNA induction was observed in iron-loaded cells and in cells depleted of iron by a permeant chelator, 2,2'-dipyridyl. Fourth, ferritin H induction by TNF-alpha and iron was additive over the entire range of iron concentrations, even at TNF-alpha doses known to maximally stimulate ferritin H mRNA levels. Nonetheless, the role of iron in translational regulation of ferritin was retained in TNF-alpha-treated cells; effective biosynthesis of TNF-alpha-induced, H-subunit-predominant ferritin protein required iron and could be enhanced by treatment of the cells with additional iron or blocked by 2,2'-dipyridyl. Finally, we observed that the TNF-alpha-mediated increase in ferritin synthesis peaked at 8 hr and was followed by a decrease in both H and L isoferritin synthesis; the addition of iron, however, reversed the late-occurring depression in ferritin synthesis. This

  20. A Nonpolar Blueberry Fraction Blunts NADPH Oxidase Activation in Neuronal Cells Exposed to Tumor Necrosis Factor-α

    PubMed Central

    Gustafson, Sally J.; Dunlap, Kriya L.; McGill, Colin M.; Kuhn, Thomas B.

    2012-01-01

    Inflammation and oxidative stress are key to the progressive neuronal degeneration common to chronic pathologies, traumatic injuries, and aging processes in the CNS. The proinflammatory cytokine tumor necrosis factor-alpha (TNF-α) orchestrates cellular stress by stimulating the production and release of neurotoxic mediators including reactive oxygen species (ROS). NADPH oxidases (NOX), ubiquitously expressed in all cells, have recently emerged as pivotal ROS sources in aging and disease. We demonstrated the presence of potent NOX inhibitors in wild Alaska bog blueberries partitioning discretely into a nonpolar fraction with minimal antioxidant capacity and largely devoid of polyphenols. Incubation of SH-SY5Y human neuroblastoma cells with nonpolar blueberry fractions obstructed the coalescing of lipid rafts into large domains disrupting NOX assembly therein and abolishing ROS production characteristic for TNF-α exposure. These findings illuminate nutrition-derived lipid raft modulation as a novel therapeutic approach to blunt inflammatory and oxidative stress in the aging or diseased CNS. PMID:22530077

  1. Human dermal mast cells contain and release tumor necrosis factor alpha, which induces endothelial leukocyte adhesion molecule 1.

    PubMed Central

    Walsh, L J; Trinchieri, G; Waldorf, H A; Whitaker, D; Murphy, G F

    1991-01-01

    Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine that mediates endothelial leukocyte interactions by inducing expression of adhesion molecules. In this report, we demonstrate that human dermal mast cells contain sizeable stores of immunoreactive and biologically active TNF-alpha within granules, which can be released rapidly into the extracellular space upon degranulation. Among normal human dermal cells, mast cells are the predominant cell type that expresses both TNF-alpha protein and TNF-alpha mRNA. Moreover, induction of endothelial leukocyte adhesion molecule 1 expression is a direct consequence of release of mast cell-derived TNF-alpha. These findings establish a role for human mast cells as "gatekeepers" of the dermal microvasculature and indicate that mast cell products other than vasoactive amines influence endothelium in a proinflammatory fashion. Images PMID:1709737

  2. A Novel Small-molecule Tumor Necrosis Factor α Inhibitor Attenuates Inflammation in a Hepatitis Mouse Model*

    PubMed Central

    Ma, Li; Gong, Haiyan; Zhu, Haiyan; Ji, Qing; Su, Pei; Liu, Peng; Cao, Shannan; Yao, Jianfeng; Jiang, Linlin; Han, Mingzhe; Ma, Xiaotong; Xiong, Dongsheng; Luo, Hongbo R.; Wang, Fei; Zhou, Jiaxi; Xu, Yuanfu

    2014-01-01

    Overexpression of tumor necrosis factor α (TNFα) is a hallmark of many inflammatory diseases, including rheumatoid arthritis, inflammatory bowel disease, and septic shock and hepatitis, making it a potential therapeutic target for clinical interventions. To explore chemical inhibitors against TNFα activity, we applied computer-aided drug design combined with in vitro and cell-based assays and identified a lead chemical compound, (E)-4-(2-(4-chloro-3-nitrophenyl) (named as C87 thereafter), which directly binds to TNFα, potently inhibits TNFα-induced cytotoxicity (IC50 = 8.73 μm) and effectively blocks TNFα-triggered signaling activities. Furthermore, by using a murine acute hepatitis model, we showed that C87 attenuates TNFα-induced inflammation, thereby markedly reducing injuries to the liver and improving animal survival. Thus, our results lead to a novel and highly specific small-molecule TNFα inhibitor, which can be potentially used to treat TNFα-mediated inflammatory diseases. PMID:24634219

  3. Targeting of Tumor Necrosis Factor Receptor 1 to Low Density Plasma Membrane Domains in Human Endothelial Cells*

    PubMed Central

    D'Alessio, Alessio; Kluger, Martin S.; Li, Jie H.; Al-Lamki, Rafia; Bradley, John R.; Pober, Jordan S.

    2010-01-01

    TNFR1 (tumor necrosis factor receptor 1) localizes to caveolae of human endothelial-derived EA.hy926 cells. Transduced TNFR1 molecules lacking amino acid residues 229–244 (spanning the transmembrane/intercellular boundary) are expressed on the cell surface equivalently to full-length TNFR1 molecules but incompletely localize to caveolae. A peptide containing this sequence pulls down CAV-1 (caveolin-1) and TNFR1 from cell lysates but fails to do so following disruption of caveolae with methyl-β-cyclodextrin. We previously reported that methyl-β-cyclodextrin eliminates caveolae and blocks tumor necrosis factor (TNF)-induced internalization of TNFR1 but not TNF-induced activation of NF-κB in EA.hy926 cells. Both CAV-1 and FLOT-2 (flotillin-2), organizing proteins of caveolae and lipid rafts, respectively, associate with caveolae in EA.hy926 cells. Small interfering RNA-mediated knockdown of CAV-1 but not FLOT-2 strikingly reduces caveolae number. Both knockdowns reduce total TNFR1 protein expression, but neither prevents TNFR1 localization to low density membrane domains, TNF-induced internalization of TNFR1, or NF-κB activation by TNF. Both CAV-1 and FLOT-2 knockdowns reduce TNF-mediated activation of stress-activated protein kinase (SAPK). However, both knockdowns reduce expression of TRAF2 (TNF receptor-associated factor-2) protein, and small interfering RNA targeting of TRAF2 also selectively inhibits SAPK activation. We conclude that TNFR1 contains a membrane-proximal sequence that targets the receptor to caveolae/lipid rafts. Neither TNFR1 targeting to nor internalization from these low density membrane domains depends upon CAV-1 or FLOT-2. Furthermore, both NF-κB and SAPK activation appear independent of both TNFR1 localization to low density membrane domains and to TNF-induced receptor internalization. PMID:20511226

  4. Inhibition of Eyes Absent Homolog 4 expression induces malignant peripheral nerve sheath tumor necrosis.

    PubMed

    Miller, S J; Lan, Z D; Hardiman, A; Wu, J; Kordich, J J; Patmore, D M; Hegde, R S; Cripe, T P; Cancelas, J A; Collins, M H; Ratner, N

    2010-01-21

    Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas without effective therapeutics. Bioinformatics was used to identify potential therapeutic targets. Paired Box (PAX), Eyes Absent (EYA), Dachsund (DACH) and Sine Oculis (SIX) genes, which form a regulatory interactive network in Drosophila, were found to be dysregulated in human MPNST cell lines and solid tumors. We identified a decrease in DACH1 expression, and increases in the expressions of PAX6, EYA1, EYA2, EYA4, and SIX1-4 genes. Consistent with the observation that half of MPNSTs develop in neurofibromatosis type 1 (NF1) patients, subsequent to NF1 mutation, we found that exogenous expression of the NF1-GTPase activating protein-related domain normalized DACH1 expression. EYA4 mRNA was elevated more than 100-fold as estimated by quantitative real-time PCR in most MPNST cell lines. In vitro, suppression of EYA4 expression using short hairpin RNA reduced cell adhesion and migration and caused cellular necrosis without affecting cell proliferation or apoptotic cell death. MPNST cells expressing shEYA4 either failed to form tumors in nude mice or formed very small tumors, with extensive necrosis but similar levels of proliferation and apoptosis as control cells. Our findings identify a role of EYA4 and possibly interacting SIX and DACH proteins in MPNSTs and suggest the EYA4 pathway as a rational therapeutic target. PMID:19901965

  5. Impedance-Based Monitoring of Ongoing Cardiomyocyte Death Induced by Tumor Necrosis Factor-α

    PubMed Central

    Qiu, Yiling; Liao, Ronglih; Zhang, Xin

    2009-01-01

    Deregulated cardiomyocyte death is a critical risk factor in a variety of cardiovascular diseases. Although various assays have been developed to detect cell responses during cell death, the capability of monitoring cell detachment will enhance the understanding of death processes by providing instant information at its early phase. In this work, we developed an impedance-sensing assay for real-time monitoring of cardiomyocyte death induced by tumor necrosis factor-α based on recording the change in cardiomyocyte adhesion to extracellular matrix. Electrochemical impedance spectroscopy was employed in impedance data processing, followed by calibration with the electrical cell-substrate impedance-sensing technique. The adhesion profile of cardiomyocytes undergoing cell death processes was recorded as the time course of equivalent cell-substrate distance. The cell detachment was detected with our assay and proved related to cell death in the following experiments, indicating its advantage against the conventional assays, such as Trypan blue exclusion. An optimal concentration of tumor necrosis factor-α (20 ng/mL) was determined to induce cardiomyocyte apoptosis rather than the combinative cell death of necrosis and apoptosis by comparing the concentration-related adhesion profiles. The cardiomyocytes undergoing apoptosis experienced an increase of cell-substrate distance from 59.1 to 89.2 nm within 24 h. The early change of cell adhesion was proved related to cardiomyocyte apoptosis in the following TUNEL test at t = 24 h, which suggested the possibility of early and noninvasive detection of cardiomyocyte apoptosis. PMID:19254558

  6. Targeting the proinflammatory cytokine tumor necrosis factor-α to alleviate cardiopulmonary bypass-induced lung injury (review).

    PubMed

    Gao, Mingxin; Xie, Baodong; Gu, Chengxiong; Li, Haitao; Zhang, Fan; Yu, Yang

    2015-04-01

    Pulmonary dysfunction is one of the most frequent complications associated with cardiopulmonary bypass (CPB). Multiple factors, including the contact of blood with the artificial surface of the CPB circuit, ischemia‑reperfusion and lung ventilator arrest elicit inflammatory reactions, consequently resulting in CPB‑induced lung injury. The proinflammatory cytokine tumor necrosis factor‑α (TNF‑α) has been demonstrated to have a critical role in mediating CPB‑induced pulmonary inflammation. The present review evaluated previous studies and summarized the effects of CPB on TNF‑α level in the serum and lung tissue of patients and animal models of CPB, the underlying mechanism of TNF‑α‑mediated lung injury and the therapeutic strategies for the inhibition of TNF‑α activity and production to attenuate CPB‑induced lung injury. TNF‑α level in the serum and lung tissue is significantly increased during and following CPB. TNF‑α mediates CPB‑induced lung damage by directly inducing apoptosis in alveolar epithelial cells and lung endothelial cells and by indirectly modulating the function of immune cells, including monocytes and macrophages. A functional neutralizing antibody to TNF‑α can reduce pulmonary TNF‑α production and attenuate CPB‑induced lung injury in a rabbit model of CPB. Inhibition of TNF‑α function and production using a neutralizing antibody to TNF‑α appears to be a promising therapeutic strategy to alleviate CPB‑induced lung injury. PMID:25483004

  7. Multiple roles of tumor necrosis factor-alpha in fracture healing.

    PubMed

    Karnes, Jonathan M; Daffner, Scott D; Watkins, Colleen M

    2015-09-01

    This review presents a summary of basic science evidence examining the influence of tumor necrosis factor-alpha (TNF-α) on secondary fracture healing. Multiple studies suggest that TNF-α, in combination with the host reservoir of peri-fracture mesenchymal stem cells, is a main determinant in the success of bone healing. Disease states associated with poor bone healing commonly have inappropriate TNF-α responses, which likely contributes to the higher incidence of delayed and nonunions in these patient populations. Appreciation of TNF-α in fracture healing may lead to new therapies to augment recovery and reduce the incidence of complications. PMID:25959413

  8. Adipose Expression of Tumor Necrosis Factor-α: Direct Role in Obesity-Linked Insulin Resistance

    NASA Astrophysics Data System (ADS)

    Hotamisligil, Gokhan S.; Shargill, Narinder S.; Spiegelman, Bruce M.

    1993-01-01

    Tumor necrosis factor-α (TNF-α) has been shown to have certain catabolic effects on fat cells and whole animals. An induction of TNF-α messenger RNA expression was observed in adipose tissue from four different rodent models of obesity and diabetes. TNF-α protein was also elevated locally and systemically. Neutralization of TNF-α in obese fa/fa rats caused a significant increase in the peripheral uptake of glucose in response to insulin. These results indicate a role for TNF-α in obesity and particularly in the insulin resistance and diabetes that often accompany obesity.

  9. Effects of interferon-gamma and tumor necrosis factor-alpha on macrophage enzyme levels

    NASA Technical Reports Server (NTRS)

    Pierangeli, Silvia S.; Sonnenfeld, Gerald

    1989-01-01

    Murine peritoneal macrophages were treated with interferon-gamma (IFN-gamma) or tumor necrosis factor-alpha (TNF). Measurements of changes in acid phosphatase and beta-glucuronidase levels were made as an indication of activation by cytokine treatment. IFN-gamma or TNF-gamma treatment resulted in a significant increase in the activities of both enzymes measured in the cell lysates. This increase was observable after 6 h of incubation, but reached its maximum level after 24 h of incubation. The effect of the treatment of the cell with both cytokines together was additive. No synergistic effect of addition of both cytokines on the enzyme levels was observed.

  10. Coexistent tumor necrosis factor receptor-associated periodic fever syndrome and Ehlers-Danlos syndrome.

    PubMed

    Yao, Qingping; Zhou, Lan; Tomecki, Kenneth J

    2012-07-01

    A 32-year-old Caucasian woman had periodic fevers, skin disease, polyarthralgia and hypermobile joints that were consistent with tumor necrosis factor receptor-associated periodic fever syndrome confirmed with a finding of R92Q missense mutation of the TNFRSFA1 gene with Ehlers-Danlos hypermobility type syndrome. They are both autosomal dominant disorders, and their coexistence suggests that they could share some phenotypic features that may require special consideration in management. Conceivably, they could share common gene mutations although no such data are available. PMID:21785959

  11. Synthesis of tumor necrosis factor α for use as a mirror-image phage display target.

    PubMed

    Petersen, Mark E; Jacobsen, Michael T; Kay, Michael S

    2016-06-21

    Tumor Necrosis Factor alpha (TNFα) is an inflammatory cytokine that plays a central role in the pathogenesis of chronic inflammatory disease. Here we describe the chemical synthesis of l-TNFα along with the mirror-image d-protein for use as a phage display target. The synthetic strategy utilized native chemical ligation and desulfurization to unite three peptide segments, followed by oxidative folding to assemble the 52 kDa homotrimeric protein. This synthesis represents the foundational step for discovering an inhibitory d-peptide with the potential to improve current anti-TNFα therapeutic strategies. PMID:27211891

  12. Evaluation of antitumor effects following tumor necrosis factor-α gene delivery using nanobubbles and ultrasound.

    PubMed

    Horie, Sachiko; Watanabe, Yukiko; Ono, Masao; Mori, Shiro; Kodama, Tetsuya

    2011-11-01

    The antitumor effects of tumor necrosis factor (TNF-α) were evaluated following transfection of TNF-α plasmid DNA into solid mouse tumors using the nanobubbles (NBs) and ultrasound (US) gene delivery system. Murine breast carcinoma (EMT6) cells expressing luciferase (1 × 10(6) cells) were injected intradermally into the flanks of 6-7-week-old male SCID mice on day 0. Ten microliters of TNF-α (5 μg/μL) or TNF-α mock plasmid DNA (5 μg/μL) with/without NBs (15 μL) and saline was injected intratumorally in a total volume of 30 μL, and tumors were exposed to US (frequency, 1 MHz; intensity, 3.0 W/cm(2); duty cycle, 20%; number of pulses, 200; and exposure time, 60 s) on days 2, 4, 7, and 9. Changes in tumor size were measured with an in vivo bioluminescent imaging system and a mechanical caliper. Changes in tumor vessel area were quantified using contrast-enhanced US imaging with Sonazoid and a high frequency US imaging system (40 MHz) and immunohistochemistry (CD31). At the mRNA level, expression of TNF-α, caspase-3, and p53 were quantified using real-time quantitative RT-PCR. At the protein level, expression of caspase-3 and p53 were confirmed by immunohistochemistry. We show that repeated TNF-α gene delivery using NBs and US can lead to the local production of TNF-α. This results in antitumor effects, including activation of p53-dependent apoptosis, decrease in tumor vessel density, and suppression of tumor size. In this study, we showed the effectiveness of using NBs and US for TNF-α gene delivery into tumor cells. PMID:21824220

  13. [Viral transfer of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in gene therapy].

    PubMed

    Wędrowska, Ewelina; Wandtke, Tomasz; Dyczek, Andrzej; Woźniak, Joanna

    2015-01-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces carcinoma cell death through the extrinsic pathway of apoptosis. Preclinical trials of gene therapy have been conducted using viral transfer of the TRAIL transgene into prostate, bladder, breast, kidney, liver, non-small cell lung cancer and also glioblastoma cells. Experiments in vitro demonstrated the extensive apoptosis of target cells as well as frequent disease regression or remission. TRAIL transfer did not show any side effects, opposite to chemotherapy. Encouraging results of TRAIL-related gene therapy were observed in rheumatoid arthritis and type 1 diabetes. Adenoviral vectors (AdV) encoding TRAIL are the most promising tool in anti-tumor therapy. They have undergone numerous modifications by increasing transfection efficiency and transgene expression in target cells. However, only one clinical phase I trial has been performed. AdV encoding the TRAIL transgene caused local inflammation and apoptosis in patients with prostate cancer. PMID:27259213

  14. Phase I study of recombinant human tumor necrosis factor-alpha in patients with advanced malignancies.

    PubMed

    Bartsch, H H; Nagel, G A; Mull, R; Flener, R; Pfizenmaier, K

    1988-01-01

    A clinical phase I trial with recombinant human tumor necrosis factor-alpha (rTNF-alpha) was performed in 30 patients with advanced malignancies. The maximal tolerated dose (MTD) by 3 times weekly intramuscular (i.m.) application was 150 micrograms m-2. Main subjective toxicities including chills, fever, hypotension, fatigue, and anorexia were dose-related. In addition, transient changes in hematologic parameters and lipid metabolism were noted. Two out of 25 evaluated patients showed a minor tumor response after eight weeks of therapy. There was evidence for an improvement of in vivo immuneresponsiveness as revealed from positive delayed type hypersensitivity (DTH) skin tests of 3 out of 6 pretherapeutically anergic patients. We conclude from this phase I trial that rTNF-alpha can be safely administered at doses up to 150 micrograms m-2 i.m., 3 times weekly, without evidence of cumulative toxicity in long-term treatment. PMID:3267369

  15. Risk of open angle glaucoma due to tumor necrosis factor alpha gene polymorphisms

    PubMed Central

    Hamid, Mona Abdel; Moemen, Leqaa; Labib, Hany; Helmy, Hazem; Elsergany, Tarek

    2016-01-01

    Introduction Axonal degeneration and retinal ganglion cell apoptosis in glaucoma is associated with tumor necrosis factor alpha (TNF-α), which is an important pro-inflammatory cytokine. The aim of this study was to determine the association between the risk of open angle glaucoma (OAG) in the Egyptian population and tumor necrosis factor alpha (TNF-α) gene polymorphisms. Methods Sixty OAG patients and 26 healthy unrelated controls were used to analyze TNF-α polymorphism G-308A using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). Results the GG genotype was found at a higher frequency in the controls than in the patients, and the AA and GA genotypes were associated strongly with OAG. Conclusion In this study, we found that the TNF-α polymorphism G-308A was associated significantly with OAG in the Egyptian population. However, there is a need for population-based studies with large numbers of subjects. Also, long-term follow up is required to verify the association between TNF-α polymorphism G-308A and glaucoma susceptibility. PMID:27054008

  16. Polymer-conjugated inhibitors of tumor necrosis factor-α for local control of inflammation.

    PubMed

    Washburn, Newell R; Prata, Joseph E; Friedrich, Emily E; Ramadan, Mohamed H; Elder, Allison N; Sun, Liang Tso

    2013-01-01

    Burns, chronic wounds, osteoarthritis, and uveitis are examples of conditions characterized by local, intense inflammatory responses that can impede healing or even further tissue degradation. The most powerful anti-inflammatory drugs available are often administered systemically, but these carry significant side effects and are not compatible for patients that have underlying complications associated with their condition. Conjugation of monoclonal antibodies that neutralize pro-inflammatory cytokines to high molecular weight hydrophilic polymers has been shown to be an effective strategy for local control of inflammation. Lead formulations are based on antibody inhibitors of tumor necrosis factor-α conjugated to hyaluronic acid having molecular weight greater than 1 MDa. This review will discuss fundamental aspects of medical conditions that could be treated with these conjugates and design principles for preparing these cytokine-neutralizing polymer conjugates. Results demonstrating that infliximab, an approved inhibitor of tumor necrosis factor-α, can be incorporated into the conjugates using a broad range of water-soluble polymers are also presented, along with a prospectus for clinical translation. PMID:23903893

  17. A disaccharide that inhibits tumor necrosis factor alpha is formed from the extracellular matrix by the enzyme heparanase.

    PubMed Central

    Lider, O; Cahalon, L; Gilat, D; Hershkoviz, R; Siegel, D; Margalit, R; Shoseyov, O; Cohen, I R

    1995-01-01

    The activation of T cells by antigens or mitogens leads to the secretion of cytokines and enzymes that shape the inflammatory response. Among these molecular mediators of inflammation is a heparanase enzyme that degrades the heparan sulfate scaffold of the extracellular matrix (ECM). Activated T cells use heparanase to penetrate the ECM and gain access to the tissues. We now report that among the breakdown products of the ECM generated by heparanase is a trisulfated disaccharide that can inhibit delayed-type hypersensitivity (DTH) in mice. This inhibition of T-cell mediated inflammation in vivo was associated with an inhibitory effect of the disaccharide on the production of biologically active tumor necrosis factor alpha (TNF-alpha) by activated T cells in vitro; the trisulfated disaccharide did not affect T-cell viability or responsiveness generally. Both the in vivo and in vitro effects of the disaccharide manifested a bell-shaped dose-response curve. The inhibitory effects of the trisulfated disaccharide were lost if the sulfate groups were removed. Thus, the disaccharide, which may be a natural product of inflammation, can regulate the functional nature of the response by the T cell to activation. Such a feedback control mechanism could enable the T cell to assess the extent of tissue degradation and adjust its behavior accordingly. PMID:7761444

  18. Inhibitory effects of somatostatin on tumor necrosis factor-alpha-induced interleukin-6 secretion in human pancreatic periacinar myofibroblasts.

    PubMed

    Andoh, Akira; Hata, Kazunori; Shimada, Mitsue; Fujino, Sanae; Tasaki, Kazuhito; Bamba, Shigeki; Araki, Yoshio; Fujiyama, Yoshihide; Bamba, Tadao

    2002-07-01

    Pancreatic periacinar myofibroblasts are considered to be therapeutic targets for the suppression of acute pancreatitis. To elucidate the mechanisms mediating the therapeutic actions of somatostatin on acute pancreatitis, we investigated how somatostatin affects the tumor necrosis factor (TNF)-alpha-induced interleukin (IL)-6 and IL-8 secretion from pancreatic myofibroblasts. Cytokine secretion was determined by enzyme-linked immunosorbent assay (ELISA) and Northern blotting. Nuclear factor (NF)-kappaB DNA-binding activity was evaluated by electrophoretic mobility shift assay (EMSAs). The expression of somatostatin receptor (SSTR) mRNA was evaluated by reverse transcription-polymerase chain reaction (RT-PCR). Somatostatin dose-dependently inhibited the TNF-alpha-induced IL-6 secretion. In comparison, the effects on IL-8 secretion were modest. Northern blot analysis demonstrated that somatostatin decreased the TNF-alpha-induced IL-6 mRNA expression, and that this effect was completely blocked by the somatostatin antagonist cyclo-somatostatin. Furthermore, somatostatin suppressed TNF-alpha-induced NF-kappaB activation. These cells bear SSTR subtypes 1 and 2. Somatostatin down-regulated the TNF-alpha-induced IL-6 secretion in human pancreatic periacinar myofibroblasts. These findings suggest that some of the therapeutic actions of somatostatin on acute pancreatitis might be mediated by reducing local IL-6 secretion in the pancreas. PMID:12060857

  19. Savinin, a lignan from Pterocarpus santalinus inhibits tumor necrosis factor-alpha production and T cell proliferation.

    PubMed

    Cho, J Y; Park, J; Kim, P S; Yoo, E S; Baik, K U; Park, M H

    2001-02-01

    Two lignans were isolated from the heartwood of Pterocarpus santalinus by activity-guided fractionation and investigated for their biological properties and molecular mechanism of action. On the basis of their spectroscopic data, these compounds were identified as savinin (1) and calocedrin (2), dibenzyl butyrolactone-type lignan compounds having an alpha-arylidene gamma-lactone structure. These lignans significantly inhibited tumor necrosis factor (TNF)-a production in lipopolysaccharide (LPS)-stimulated RAW264.7 cells, and T cell proliferation elicited by concanavalin (Con A), without displaying cytotoxicity. The molecular inhibitory mechanism of compound 1 was confirmed to be mediated by the non-polar butyrolactone ring, according to a structure-relationship study with structurally related and unrelated compounds, such as arctigenin (a dibenzyl butyrolactone type lignan), eudesmin (a furofuran type lignan), isolariciresinol (a dibenzylbutane type lignan), and cynaropicrin (a sesquiterpene lactone). The results suggest that savinin may act as an active principle in the reported biological activities of P. santalinus, such as antiinflammatory effect, by mediation of the butyrolactone ring as a valuable pharmacophore. PMID:11217086

  20. Tumor Necrosis Factor Alpha and Interleukin 1β Up-Regulate Gastric Mucosal Fas Antigen Expression in Helicobacter pylori Infection

    PubMed Central

    Houghton, JeanMarie; Macera-Bloch, Lisa S.; Harrison, Lawrence; Kim, Kyung H.; Korah, Reju M.

    2000-01-01

    Fas-mediated gastric mucosal apoptosis is gaining attention as a cause of tissue damage due to Helicobacter pylori infection. We explored the effects of H. pylori directly, and the effects of the inflammatory environment established subsequent to H. pylori infection, on Fas-mediated apoptosis in a nontransformed gastric mucosal cell line (RGM-1). Exposure to H. pylori-activated peripheral blood mononuclear cells (PBMCs), but not H. pylori itself, induced Fas antigen (Fas Ag) expression, indicating a Fas-regulatory role for inflammatory cytokines in this system. Of various inflammatory cytokines tested, only interleukin 1β and tumor necrosis factor alpha induced Fas Ag expression, and removal of either of these from the conditioned medium abrogated the response. When exposed to Fas ligand, RGM-1 cells treated with PBMC-conditioned medium underwent massive and rapid cell death, interestingly, with a minimal effect on total cell numbers early on. Cell cycle analysis revealed a substantial increase in S phase cells among cells exposed to Fas ligand, suggesting an increase in their proliferative response. Taken together, these data indicate that the immune environment secondary to H. pylori infection plays a critical role in priming gastric mucosal cells to undergo apoptosis or to proliferate based upon their Fas Ag status. PMID:10678925

  1. Melatonin reversed tumor necrosis factor-alpha-inhibited osteogenesis of human mesenchymal stem cells by stabilizing SMAD1 protein.

    PubMed

    Lian, Chengjie; Wu, Zizhao; Gao, Bo; Peng, Yan; Liang, Anjing; Xu, Caixia; Liu, Lei; Qiu, Xianjian; Huang, Junjun; Zhou, Hang; Cai, Yifeng; Su, Peiqiang; Huang, Dongsheng

    2016-10-01

    Tumor necrosis factor-alpha (TNFα) plays a pivotal role in inflammation-related osteoporosis through the promotion of bone resorption and suppression of bone formation. Numerous drugs have been produced to treat osteoporosis by inhibiting bone resorption, but they offer few benefits to bone formation, which is what is needed by patients with severe bone loss. Melatonin, which can exert both anti-inflammatory and pro-osteogenic effects, shows promise in overcoming TNFα-inhibited osteogenesis and deserves further research. This study demonstrated that melatonin rescued TNFα-inhibited osteogenesis of human mesenchymal stem cells and that the interactions between SMURF1 and SMAD1 mediated the crosstalk between melatonin signaling and TNFα signaling. Additionally, melatonin treatment was found to downregulate TNFα-induced SMURF1 expression and then decrease SMURF1-mediated ubiquitination and degradation of SMAD1 protein, leading to steady bone morphogenetic protein-SMAD1 signaling activity and restoration of TNFα-impaired osteogenesis. Thus, melatonin has prospects for treating osteoporosis caused by inflammatory factors due to its multifaceted functions on regulation of bone formation, bone resorption, and inflammation. Further studies will focus on unveiling the specific mechanisms by which melatonin downregulates SMURF1 expression and confirming the clinical therapeutic value of melatonin in the prevention and therapy of bone loss associated with inflammation. PMID:27265199

  2. Roles of tumor necrosis factor receptor associated factor 3 (TRAF3) and TRAF5 in immune cell functions

    PubMed Central

    Hildebrand, Joanne M.; Yi, Zuoan; Buchta, Claire M.; Poovassery, Jayakumar; Stunz, Laura L.; Bishop, Gail A.

    2011-01-01

    Summary A large and diverse group of receptors utilizes the family of cytoplasmic signaling proteins known as tumor necrosis factor receptor (TNFR)-associated factors (TRAFs). In recent years, there has been a resurgence of interest and exploration of the roles played by TRAF3 and TRAF5 in cellular regulation, particularly in cells of the immune system, the cell types of focus in this review. This work has revealed that TRAF3 and TRAF5 can play diverse roles for different receptors even in the same cell type, as well as distinct roles in different cell types. Evidence indicates that TRAF3 and TRAF5 play important roles beyond the TNFR-superfamily (SF) and viral mimics of its members, mediating certain innate immune receptor and cytokine receptor signals, and most recently, signals delivered by the T-cell receptor (TCR) signaling complex. Additionally, much research has demonstrated the importance of TRAF3-mediated cellular regulation via its cytoplasmic interactions with additional signaling proteins. In particular, we discuss below evidence for the participation by TRAF3 in a number of the regulatory post-translational modifications involving ubiquitin that are important in various signaling pathways. PMID:22017431

  3. Epidermal Platelet-activating Factor Receptor Activation and Ultraviolet B Radiation Result in Synergistic Tumor Necrosis Factor-alpha Production

    PubMed Central

    Wolverton, Jay E.; Al-Hassani, Mohammed; Yao, Yongxue; Zhang, Qiwei; Travers, Jeffrey B.

    2010-01-01

    Ultraviolet B radiation (UVB) is a potent stimulator of epidermal cytokine production which has been implicated in photoaggravated dermatoses. In addition to cytokines such as tumor necrosis factor-α (TNF-α), UVB generates bioactive lipids including platelet-activating factor (PAF). Our previous studies have demonstrated that UVB-mediated production of keratinocyte TNF-α is in part due to PAF. The current studies use a human PAF-receptor (PAF-R) negative epithelial cell line transduced with PAF-Rs and PAF–R-deficient mice to demonstrate that activation of the epidermal PAF-R along with UVB irradiation results in a synergistic production of TNF-α. It should be noted that PAF-R effects are mimicked by the protein kinase C (PKC) agonist phorbol myristic acetate, and are inhibited by pharmacological antagonists of the PKC gamma isoenzyme. These studies suggest that concomitant PAF-R activation and UVB irradiation results in a synergistic production of the cytokine TNF-α which is mediated in part via PKC. These studies provide a novel potential mechanism for photosensitivity responses. PMID:19769579

  4. Nitric-oxide-induced necrosis and apoptosis in PC12 cells mediated by mitochondria.

    PubMed

    Bal-Price, A; Brown, G C

    2000-10-01

    Nitric oxide (NO) can trigger either necrotic or apoptotic cell death. We have used PC12 cells to investigate the extent to which NO-induced cell death is mediated by mitochondria. Addition of NO donors, 1 mM S-nitroso-N-acetyl-DL-penicillamine (SNAP) or 1 mM diethylenetriamine-NO adduct (NOC-18), to PC12 cells resulted in a steady-state level of 1-3 microM: NO, rapid and almost complete inhibition of cellular respiration (within 1 min), and a rapid decrease in mitochondrial membrane potential within the cells. A 24-h incubation of PC12 cells with NO donors (SNAP or NOC-18) or specific inhibitors of mitochondrial respiration (myxothiazol, rotenone, or azide), in the absence of glucose, caused total ATP depletion and resulted in 80-100% necrosis. The presence of glucose almost completely prevented the decrease in ATP level and the increase in necrosis induced by the NO donors or mitochondrial inhibitors, suggesting that the NO-induced necrosis in the absence of glucose was due to the inhibition of mitochondrial respiration and subsequent ATP depletion. However, in the presence of glucose, NO donors and mitochondrial inhibitors induced apoptosis of PC12 cells as determined by nuclear morphology. The presence of apoptotic cells was prevented completely by benzyloxycarbonyl-Val-Ala-fluoromethyl ketone (a nonspecific caspase inhibitor), indicating that apoptosis was mediated by caspase activation. Indeed, both NO donors and mitochondrial inhibitors in PC12 cells caused the activation of caspase-3- and caspase-3-processing-like proteases. Caspase-1 activity was not activated. Cyclosporin A (an inhibitor of the mitochondrial permeability transition pore) decreased the activity of caspase-3- and caspase-3-processing-like proteases after treatment with NO donors, but was not effective in the case of the mitochondrial inhibitors. The activation of caspases was accompanied by the release of cytochrome c from mitochondria into the cytosol, which was partially prevented by

  5. Semiquantitative Analysis Using Thallium-201 SPECT for Differential Diagnosis Between Tumor Recurrence and Radiation Necrosis After Gamma Knife Surgery for Malignant Brain Tumors

    SciTech Connect

    Matsunaga, Shigeo; Shuto, Takashi; Takase, Hajime; Ohtake, Makoto; Tomura, Nagatsuki; Tanaka, Takahiro; Sonoda, Masaki

    2013-01-01

    Purpose: Semiquantitative analysis of thallium-201 chloride single photon emission computed tomography ({sup 201}Tl SPECT) was evaluated for the discrimination between recurrent brain tumor and delayed radiation necrosis after gamma knife surgery (GKS) for metastatic brain tumors and high-grade gliomas. Methods and Materials: The medical records were reviewed of 75 patients, including 48 patients with metastatic brain tumor and 27 patients with high-grade glioma who underwent GKS in our institution, and had suspected tumor recurrence or radiation necrosis on follow-up neuroimaging and deteriorating clinical status after GKS. Analysis of {sup 201}Tl SPECT data used the early ratio (ER) and the delayed ratio (DR) calculated as tumor/normal average counts on the early and delayed images, and the retention index (RI) as the ratio of DR to ER. Results: A total of 107 tumors were analyzed with {sup 201}Tl SPECT. Nineteen lesions were removed surgically and histological diagnoses established, and the other lesions were evaluated with follow-up clinical and neuroimaging examinations after GKS. The final diagnosis was considered to be recurrent tumor in 65 lesions and radiation necrosis in 42 lesions. Semiquantitative analysis demonstrated significant differences in DR (P=.002) and RI (P<.0001), but not in ER (P=.372), between the tumor recurrence and radiation necrosis groups, and no significant differences between metastatic brain tumors and high-grade gliomas in all indices (P=.926 for ER, P=.263 for DR, and P=.826 for RI). Receiver operating characteristics analysis indicated that RI was the most informative index with the optimum threshold of 0.775, which provided 82.8% sensitivity, 83.7% specificity, and 82.8% accuracy. Conclusions: Semiquantitative analysis of {sup 201}Tl SPECT provides useful information for the differentiation between tumor recurrence and radiation necrosis in metastatic brain tumors and high-grade gliomas after GKS, and the RI may be the most

  6. TUMOR NECROSIS FACTOR-α INCREASES BDNF EXPRESSION IN TRIGEMINAL GANGLION NEURONS IN AN ACTIVITY-DEPENDENT MANNER

    PubMed Central

    Bałkowiec-Iskra, Ewa; Vermehren-Schmaedick, Anke; Balkowiec, Agnieszka

    2011-01-01

    Many chronic trigeminal pain conditions, such as migraine or temporo-mandibular disorders, are associated with inflammation within peripheral endings of trigeminal ganglion (TG) sensory neurons. A critical role in mechanisms of neuroinflammation is attributed to proinflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α (TNFα) that also contribute to mechanisms of persistent neuropathic pain resulting from nerve injury. However, the mechanisms of cytokine-mediated synaptic plasticity and nociceptor sensitization are not completely understood. In the present study, we examined the effects of TNFα on neuronal expression of brain-derived neurotrophic factor (BDNF), whose role in synaptic plasticity and sensitization of nociceptive pathways is well documented. We show that 4- and 24-hr treatment with TNFα increases BDNF mRNA and protein, respectively, in neuron-enriched dissociated cultures of rat TG. TNFα increases the phosphorylated form of the cyclic adenosine monophosphate-responsive element binding protein (CREB), a transcription factor involved in regulation of BDNF expression in neurons, and activates transcription of BDNF exon IV (former exon III) and, to a lesser extent, exon VI (former exon IV), but not exon I. TNFα-mediated increase in BDNF expression was accompanied by increase in calcitonin gene-related peptide (CGRP), which is consistent with previously published studies, and indicates that both peptides are similarly regulated in TG neurons by inflammatory mediators. The effect of TNFα on BDNF expression is dependent on sodium influx through TTX-sensitive channels and on p38-mitogen-activated protein kinase. Moreover, electrical stimulation and forskolin, known to increase intracellular cAMP, potentiate the TNFα-mediated upregulation of BDNF expression. This study provides new evidence for a direct action of proinflammatory cytokines on TG primary sensory neurons, and reveals a mechanism through which TNFα stimulates de novo

  7. Use of the tumor necrosis factor-blockers for Crohn's disease

    PubMed Central

    Thomson, Alan BR; Gupta, Milli; Freeman, Hugh J

    2012-01-01

    The use of anti-tumor necrosis factor-α therapy for inflammatory bowel disease represents the most important advance in the care of these patients since the publication of the National Co-operative Crohn’s disease study thirty years ago. The recommendations of numerous consensus groups worldwide are now supported by a wealth of clinical trials and several meta-analyses. In general, it is suggested that tumor necrosis factor-α blockers (TNFBs) are indicated (1) for persons with moderately-severe Crohn’s disease or ulcerative colitis (UC) who have failed two or more causes of glucocorticosteroids and an acceptably long cause (8 wk to 12 wk) of an immune modulator such as azathioprine or methotrexate; (2) non-responsive perianal disease; and (3) severe UC not responding to a 3-d to 5-d course of steroids. Once TNFBs have been introduced and the patient is responsive, therapy given by the IV and SC rate must be continued. It remains open to definitive evidence if concomitant immune modulators are required with TNFB maintenance therapy, and when or if TNFB may be weaned and discontinued. The supportive evidence from a single study on the role of early versus later introduction of TNFB in the course of a patient’s illness needs to be confirmed. The risk/benefit profile of TNFB appears to be acceptable as long as the patient is immunized and tested for tuberculosis and viral hepatitis before the initiation of TNFB, and as long as the long-term adverse effects on the development of lymphoma and other tumors do not prone to be problematic. Because the rates of benefits to TNFB are modest from a population perspective and the cost of therapy is very high, the ultimate application of use of TNFBs will likely be established by cost/benefit studies. PMID:23002356

  8. Upregulated RIP3 Expression Potentiates MLKL Phosphorylation-Mediated Programmed Necrosis in Toxic Epidermal Necrolysis.

    PubMed

    Kim, Sue Kyung; Kim, Woo-Jung; Yoon, Jung-Ho; Ji, Jae-Hoon; Morgan, Michael J; Cho, Hyeseong; Kim, You Chan; Kim, You-Sun

    2015-08-01

    Toxic epidermal necrolysis (TEN) is a severe adverse drug reaction involving extensive keratinocyte death in the epidermis. Histologically, the skin from TEN patients exhibits separation at the dermo-epidermal junction and accompanying necrosis of epidermal keratinocytes. Receptor-interacting protein kinase-3 (RIP3 or RIPK3) is an essential part of the cellular machinery that executes "programmed", or "regulated", necrosis and has a key role in spontaneous cell death and inflammation in keratinocytes under certain conditions. Here we show that RIP3 expression is highly upregulated in skin sections from TEN patients and may therefore contribute to the pathological damage in TEN through activation of programmed necrotic cell death. The expression level of mixed lineage kinase domain-like protein (MLKL), a key downstream component of RIP3, was not significantly different in skin lesions of TEN. However, elevated MLKL phosphorylation was observed in the skin from TEN patients, indicating the presence of RIP3-dependent programmed necrosis. Importantly, in an in vitro model of TEN, dabrafenib, an inhibitor of RIP3, prevented RIP3-mediated MLKL phosphorylation and decreased cell death. Results from this study suggest that the high expression of RIP3 in keratinocytes from TEN patients potentiates MLKL phosphorylation/activation and necrotic cell death. Thus, RIP3 represents a potential target for treatment of TEN. PMID:25748555

  9. [Systemic versus local therapy with recombinant tumor necrosis factor-alpha (r-TNF-alpha) in patients with advanced tumors].

    PubMed

    Bartsch, H H; Pfizenmaier, K; Schröder, M; Nagel, G A

    1989-06-01

    44 patients with different advanced malignant tumors were treated with recombinant Tumor-necrosis factor alpha (rTNF-alpha) in two Phase-I trials. 30 patients received rTNF-alpha 3 x/week intramuscular in doses between 25-300 mcg. 14 patients were treated intra/peritumoral with rTNF-alpha in the same dose range. The maximal tolerated dose (MTD) was 150 mcg/m2 for both ways of application. The duration of therapy was 1-26 weeks for systemic application and 2-20 weeks for local treatment. 25 patients treated systemically were evaluable for response. In 2 patients a minor response (MR) and in 9 patients stable disease was observed. 5/14 patients receiving rTNF-alpha locally showed a significant tumor regression (3 PR, 2 MR). Main side effects were dose dependent fever, chills, anorexia and nausea. In doses greater than 50mcg/m2 a decrease of blood pressure according to WHO III was noted. Hematologic toxicity included a transient decrease of leucocytes and platelets without indicating a cumulative hematologic toxicity. There were no further organ toxicities. The experience from both phase-I trials indicate a definite antitumoral activity of rTNF-alpha suggesting that locoregional treatment might be superior to systemic application. The side effects observed might be a limitation for larger clinical trials. PMID:2668836

  10. Suppression of tumor cell proliferation by quinine via the inhibition of the tumor necrosis factor receptor‑associated factor 6‑AKT interaction.

    PubMed

    Liu, Wenjuan; Qi, Yonghao; Liu, Lingyu; Tang, Yu; Wei, Jing; Zhou, Lijun

    2016-09-01

    Protein kinase B (AKT), is a pivotal component of pathways associated with cell survival, metabolism, invasion and metastasis. AKT mediates anti‑apoptotic and proliferative signaling in response to essential cytokines. Tumor necrosis factor receptor‑associated factor (TRAF)6, an E3 ubiquitin ligase, has been shown to ubiquitylate, as well as activate AKT. The present study used computational methods to determine the relevant amino acid residues at the binding site of TRAF6 and selected small molecules, which may bind to TRAF6. An ex vivo assay was performed to determine their antitumor activities and the possible mechanism of action. Quinine, a natural alkaloid that is well‑known for its therapeutic treatment of malaria, exhibited a distinct antiproliferative and pro‑apoptotic effect in HeLa and A549 tumor cell lines via the inhibition of the antiapoptotic protein, B‑cell lymphoma (BCL)‑2, and activation of the pro‑apoptotic factor, BCL‑2‑associated X protein. Quinine inhibited the lipopolysaccharide (LPS)‑induced activation of AKT by inhibiting its phosphorylation at Thr‑308 and Ser‑473, and reversing LPS‑induced proliferation. These results suggested that the inhibition of AKT activation via targeting of TRAF6 with quinine may be a viable anticancer therapeutic approach and a successful example of the alternative use of the original therapeutic properties of this well‑known natural product. PMID:27430155

  11. Selective cytotoxicity of transformed cells but not normal cells by a sialoglycopeptide growth regulator in the presence of tumor necrosis factor

    NASA Technical Reports Server (NTRS)

    Woods, K. M.; Fattaey, H.; Johnson, T. C.; Chapes, S. K.; Spooner, B. S. (Principal Investigator)

    1994-01-01

    The tumor necrosis factor-alpha (TNF)-resistant, SV40-transformed, murine fibroblast cell lines, F5b and F5m, became sensitive to TNF-mediated cytolysis after treatment with a biologically active 18 kDa peptide fragment (SGP) derived from a 66-kDa parental cell surface sialoglycoprotein. Neither TNF nor the SGP alone exhibited cytotoxicity to the two SV40-transformed cell lines. However, Balb/c 3T3 cells, incubated with SGP alone or with SGP and TNF, were not killed. Therefore, SGP can selectively sensitize cells for TNF alpha-mediated cytotoxicity. This selective sensitization may be due to the previously documented ability of the SGP to selectively mediate cell cycle arrest.

  12. Aminoguanidine and curcumin attenuated tumor necrosis factor (TNF)-α-induced oxidative stress, colitis and hepatotoxicity in mice.

    PubMed

    Mouzaoui, Souad; Rahim, Ibtissem; Djerdjouri, Bahia

    2012-01-01

    The up regulation of gut mucosal cytokines such as tumor necrosis factor (TNF)-α and oxidative stress have been related to inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn's disease (CD). This study investigated an immune-mediated model of colitis. TNF-α injected intraperitonally to mice induced a dose-dependent recruitment of neutrophils into abdominal mesentery. The leukocytes influx induced by TNF-α (10 μg kg(-1) body weight) increased by 3 fold liver and colon damage scores. TNF-α-colitis was characterized by hemorrhagic edemas and crypt abscesses massively infiltrated by inflammatory cells, namely neutrophils. Moreover, TNF-α-toxicity resulted in liver steatosis and foci of necrosis infiltrated by Kupffer cells and neutrophils in parenchyma and around the centrilobular veins. The involvement of oxidative stress was evaluated using aminoguanidine (AG) as selective inhibitor of inducible NO synthase (iNOS) and curcumin (Cur), the polyphenolic antioxidant of turmeric (Curcuma longa L.). TNF-α-toxicity led to significant increase in myeloperoxidase (MPO, an index of neutrophils infiltration), nitrites (stable nitric oxide metabolites) and malondialdehyde (MDA, a marker of lipid peroxides) levels and cell apoptosis in liver and colon. AG and Cur treatments significantly attenuated the hallmarks of oxidative stress, neutrophils influx and ROS-related cellular and histological damages, in TNF-α-treated mice. Taken together, our results provide insights into the role of phagocytes-derived oxidants in TNF-α-colitis in mice. Cur and AG, by inhibiting neutrophils priming and iNOsynthase could be effective against oxidative bowel damages induced in IBD by imbalanced gut immune response. PMID:22036766

  13. Tumor necrosis factor antagonists in the treatment of multicentric reticulohistiocytosis: Current clinical evidence.

    PubMed

    Zhao, Hongjun; Wu, Chunmei; Wu, Mengyun; Zhou, Yaou; Zhu, Honglin; Li, Yisha; You, Yunhui; Luo, Hui; Wang, Lijing; Zuo, Xiaoxia

    2016-07-01

    Multicentric reticulohistiocytosis (MRH) is a rare and debilitating systemic disorder characterized by cutaneous nodules and destructive polyarthritis. Due to its unknown etiology, the treatment of MRH varies with different rates of success, which causes treatment options to be rather independent and empirical. In the present study, a case of a 48‑year‑old woman with a 12‑month history of polyarthralgia and skin nodules was reported. Biopsy samples, which were obtained from her skin eruption exhibited dermal infiltration with histiocytes and multinucleated giant cells. Immunohistochemical staining indicated positivity for CD68. The patient was diagnosed with MRH and treated with a combination therapy of infliximab, prednisolone and methotrexate. Her symptoms improved markedly within 2 weeks. Following the results of this case study, a systematic review of 17 cases of MRH treated with tumor necrosis factor (TNF) antagonists was performed, and the efficacy of anti‑TNF treatment in MRH was analyzed. PMID:27175854

  14. Progress with anti-tumor necrosis factor therapeutics for the treatment of inflammatory bowel disease.

    PubMed

    Fernandes, Carlos; Allocca, Mariangela; Danese, Silvio; Fiorino, Gionata

    2015-01-01

    Anti-tumor necrosis factor (TNF) therapy is a valid, effective and increasingly used option in inflammatory bowel disease management. Nevertheless, further knowledge and therapeutic indications regarding these drugs are still evolving. Anti-TNF therapy may be essential to achieve recently proposed end points, namely mucosal healing, prevention of bowel damage and prevention of patient's disability. Anti-TNF drugs are also suggested to be more effective in early disease, particularly in early Crohn's disease. Moreover, its efficacy for prevention of postoperative recurrence in Crohn's disease is still debated. Costs and adverse effects, the relevance of drug monitoring and the possibility of anti-TNF therapy withdrawal in selected patients are still debated issues. This review aimed to describe and discuss the most relevant data about the progress with anti-TNF therapy for the management of inflammatory bowel disease. PMID:25713992

  15. Tumor necrosis factor-α impairs oligodendroglial differentiation through a mitochondria-dependent process

    PubMed Central

    Bonora, M; De Marchi, E; Patergnani, S; Suski, J M; Celsi, F; Bononi, A; Giorgi, C; Marchi, S; Rimessi, A; Duszyński, J; Pozzan, T; Wieckowski, M R; Pinton, P

    2014-01-01

    Mitochondrial defects, affecting parameters such as mitochondrial number and shape, levels of respiratory chain complex components and markers of oxidative stress, have been associated with the appearance and progression of multiple sclerosis. Nevertheless, mitochondrial physiology has never been monitored during oligodendrocyte progenitor cell (OPC) differentiation, especially in OPCs challenged with proinflammatory cytokines. Here, we show that tumor necrosis factor alpha (TNF-α) inhibits OPC differentiation, accompanied by altered mitochondrial calcium uptake, mitochondrial membrane potential, and respiratory complex I activity as well as increased reactive oxygen species production. Treatment with a mitochondrial uncoupler (FCCP) to mimic mitochondrial impairment also causes cells to accumulate at the progenitor stage. Interestingly, AMP-activated protein kinase (AMPK) levels increase during TNF-α exposure and inhibit OPC differentiation. Overall, our data indicate that TNF-α induces metabolic changes, driven by mitochondrial impairment and AMPK activation, leading to the inhibition of OPC differentiation. PMID:24658399

  16. Tumor necrosis factor antagonists in the treatment of multicentric reticulohistiocytosis: Current clinical evidence

    PubMed Central

    ZHAO, HONGJUN; WU, CHUNMEI; WU, MENGYUN; ZHOU, YAOU; ZHU, HONGLIN; LI, YISHA; YOU, YUNHUI; LUO, HUI; WANG, LIJING; ZUO, XIAOXIA

    2016-01-01

    Multicentric reticulohistiocytosis (MRH) is a rare and debilitating systemic disorder characterized by cutaneous nodules and destructive polyarthritis. Due to its unknown etiology, the treatment of MRH varies with different rates of success, which causes treatment options to be rather independent and empirical. In the present study, a case of a 48-year-old woman with a 12-month history of polyarthralgia and skin nodules was reported. Biopsy samples, which were obtained from her skin eruption exhibited dermal infiltration with histiocytes and multinucleated giant cells. Immunohistochemical staining indicated positivity for CD68. The patient was diagnosed with MRH and treated with a combination therapy of infliximab, prednisolone and methotrexate. Her symptoms improved markedly within 2 weeks. Following the results of this case study, a systematic review of 17 cases of MRH treated with tumor necrosis factor (TNF) antagonists was performed, and the efficacy of anti-TNF treatment in MRH was analyzed. PMID:27175854

  17. SLE - Complex cytokine effects in a complex autoimmune disease: tumor necrosis factor in systemic lupus erythematosus

    PubMed Central

    Aringer, Martin; Smolen, Josef S

    2003-01-01

    Tumor necrosis factor (TNF) is a proinflammatory cytokine and a B-cell growth factor. It has numerous possible effects on T lymphocytes and dendritic cells, and it influences apoptosis. These differential effects may in part explain why patients under TNF-blocker therapy can develop autoantibodies to nuclear antigens, and may shed some light on the finding that low TNF fosters autoimmune disease in some mouse strains. On the contrary, TNF is increased in the blood and in the inflamed kidneys of systemic lupus erythematosus patients. Several studies in lupus-prone mice other than the F1 generation of New Zealand Black mice crossed with New Zealand White mice suggest that TNF is highly proinflammatory in the efferent limb and is potentially detrimental in lupus organ disease. Therefore, TNF blockade probably constitutes an efficacious therapeutic option. PMID:12823847

  18. Alopecia secondary to anti-tumor necrosis factor-alpha therapy.

    PubMed

    Ribeiro, Lara Beatriz Prata; Rego, Juliana Carlos Gonçalves; Estrada, Bruna Duque; Bastos, Paula Raso; Piñeiro Maceira, Juan Manuel; Sodré, Celso Tavares

    2015-01-01

    Biologic drugs represent a substantial progress in the treatment of chronic inflammatory immunologic diseases. However, its crescent use has revealed seldom reported or unknown adverse reactions, mainly associated with anti-tumor necrosis factor (anti-TNF). Psoriasiform cutaneous reactions and few cases of alopecia can occur in some patients while taking these drugs. Two cases of alopecia were reported after anti-TNF therapy. Both also developed psoriasiform lesions on the body. This is the second report about a new entity described as 'anti-TNF therapy-related alopecia', which combines clinical and histopathological features of both alopecia areata and psoriatic alopecia. The recognition of these effects by specialists is essential for the proper management and guidance of these patients. PMID:25830994

  19. Fatigue mechanisms in patients with cancer: effects of tumor necrosis factor and exercise on skeletal muscle

    NASA Technical Reports Server (NTRS)

    St Pierre, B. A.; Kasper, C. E.; Lindsey, A. M.

    1992-01-01

    Fatigue is a common adverse effect of cancer and its therapy. However, the specific mechanisms underlying cancer fatigue are unclear. One physiologic mechanism may involve changes in skeletal muscle protein stores or metabolite concentration. A reduction in skeletal muscle protein stores may result from endogenous tumor necrosis factor (TNF) or from TNF administered as antineoplastic therapy. This muscle wasting would require patients to exert an unusually high amount of effort to generate adequate contractile force during exercise performance or during extended periods of sitting or standing. This additional effort could result in the onset of fatigue. Additionally, cancer fatigue may develop or become exacerbated during exercise as a consequence of changes in the concentration of skeletal muscle metabolites. These biochemical alterations may interfere with force that is produced by the muscle contractile proteins. These physiologic changes may play a role in the decision to include exercise in the rehabilitation plans of patients with cancer. They also may affect ideas about fatigue.

  20. Regulatory roles of tumor necrosis factor alpha-induced proteins (TNFAIPs) 3 and 9 in arthritis.

    PubMed

    Matsumoto, Isao; Inoue, Asuka; Takai, Chinatsu; Umeda, Naoto; Tanaka, Yuki; Kurashima, Yuko; Sumida, Takayuki

    2014-07-01

    Tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) have proved to be important in rheumatoid arthritis (RA) because the outcome of RA has greatly improved with the recent availability of biologics targeting them. It is well accepted that these cytokines are involved in the activation of the nuclear factor-κB (NF-κB) signaling pathway, but our understanding of the dependency of these pro-inflammatory cytokines and the link between them in RA is currently limited. Recently, we and others proved the importance of TNFα-induced protein (TNFAIP), due to the spontaneous development of arthritis in deficient animals that are dependent on IL-6. To date, nine TNFAIPs have been identified, and TNFAIP3 and TNFAIP9 were found to be clearly associated with mouse and human arthritis. In this review, we compare and discuss recent TNFAIP topics, especially focusing on TNFAIP3 and TNFAIP9 in autoimmune arthritis in mice and humans. PMID:24704577

  1. Unusual location of tuberculosis in the course of tumor necrosis factor α inhibitor therapy

    PubMed Central

    Brzezicki, Jan; Rymko, Marcin; Jeka, Sławomir

    2015-01-01

    Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis complex mycobacteria. Extrapulmonary tuberculosis usually develops more than two years after infection or many years later. Factors favoring onset of the disease are malnutrition, older age, renal failure, diabetes, cancer, immunosuppression and biological treatment, e.g. tumor necrosis factor α (TNF-α) inhibitors. The paper presents a case of a 56-year-old patient with ankylosing spondylitis treated with infliximab, diagnosed with tuberculosis of the spleen. The unusual location and uncharacteristic symptoms created a lot of diagnostic difficulties, particularly as during qualification for biological treatment tests are performed to exclude infection with Mycobacterium tuberculosis. Pharmacological treatment of tuberculosis is typical, but in the case of tuberculosis of the spleen, splenectomy also is a method of treatment. The decision was made to implement pharmacological treatment, which proved to be effective, so the patient avoided surgery.

  2. Bilateral diaphragmatic paralysis associated with the use of the tumor necrosis factor-alpha inhibitor adalimumab

    PubMed Central

    Martin, Alan William; Rosenblatt, Randall Lee

    2014-01-01

    A 51-year-old woman was referred for evaluation of progressive dyspnea of 3 months— duration. She had received 3 doses of adalimumab for treatment of rheumatoid arthritis prior to the onset of her dyspnea. Her chest examination revealed absent diaphragmatic movement with inspiration. Spirometry showed a severe restrictive defect. Radiologic studies confirmed the diagnosis of bilateral diaphragmatic paralysis. Laboratory and radiologic workup excluded other possible causes of the diagnosis. Adalimumab was discontinued, and she was treated with bilevel positive airway pressure ventilation and intravenous immunoglobulin. Three months later, the diaphragmatic paralysis persisted. This is the second reported case of bilateral diaphragmatic paralysis occurring in a patient who had received adalimumab. Acute neuropathies are rare side effects of tumor necrosis factor-alpha inhibitors. PMID:24688191

  3. Tumor necrosis factor receptor-associated periodic syndrome managed with the couple canakinumab-alendronate.

    PubMed

    Lopalco, Giuseppe; Rigante, Donato; Vitale, Antonio; Frediani, Bruno; Iannone, Florenzo; Cantarini, Luca

    2015-04-01

    Management of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is puzzling, and therapeutic choices can be complicated, due to both wide genetic heterogeneity and protean clinical phenotype. We report on a 35-year-old female who was diagnosed with TRAPS, after finding the V95M mutation on the TNFRSF1A gene; who was treated in order with etanercept, anakinra, and canakinumab (150 mg/every 8 weeks by subcutaneous injection, then increased to 150 mg every 4 weeks); and who started therapy with oral alendronate (70 mg/weekly) to control her osteoporosis. Alendronate combined with canakinumab led to the optimal clinical control of all TRAPS manifestations and normalization of inflammatory markers. Further studies should be performed to clarify bisphosphonates' role in the scenery of autoinflammatory disorders. PMID:24609716

  4. Bilirubin release induced by tumor necrosis factor in combination with galactosamine is toxic to mice.

    PubMed

    Van Molle, W; Libert, C

    2003-08-01

    Application of tumor necrosis factor (TNF) in combination with galactosamine (GalN) in mice causes severe apoptosis of hepatocytes, resulting in complete destruction of the liver. Administration of high levels of unconjugated bilirubin and abnormally high production of unconjugated bilirubin have been reported to cause liver damage and are associated with several human pathologies. Serum alanine aminotransferase as well as total and direct bilirubin levels in mice were determined. Bilirubin levels are shown to significantly increase after a challenge with TNF/GalN in mice. Pretreatment with a heme oxygenase-1 inhibitor significantly prevents this release in bilirubin and offers significant protection against TNF/GalN-induced lethality. A correlation between the release of unconjugated bilirubin and the toxicity accompanied with this release is provided. PMID:12906872

  5. Modulation of Endogenous Hormone Action by Recombinant Human Tumor Necrosis Factor

    NASA Astrophysics Data System (ADS)

    Warren, Robert S.; Donner, David B.; Fletcher Starnes, H.; Brennan, Murray F.

    1987-12-01

    Tumor necrosis factor (TNF) has been implicated in the toxic manifestations of overwhelming bacterial infection and in the tissue wasting that often accompanies prolonged infections and malignancy. We have examined a possible role of TNF in the early metabolic alterations following acute tissue injury or sepsis. Recombinant human TNF stimulated rat liver amino acid uptake up to 5-fold in vivo and there was a concomitant increase in plasma glucagon. In vitro TNF had no direct effect on hepatocyte amino acid uptake, but it markedly enhanced the stimulation of amino acid transport by glucagon, without an alteration in binding of glucagon to hepatocytes. This permissive effect of TNF on glucagon action represents an interrelationship between the immune and endocrine systems, and it may help to explain the mechanism of hormonal regulation of both the anabolic and catabolic responses to acute injury.

  6. ATAR, a novel tumor necrosis factor receptor family member, signals through TRAF2 and TRAF5.

    PubMed

    Hsu, H; Solovyev, I; Colombero, A; Elliott, R; Kelley, M; Boyle, W J

    1997-05-23

    Members of tumor necrosis factor receptor (TNFR) family signal largely through interactions with death domain proteins and TRAF proteins. Here we report the identification of a novel TNFR family member ATAR. Human and mouse ATAR contain 283 and 276 amino acids, respectively, making them the shortest known members of the TNFR superfamily. The receptor is expressed mainly in spleen, thymus, bone marrow, lung, and small intestine. The intracellular domains of human and mouse ATAR share only 25% identity, yet both interact with TRAF5 and TRAF2. This TRAF interaction domain resides at the C-terminal 20 amino acids. Like most other TRAF-interacting receptors, overexpression of ATAR activates the transcription factor NF-kappaB. Co-expression of ATAR with TRAF5, but not TRAF2, results in synergistic activation of NF-kappaB, suggesting potentially different roles for TRAF2 and TRAF5 in post-receptor signaling. PMID:9153189

  7. Extensive genetic polymorphism in the human tumor necrosis factor region and relation to extended HLA haplotypes.

    PubMed Central

    Jongeneel, C V; Briant, L; Udalova, I A; Sevin, A; Nedospasov, S A; Cambon-Thomsen, A

    1991-01-01

    We have identified three polymorphic microsatellites (which we call TNFa, TNFb, and TNFc) within a 12-kilobase region of the human major histocompatibility complex (MHC) that includes the tumor necrosis factor (TNF) locus. TNFc is located within the first intron of the TNF-beta gene and has only 2 alleles. TNFa and TNFb are 3.5 kilobases upstream (telomeric) of the TNF-beta gene and have at least 13 and 7 alleles, respectively. TNFa, -b, and -c alleles are in linkage disequilibrium with alleles at other loci within the MHC, including class I, class II, and class III. TNFa, -b, and -c alleles are also associated with extended HLA haplotypes. These TNF polymorphisms will allow a thorough genetic analysis of the involvement of TNF in MHC-linked pathologies. Images PMID:1946393

  8. Targeting of the Tumor Necrosis Factor Receptor Superfamily for Cancer Immunotherapy

    PubMed Central

    2013-01-01

    The tumor necrosis factor (TNF) ligand and cognate TNF receptor superfamilies constitute an important regulatory axis that is pivotal for immune homeostasis and correct execution of immune responses. TNF ligands and receptors are involved in diverse biological processes ranging from the selective induction of cell death in potentially dangerous and superfluous cells to providing costimulatory signals that help mount an effective immune response. This diverse and important regulatory role in immunity has sparked great interest in the development of TNFL/TNFR-targeted cancer immunotherapeutics. In this review, I will discuss the biology of the most prominent proapoptotic and co-stimulatory TNF ligands and review their current status in cancer immunotherapy. PMID:23840967

  9. Tumor necrosis factor alpha negatively regulates hepatitis B virus gene expression in transgenic mice.

    PubMed Central

    Gilles, P N; Fey, G; Chisari, F V

    1992-01-01

    It is well known that several inflammatory cytokines can modulate hepatocellular gene expression in a complex physiological process known as the hepatic acute-phase response. Since hepatitis B virus (HBV) characteristically induces a vigorous lymphomononuclear inflammatory response in the liver during acute and chronic hepatitis, it is possible that hepatocellular HBV gene expression may also be modulated by one or more of the cytokines produced by these cells. Using bacterial lipopolysaccharide (LPS) as a surrogate inducer of inflammatory cytokines in vivo, we have tested this hypothesis in a transgenic mouse model system. In experiments with two independent transgenic mouse lineages that express the HBV envelope region under the control of either HBV or cellular promoters, we observed a 50 to 80% reduction in the hepatic steady-state content of a 2.1-kb HBV mRNA following administration of a single intraperitoneal dose of LPS. The regulatory influence of several inflammatory cytokines known to be induced by LPS was also examined in this system. The negative regulatory effect of LPS was consistently reproduced by the administration of a single nontoxic dose of tumor necrosis factor alpha, and it was occasionally observed following the administration of high doses of alpha interferon and interleukin-6, while no effect was detectable in response to high-dose interleukin-1 alpha or to gamma interferon. These observations suggest that tumor necrosis factor alpha and perhaps other cytokines may activate a heretofore unsuspected intracellular pathway that negatively regulates HBV gene expression. The intracellular mechanism(s) responsible for this effect and its pathophysiologic relevance remain to be elucidated. Images PMID:1583737

  10. Female temperament, tumor development and life span: relation to glucocorticoid and tumor necrosis factor alpha levels in rats.

    PubMed

    Cavigelli, Sonia A; Bennett, Jeanette M; Michael, Kerry C; Klein, Laura Cousino

    2008-07-01

    Behavioral characteristics closely associated with specific physiological profiles present an important area of research in understanding health disparities. In particular, glucocorticoid overproduction may be an important factor moderating disease progression; natural variance in production of this steroid has been proposed as one mechanism underlying individual differences in health and disease. In the current paper, we examined immune parameters in female rats of two different behavioral types previously shown to have differential glucocorticoid production and life spans. We categorized young female rats according to their behavioral response to novelty (high- or low-locomotion), and compared their glucocorticoid production, adrenal size, thymus size, tumor necrosis factor-alpha (TNF-alpha) production, tumor development and life span. As expected, high-locomotion females produced more glucocorticoids and had larger adrenal glands during young adulthood than did low-locomotion females. High-locomotion females had significantly smaller thymuses and reduced TNF-alpha levels compared to low-locomotion, suggesting altered immune function in young adulthood. Finally, high-locomotion females had shorter life spans than did low-locomotion females, and this was particularly true in females that developed pituitary tumors, but not in those that developed mammary tumors. These results, along with other published findings, suggest that high-locomotion rodent females experience life-long elevations in glucocorticoid responses to novelty, and that these elevated levels may be comparable to chronic stress. This naturally occurring endocrine profile may influence immune responses which in turn could affect disease susceptibility. Variance in immune function across personality types may be partially moderated by natural variance in glucocorticoid production. PMID:18155400

  11. Two sides of one coin: massive hepatic necrosis and progenitor cell-mediated regeneration in acute liver failure

    PubMed Central

    Weng, Hong-Lei; Cai, Xiaobo; Yuan, Xiaodong; Liebe, Roman; Dooley, Steven; Li, Hai; Wang, Tai-Ling

    2015-01-01

    Massive hepatic necrosis is a key event underlying acute liver failure, a serious clinical syndrome with high mortality. Massive hepatic necrosis in acute liver failure has unique pathophysiological characteristics including extremely rapid parenchymal cell death and removal. On the other hand, massive necrosis rapidly induces the activation of liver progenitor cells, the so-called “second pathway of liver regeneration.” The final clinical outcome of acute liver failure depends on whether liver progenitor cell-mediated regeneration can efficiently restore parenchymal mass and function within a short time. This review summarizes the current knowledge regarding massive hepatic necrosis and liver progenitor cell-mediated regeneration in patients with acute liver failure, the two sides of one coin. PMID:26136687

  12. Two sides of one coin: massive hepatic necrosis and progenitor cell-mediated regeneration in acute liver failure.

    PubMed

    Weng, Hong-Lei; Cai, Xiaobo; Yuan, Xiaodong; Liebe, Roman; Dooley, Steven; Li, Hai; Wang, Tai-Ling

    2015-01-01

    Massive hepatic necrosis is a key event underlying acute liver failure, a serious clinical syndrome with high mortality. Massive hepatic necrosis in acute liver failure has unique pathophysiological characteristics including extremely rapid parenchymal cell death and removal. On the other hand, massive necrosis rapidly induces the activation of liver progenitor cells, the so-called "second pathway of liver regeneration." The final clinical outcome of acute liver failure depends on whether liver progenitor cell-mediated regeneration can efficiently restore parenchymal mass and function within a short time. This review summarizes the current knowledge regarding massive hepatic necrosis and liver progenitor cell-mediated regeneration in patients with acute liver failure, the two sides of one coin. PMID:26136687

  13. RXFP1 is Targeted by Complement C1q Tumor Necrosis Factor-Related Factor 8 in Brain Cancer

    PubMed Central

    Thanasupawat, Thatchawan; Glogowska, Aleksandra; Burg, Maxwell; Wong, G. William; Hoang-Vu, Cuong; Hombach-Klonisch, Sabine; Klonisch, Thomas

    2015-01-01

    The relaxin-like RXFP1 ligand–receptor system has important functions in tumor growth and tissue invasion. Recently, we have identified the secreted protein, CTRP8, a member of the C1q/tumor necrosis factor-related protein (CTRP) family, as a novel ligand of the relaxin receptor, RXFP1, with functions in brain cancer. Here, we review the role of CTRP members in cancers cells with particular emphasis on CTRP8 in glioblastoma. PMID:26322020

  14. RXFP1 is Targeted by Complement C1q Tumor Necrosis Factor-Related Factor 8 in Brain Cancer.

    PubMed

    Thanasupawat, Thatchawan; Glogowska, Aleksandra; Burg, Maxwell; Wong, G William; Hoang-Vu, Cuong; Hombach-Klonisch, Sabine; Klonisch, Thomas

    2015-01-01

    The relaxin-like RXFP1 ligand-receptor system has important functions in tumor growth and tissue invasion. Recently, we have identified the secreted protein, CTRP8, a member of the C1q/tumor necrosis factor-related protein (CTRP) family, as a novel ligand of the relaxin receptor, RXFP1, with functions in brain cancer. Here, we review the role of CTRP members in cancers cells with particular emphasis on CTRP8 in glioblastoma. PMID:26322020

  15. Tumor Necrosis Factor-alpha Stimulates the Overproduction of Intestinal Apolipoprotein B48-containing Very Low Density Lipoproproteins

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Tumor necrosis factor-alpha(a)(TNFa), a proinflammatory cytokine, is involved in obesity-associated pathologies including type 2 diabetes and atherosclerosis. TNFa enhanced postprandial apoB48-VLDL1 overproduction by about 89% compared with the control after 90 min olive oil loading; TNFa did not si...

  16. Microglial Derived Tumor Necrosis Factor-α Drives Alzheimer’s Disease-Related Neuronal Cell Cycle Events

    PubMed Central

    Bhaskar, Kiran; Maphis, Nicole; Xu, Guixiang; Varvel, Nicholas H.; Kokiko-Cochran, Olga N; Weick, Jason P.; Staugaitis, Susan M.; Cardona, Astrid; Ransohoff, Richard M.; Herrup, Karl; Lamb, Bruce T.

    2013-01-01

    Massive neuronal loss is a key pathological hallmark of Alzheimer’s disease (AD). However, the mechanisms are still unclear. Here we demonstrate that neuroinflammation, cell autonomous to microglia, is capable of inducing neuronal cell cycle events (CCEs), which are toxic for terminally differentiated neurons. First, oligomeric amyloid-beta peptide (ApO)-mediated microglial activation induced neuronal CCEs via the tumor-necrosis factor-α (TNFα) and the c-Jun Kinase (JNK) signaling pathway. Second, adoptive transfer of CD11b+ microglia from AD transgenic mice (R1.40) induced neuronal cyclin D1 expression via TNFα signaling pathway. Third, genetic deficiency of TNFα in R1.40 mice (R1 .40-Tnfα−/−) iled to induce neuronal CCEs. Finally, the mitotically active neurons spatially co-exist with F4/80+ activated microglia in the human AD brain and that a portion of these neurons are apoptotic. Together our data suggest a cell-autonomous role of microglia, and identify TNFα as the responsible cytokine, in promoting neuronal CCEs in the pathogenesis of AD. PMID:24141019

  17. Vascular endothelial growth factor promotes macrophage apoptosis through stimulation of tumor necrosis factor superfamily member 14 (TNFSF14/LIGHT).

    PubMed

    Petreaca, Melissa L; Yao, Min; Ware, Carl; Martins-Green, Manuela M

    2008-01-01

    Resolution of inflammation is critical for normal wound healing. Inflammation is prolonged and fails to resolve properly in chronic wounds. We used in vivo and in vitro approaches to show that vascular endothelial growth factor (VEGF) induces macrophage apoptosis and to delineate mechanisms involved in this process. VEGF inhibition during wound healing leads to an increased number of macrophages remaining in wounds, suggesting the involvement of VEGF in removal of these cells from the wound. If this effect has physiological relevance, it likely occurs via apoptosis. We show that VEGF increases apoptosis of macrophages in vitro using Annexin V-FITC staining and caspase activation. Microarray analysis, reverse transcription-polymerase chain reaction, and immunoblotting showed that VEGF increases the expression of tumor necrosis factor superfamily member 14 (TNFSF14/LIGHT) in macrophages. We also show that in macrophages LIGHT promotes apoptosis through the lymphotoxin beta receptor. Moreover, inhibition of LIGHT prevents VEGF-induced death, suggesting that LIGHT mediates VEGF-induced macrophage apoptosis. Taken together, our results identify a novel role for VEGF and for LIGHT in macrophage apoptosis during wound healing, an event critical in the resolution of inflammation. This finding may lead to the development of new strategies to improve resolution of inflammation in problematic wounds. PMID:19128255

  18. A pathogenic role for tumor necrosis factor-related apoptosis-inducing ligand in chronic obstructive pulmonary disease.

    PubMed

    Haw, T J; Starkey, M R; Nair, P M; Pavlidis, S; Liu, G; Nguyen, D H; Hsu, A C; Hanish, I; Kim, R Y; Collison, A M; Inman, M D; Wark, P A; Foster, P S; Knight, D A; Mattes, J; Yagita, H; Adcock, I M; Horvat, J C; Hansbro, P M

    2016-07-01

    Chronic obstructive pulmonary disease (COPD) is a life-threatening inflammatory respiratory disorder, often induced by cigarette smoke (CS) exposure. The development of effective therapies is impaired by a lack of understanding of the underlining mechanisms. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine with inflammatory and apoptotic properties. We interrogated a mouse model of CS-induced experimental COPD and human tissues to identify a novel role for TRAIL in COPD pathogenesis. CS exposure of wild-type mice increased TRAIL and its receptor messenger RNA (mRNA) expression and protein levels, as well as the number of TRAIL(+)CD11b(+) monocytes in the lung. TRAIL and its receptor mRNA were also increased in human COPD. CS-exposed TRAIL-deficient mice had decreased pulmonary inflammation, pro-inflammatory mediators, emphysema-like alveolar enlargement, and improved lung function. TRAIL-deficient mice also developed spontaneous small airway changes with increased epithelial cell thickness and collagen deposition, independent of CS exposure. Importantly, therapeutic neutralization of TRAIL, after the establishment of early-stage experimental COPD, reduced pulmonary inflammation, emphysema-like alveolar enlargement, and small airway changes. These data provide further evidence for TRAIL being a pivotal inflammatory factor in respiratory diseases, and the first preclinical evidence to suggest that therapeutic agents that target TRAIL may be effective in COPD therapy. PMID:26555706

  19. Spontaneous and stimulated release of tumor necrosis factor-alpha (TNF) from blood monocytes of miners with coal workers' pneumoconiosis.

    PubMed

    Borm, P J; Palmen, N; Engelen, J J; Buurman, W A

    1988-12-01

    It is generally accepted that fibrotic lung diseases are mediated by macrophage-derived cytokines. We investigated the release of the monokine tumor necrosis factor-alpha (TNF) from blood monocytes in a group of 66 coal miners and 12 non-dust-exposed individuals. Twenty-seven miners had simple Coal Workers' Pneumoconiosis (CWP). Control miners (n = 39) were matched with respect to age, years underground, and smoking. Monocytes were assayed for TNF release, spontaneously or in response to soluble (endotoxin) or particulate (coal mine dust, silica) stimulation. TNF was measured with a TNF-specific ELISA. Monocytes of all subjects responded to stimulants by the release of TNF. Dust-exposed controls' monocytes revealed higher TNF release as compared to normal controls. The greatest discriminator between control miners and cases (CWP) was coal mine dust-induced TNF release. Interestingly, the largest difference was observed between controls and those cases with a small number of opacities (0/1, 1/0, 1/1, and 1/2), giving an odds ratio of 6.3 to find an individual with a "high" dust-induced TNF release in the patient group. PMID:2849351

  20. Pathophysiological roles of microvascular alterations in pulmonary inflammatory diseases: possible implications of tumor necrosis factor-alpha and CXC chemokines

    PubMed Central

    Orihara, Kanami; Matsuda, Akio

    2008-01-01

    Chronic obstructive pulmonary disease (COPD) and bronchial asthma are common respiratory diseases that are caused by chronic inflammation of the airways. Although these diseases are mediated by substantially distinct immunological reactions, especially in mild cases, they both show increased numbers of neutrophils, increased production of tumor necrosis factor-alpha (TNF-α) and poor responses to corticosteroids, particularly in patients with severe diseases. These immunological alterations may contribute strongly to airway structural changes, commonly referred to as airway remodeling. Microvascular alterations, a component of airway remodeling and caused by chronic inflammation, are observed and appear to be clinically involved in both diseases. It has been well established that vascular endothelial growth factor (VEGF) plays important roles in the airway microvascular alterations in mild and moderate cases of both diseases, but any role that VEGF might play in severe cases of these diseases remains unclear. Here, we review recent research findings, including our own data, and discuss the possibility that TNF-α and its associated CXC chemokines play roles in microvascular alterations that are even more crucial than those of VEGF in patients with severe COPD or asthma. PMID:19281078

  1. Tumor Necrosis Factor α Regulates Endothelial Progenitor Cell Migration via CADM1 and NF-kB.

    PubMed

    Prisco, Anthony R; Hoffmann, Brian R; Kaczorowski, Catherine C; McDermott-Roe, Chris; Stodola, Timothy J; Exner, Eric C; Greene, Andrew S

    2016-07-01

    Shortly after the discovery of endothelial progenitor cells (EPCs) in 1997, many clinical trials were conducted using EPCs as a cellular based therapy with the goal of restoring damaged organ function by inducing growth of new blood vessels (angiogenesis). Results were disappointing, largely because the cellular and molecular mechanisms of EPC-induced angiogenesis were not clearly understood. Following injection, EPCs must migrate to the target tissue and engraft prior to induction of angiogenesis. In this study EPC migration was investigated in response to tumor necrosis factor α (TNFα), a pro-inflammatory cytokine, to test the hypothesis that organ damage observed in ischemic diseases induces an inflammatory signal that is important for EPC homing. In this study, EPC migration and incorporation were modeled in vitro using a coculture assay where TNFα treated EPCs were tracked while migrating toward vessel-like structures. It was found that TNFα treatment of EPCs increased migration and incorporation into vessel-like structures. Using a combination of genomic and proteomic approaches, NF-kB mediated upregulation of CADM1 was identified as a mechanism of TNFα induced migration. Inhibition of NF-kB or CADM1 significantly decreased migration of EPCs in vitro suggesting a role for TNFα signaling in EPC homing during tissue repair. Stem Cells 2016;34:1922-1933. PMID:26867147

  2. Transactivation of human immunodeficiency virus type 1 long terminal repeats by cell surface tumor necrosis factor alpha.

    PubMed Central

    Tadmori, W; Mondal, D; Tadmori, I; Prakash, O

    1991-01-01

    Tumor necrosis factor alpha (TNF-alpha) is expressed in secreted and cell surface (csTNF-alpha) forms by activated monocytic and T cells. In this report, we demonstrate that csTNF-alpha may predominantly regulate the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) activation in the promonocytic cell line U937 and in the Epstein-Barr virus-transformed B-cell line BH1. Anti-TNF-alpha antibody suppressed both the constitutive expression of the HIV-1 LTR in BH1 cells and the expression induced by phorbol 12-myristate 13-acetate in U937 cells. This suppression was found to be mediated via csTNF-alpha. No correlation between the HIV-1 LTR activation and the secretion of TNF-alpha was evident in these cell lines. Suppression of TNF-alpha secretion by cyclosporin A or by a serine protease inhibitor did not suppress the HIV-1 LTR activation. These observations suggest a novel biological role for csTNF-alpha in the immunopathogenesis of AIDS. PMID:1942242

  3. Automated ensemble segmentation of epithelial proliferation, necrosis, and fibrosis using scatter tumor imaging

    NASA Astrophysics Data System (ADS)

    Garcia-Allende, P. Beatriz; Conde, Olga M.; Krishnaswamy, Venkataramanan; Hoopes, P. Jack; Pogue, Brian W.; Mirapeix, Jesus; Lopez-Higuera, Jose M.

    2010-04-01

    Conventional imaging systems used today in surgical settings rely on contrast enhancement based on color and intensity and they are not sensitive to morphology changes at the microscopic level. Elastic light scattering spectroscopy has been shown to distinguish ultra-structural changes in tissue. Therefore, it could provide this intrinsic contrast being enormously useful in guiding complex surgical interventions. Scatter parameters associated with epithelial proliferation, necrosis and fibrosis in pancreatic tumors were previously estimated in a quantitative manner. Subtle variations were encountered across the distinct diagnostic categories. This work proposes an automated methodology to correlate these variations with their corresponding tumor morphologies. A new approach based on the aggregation of the predictions of K-nearest neighbors (kNN) algorithm and Artificial Neural Networks (ANNs) has been developed. The major benefit obtained from the combination of the distinct classifiers is a significant increase in the number of pixel localizations whose corresponding tissue type is reliably assured. Pseudo-color diagnosis images are provided showing a strong correlation with sample segmentations performed by a veterinary pathologist.

  4. A comparison of the intoxication pathways of tumor necrosis factor and diphtheria toxin

    SciTech Connect

    Chang, M.P.

    1988-01-01

    The mechanism by which tumor necrosis factor-alpha (TNF) initiates tumor cell destruction is unknown. We have approached this problem by comparing the biological properties of TNF with diphtheria toxin (DTx), a well-characterized cytotoxin. Initial studies with human U937 cells revealed that a transient exposure to low pH enhances the cytotoxic activity of TNF. Detailed studies on the interaction of TNF with pure lipid vesicles revealed that the acid-enhanced cytolytic activity of this cytokine is correlated with the acquisition of membrane binding and insertion properties. Significantly, an increase in target membrane stabilization was observed in the presence of TNF; hence, TNF is not directly lytic for membranes. In susceptible target cells, DTx induces the release of {sup 51}Cr- and {sup 75}Se-labeled proteins within 7 h. Although DTx-triggered cell death has generally been accepted as a straightforward effect of translation inhibition, little or no cell lysis was observed over a 20-30 h period when target cells were exposed to cycloheximide, amino acid deficient medium or metabolic poisons even though protein synthesis was inhibited to levels observed with DTx. The protein synthesis inhibition and cytolytic activities of DTx showed similar dose-dependencies, target cell specificities, and sensitivities to NH{sub 4}Cl inhibition. DTx-induced DNA fragmentation preceded cells lysis and did not occur in cells that were treated with the other protein synthesis inhibitors.

  5. Phase I trial of intramuscularly administered tumor necrosis factor in patients with advanced cancer.

    PubMed

    Jakubowski, A A; Casper, E S; Gabrilove, J L; Templeton, M A; Sherwin, S A; Oettgen, H F

    1989-03-01

    A phase I trial of intramuscularly administered recombinant human tumor necrosis factor (rTNF) was conducted in 19 adult patients with advanced solid tumors. The agent was administered daily for up to five consecutive days every other week for two to four courses. Doses of rTNF ranged from 5 to 200 micrograms/m2/d. Dose-limiting toxicities were encountered at doses greater than 100 micrograms/m2/d. Toxicities included tenderness, erythema and induration at the site of injection, fatigue, fever, chills, headache, anorexia, nausea, vomiting, and diarrhea. Moderate to marked reductions in WBC and platelet counts were observed regularly at the highest dose levels, but none were clinically significant. Hepatic enzyme elevation was seen frequently, and two patients developed hyperbilirubinemia. Only one of seven patients treated with doses greater than 100 micrograms/m2/d completed the planned course of therapy. Even at the highest dose levels, serum concentrations of rTNF could only rarely be detected in the serum. No therapeutic responses were observed. The maximal tolerated dose (MTD) of rTNF in this trial was 150 micrograms/m2/d, administered for two courses. PMID:2918329

  6. Lovastatin and tumor necrosis factor-alpha exhibit potentiated antitumor effects against Ha-ras-transformed murine tumor via inhibition of tumor-induced angiogenesis.

    PubMed

    Feleszko, W; Bałkowiec, E Z; Sieberth, E; Marczak, M; Dabrowska, A; Giermasz, A; Czajka, A; Jakóbisiak, M

    1999-05-17

    Lovastatin, a drug commonly used in the treatment of hypercholesterolemia, has previously been reported to exert potentiated antitumor activity when combined with either tumor necrosis factor-alpha (TNF-alpha), cisplatin or doxorubicin in a melanoma model in mice. Since lovastatin interferes with the function of ras oncogene-encoded (Ras) proteins, we have investigated the antitumor activity of lovastatin and TNF-alpha using a Ha-ras-transformed murine tumor model. In in vitro studies, lovastatin inhibited the growth of cells transformed with Ha-ras oncogene (Ras-3T3 and HBL100-ras cells) more effectively than control NIH-3T3 and HBL100-neo cells. In in vivo experiments, the Ras-3T3 tumor demonstrated significantly increased sensitivity to combined treatment with both lovastatin (50 mg/kg) and TNF-alpha (1 microg/day) compared with either agent alone. Combined treatment with both agents also resulted in greater inhibition of blood-vessel formation. Ras-3T3 tumor cells produced increased amounts of vascular endothelial growth factor (VEGF) and lovastatin effectively suppressed VEGF production by these cells. Our results suggest that lovastatin increases antitumor activity of TNF-alpha against tumor cells transformed with v-Ha-ras oncogene via inhibition of tumor-induced blood-vessel formation. PMID:10225445

  7. Necrosis targeted radiotherapy with iodine-131-labeled hypericin to improve anticancer efficacy of vascular disrupting treatment in rabbit VX2 tumor models

    PubMed Central

    Shao, Haibo; Zhang, Jian; Sun, Ziping; Chen, Feng; Dai, Xu; Li, Yaming; Ni, Yicheng; Xu, Ke

    2015-01-01

    A viable rim of tumor cells surrounding central necrosis always exists and leads to tumor recurrence after vascular disrupting treatment (VDT). A novel necrosis targeted radiotherapy (NTRT) using iodine-131-labeled hypericin (131I-Hyp) was specifically designed to treat viable tumor rim and improve tumor control after VDT in rabbit models of multifocal VX2 tumors. NTRT was administered 24 hours after VDT. Tumor growth was significantly slowed down by NTRT with a smaller tumor volume and a prolonged tumor doubling time (14.4 vs. 5.7 days), as followed by in vivo magnetic resonance imaging over 12 days. The viable tumor rims were well inhibited in NTRT group compared with single VDT control group, as showed on tumor cross sections at day 12 (1 vs. 3.7 in area). High targetability of 131I-Hyp to tumor necrosis was demonstrated by in vivo SPECT as high uptake in tumor regions lasting over 9 days with 4.26 to 98 times higher radioactivity for necrosis versus the viable tumor and other organs by gamma counting, and with ratios of 7.7–11.7 and 10.5–13.7 for necrosis over peri-tumor tissue by autoradiography and fluorescence microscopy, respectively. In conclusion, NTRT improved the anticancer efficacy of VDT in rabbits with VX2 tumors. PMID:26036625

  8. Analysis of Tumor Necrosis Factor Function Using the Resonant Recognition Model.

    PubMed

    Cosic, Irena; Cosic, Drasko; Lazar, Katarina

    2016-06-01

    The tumor necrosis factor (TNF) is a complex protein that plays a very important role in a number of biological functions including apoptotic cell death, tumor regression, cachexia, inflammation inhibition of tumorigenesis and viral replication. Its most interesting function is that it is an inhibitor of tumorigenesis and inductor of apoptosis. Thus, the TNF could be a good candidate for cancer therapy. However, the TNF has also inflammatory and toxic effects. Therefore, it would be very important to understand complex functions of the TNF and consequently be able to predict mutations or even design the new TNF-related proteins that will have only a tumor inhibition function, but not other side effects. This can be achieved by applying the resonant recognition model (RRM), a unique computational model of analysing macromolecular sequences of proteins, DNA and RNA. The RRM is based on finding that certain periodicities in distribution of free electron energies along protein, DNA and RNA are strongly correlated to the biological function of these macromolecules. Thus, based on these findings, the RRM has capabilities of protein function identification, prediction of bioactive amino acids and protein design with desired biological function. Using the RRM, we separate different functions of TNF as different periodicities (frequencies) within the distribution of free energy electrons along TNF protein. Interestingly, these characteristic TNF frequencies are related to previously identified characteristics of proto-oncogene and oncogene proteins describing TNF involvement in oncogenesis. Consequently, we identify the key amino acids related to the crucial TNF function, i.e. receptor recognition. We have also designed the peptide which will have the ability to recognise the receptor without side effects. PMID:27286856

  9. Antibodies against amino acids 1-15 of tumor necrosis factor block its binding to cell-surface receptor.

    PubMed Central

    Socher, S H; Riemen, M W; Martinez, D; Friedman, A; Tai, J; Quintero, J C; Garsky, V; Oliff, A

    1987-01-01

    Human tumor necrosis factor (hTNF) mediates a variety of biologic activities, which are dependent on the attachment of hTNF to cell-surface receptors. To identify regions of the hTNF protein involved in binding hTNF to its receptor, we prepared five synthetic peptides [hTNF-(1-15), hTNF-(1-31), hTNF-(65-79), hTNF-(98-111), and hTNF-(124-141)] and two hydroxylamine cleavage fragments [hTNF-(1-39) and hTNF-(40-157)] of hTNF. The hTNF-synthetic peptides and hTNF fragments were tested in hTNF receptor binding assays and in two biologic assays: cytolysis of tumor cells and suppression of lipoprotein lipase in adipocytes. Neither the synthetic peptides nor hTNF fragments were active agonists or antagonists in these assays. The synthetic peptides were also conjugated to thyroglobulin, and peptide-specific antisera were raised. All five peptide-thyroglobulin conjugates induced antibody responses to the immunizing peptide and to hTNF. Each antiserum was tested for antagonist activity in hTNF binding assays. Only antisera raised against hTNF-(1-15) or hTNF-(1-31) and antisera against whole hTNF blocked binding. IgGs purified from these three antisera also block hTNF-induced cytolysis and lipoprotein lipase suppression. We conclude that antibodies that recognize the N-terminus of hTNF block the attachment of hTNF to its cellular receptor and inhibit the biologic effects of hTNF. PMID:2827156

  10. Multiorgan chronic inflammatory hepatobiliary pancreatic murine model deficient in tumor necrosis factor receptors 1 and 2

    PubMed Central

    Oz, Helieh S

    2016-01-01

    AIM: To provoke persistent/chronic multiorgan inflammatory response and to contribute to stones formation followed by fibrosis in hepatobiliary and pancreatic tissues. METHODS: Tumor necrosis factor receptors 1 and 2 (TNFR1/R2) deficient mice reared in-house were given dibutyltin dichloride (DBTC) twice within 10 d by oral gavage delivery. Sham control animals received vehicle treatment and naïve animals remained untreated throughout the study. Animals were monitored daily for symptoms of pain and discomfort. The abdominal and hindpaw hypersensitivity were assessed with von Frey microfilaments. Exploratory behaviors were recorded at the baseline, after initiation of treatment, and before study termination. Histopathological changes were examined postmortem in tissues. Collagen accumulation and fibrosis were confirmed with Sirius Red staining. RESULTS: Animals lost weight after oral administration of DBTC and developed persistent inflammatory abdominal and hindpaw hypersensitivity compared to sham-treated controls (P < 0.0001). These pain related secondary mechanical hypersensitivity responses increased more than 2-fold in DBTC-treated animals. The drastically diminished rearing and grooming rates persisted after DBTC administration throughout the study. Gross as well as micropathology at one month confirmed that animals treated with DBTC developed chronic hepatobiliary injuries evidenced with activation of stellate cells, multifocal necrosis, fatty degeneration of hepatocytes, periportal infiltration of inflammatory cells, and prominent biliary ductal dilation. The severity of hepatitis was scored 3.7 ± 0.2 (severe) in DBTC-treated animals vs score 0 (normal) in sham-treated animals. Fibrotic thickening was extensive around portal ducts, in hepatic parenchyma as well as in lobular pancreatic structures and confirmed with Sirius Red histopathology. In addition, pancreatic microarchitecture was presented with distortion of islets, and parenchyma, infiltration of

  11. Infection of human fallopian tube epithelial cells with Neisseria gonorrhoeae protects cells from tumor necrosis factor alpha-induced apoptosis.

    PubMed

    Morales, Priscilla; Reyes, Paz; Vargas, Macarena; Rios, Miguel; Imarai, Mónica; Cardenas, Hugo; Croxatto, Horacio; Orihuela, Pedro; Vargas, Renato; Fuhrer, Juan; Heckels, John E; Christodoulides, Myron; Velasquez, Luis

    2006-06-01

    Following infection with Neisseria gonorrhoeae, bacteria may ascend into the Fallopian tubes (FT) and induce salpingitis, a major cause of infertility. In the FT, interactions between mucosal epithelial cells and gonococci are pivotal events in the pathogen's infection cycle and the inflammatory response. In the current study, primary FT epithelial cells were infected in vitro with different multiplicities of infection (MOI) of Pil+ Opa+ gonococci. Bacteria showed a dose-dependent association with cells and induced the secretion of tumor necrosis factor alpha (TNF-alpha). A significant finding was that gonococcal infection (MOI = 1) induced apoptosis in approximately 30% of cells, whereas increasing numbers of bacteria (MOI = 10 to 100) did not induce apoptosis. Apoptosis was observed in only 11% of cells with associated bacteria, whereas >84% of cells with no adherent bacteria were apoptotic. TNF-alpha was a key contributor to apoptosis, since (i) culture supernatants from cells infected with gonococci (MOI = 1) induced apoptosis in naïve cultures, suggesting that a soluble factor was responsible; (ii) gonococcal infection-induced apoptosis was inhibited with anti-TNF-alpha antibodies; and (iii) the addition of exogenous TNF-alpha induced apoptosis, which was inhibited by the presence of increasing numbers of bacteria (MOI = 10 to 100). These data suggest that TNF-alpha-mediated apoptosis of FT epithelial cells is likely a primary host defense mechanism to prevent pathogen colonization. However, epithelial cell-associated gonococci have evolved a mechanism to protect the cells from undergoing TNF-alpha-mediated apoptosis, and this modulation of the host innate response may contribute to establishment of infection. Understanding the antiapoptotic mechanisms used by Neisseria gonorrhoeae will inform the pathogenesis of salpingitis and could suggest new intervention strategies for prevention and treatment of the disease. PMID:16714596

  12. Toll-like receptor 9 regulates tumor necrosis factor-alpha expression by different mechanisms. Implications for osteoclastogenesis.

    PubMed

    Amcheslavsky, Alla; Zou, Wei; Bar-Shavit, Zvi

    2004-12-24

    CpG oligodeoxynucleotides (CpG-ODNs), mimicking bacterial DNA, stimulate osteoclastogenesis via Toll-like receptor 9 (TLR9) in receptor activator of NF-kappa B ligand (RANKL)-primed osteoclast precursors. This activity is mediated via tumor necrosis factor (TNF)-alpha induction by CpG-ODN. To further reveal the role of the cytokine in TLR9-mediated osteoclastogenesis, we compared the ability of CpG-ODN to induce osteoclastogenesis in two murine strains, BALB/c and C57BL/6, expressing different TNF-alpha alleles. The induction of osteoclastogenesis and TNF-alpha release by CpG-ODN was by far more noticeable in BALB/c-derived than in C57BL/6-derived osteoclast precursors. Unexpectedly, as revealed by Northern analysis, CpG-ODN induction of TNF-alpha mRNA increase was more efficient in C57BL/6-derived cells. The cytokine transcript abundance was increased due to both increased message stability and rate of transcription. The difference between the two cell types was the result of a higher transcription rate in CpG-ODN-induced C57BL/6-derived cells caused by a single nucleotide polymorphism in kappa B2a site within the TNF-alpha promoter sequence. CpG-ODN enhanced the rate of the cytokine translation in BALB/c-derived cells. Thus, CpG-ODN modulated both transcription and translation of TNF-alpha. The induction of transcription was more evident in C57BL/6-derived cells, while the induction of translation took place only in BALB/c-derived osteoclast precursors. Altogether the cytokine was induced to a larger extent in BALB/c-derived osteoclast precursors, consistent with the increased CpG-ODN osteoclastogenic effect in these cells. PMID:15485822

  13. Identification of tumor necrosis factor as a transcriptional regulator of the phosphoenolpyruvate carboxykinase gene following endotoxin treatment of mice.

    PubMed Central

    Hill, M R; McCallum, R E

    1992-01-01

    The decreased synthesis of hepatic phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting enzyme of gluconeogenesis, that occurs during endotoxemia was shown previously in rats to occur at the transcriptional level. In the current study, the exogenous administration of human recombinant tumor necrosis factor (TNF), a proximal mediator of endotoxic shock, reduced the PEPCK transcription rate, mRNAPEPCK levels, and PEPCK enzyme activity in a time- and dose-dependent manner in CD-1 mice. Comparable amounts of circulating TNF were measured in mice 2 h after injection of human recombinant TNF (10(5) U) or a 50% lethal dose of Escherichia coli endotoxin (20 mg/kg). Direct action of TNF to decrease the PEPCK transcription rate was confirmed in vitro with H-4-II-E Reuber hepatoma cells, in which a dose-dependent inhibition of PEPCK transcription was observed with 1 to 100 U of TNF per ml. A role for TNF-elicited changes in PEPCK gene expression during endotoxemia was confirmed by the protective effect of rabbit polyclonal antibodies to recombinant murine TNF. C57BL/6 mice passively immunized with anti-TNF 4 h prior to endotoxin challenge exhibited normal PEPCK enzyme activity. Neutralization of circulating TNF with anti-TNF failed, however, to prevent the hypoglycemia commonly observed during endotoxemia, suggesting the participation of other mediators. Anti-TNF treatment reduced circulating interleukins 1 and 6 at 3 and 6 h after endotoxin treatment, respectively. These results suggest that during endotoxemia, the development of hypoglycemia is multifaceted and that several cytokines are most likely involved. The findings from the Reuber hepatoma cell model afford an opportunity in future work to map putative cytokine response elements in the PEPCK promoter responsible for perturbed hormonal regulation of the gene during endotoxemia. PMID:1398916

  14. Modulation of in Vivo Tumor Radiation Response via Gold Nanoshell-Mediated Vascular-Focused Hyperthermia: Characterizing an Integrated Antihypoxic and Localized Vascular Disrupting Targeting Strategy

    PubMed Central

    Diagaradjane, Parmeswaran; Shetty, Anil; Wang, James C.; Elliott, Andrew M.; Schwartz, Jon; Shentu, Shujun; Park, Hee C.; Deorukhkar, Amit; Stafford, R. Jason; Cho, Sang H.; Tunnell, James W.; Hazle, John D.; Krishnan, Sunil

    2014-01-01

    We report noninvasive modulation of in vivo tumor radiation response using gold nanoshells. Mild-temperature hyperthermia generated by near-infrared illumination of gold nanoshell-laden tumors, noninvasively quantified by magnetic resonance temperature imaging, causes an early increase in tumor perfusion that reduces the hypoxic fraction of tumors. A subsequent radiation dose induces vascular disruption with extensive tumor necrosis. Gold nanoshells sequestered in the perivascular space mediate these two tumor vasculature-focused effects to improve radiation response of tumors. This novel integrated antihypoxic and localized vascular disrupting therapy can potentially be combined with other conventional antitumor therapies. PMID:18412402

  15. Tumor necrosis factor-alpha induces Cl- and K+ secretion in human distal colon driven by prostaglandin E2.

    PubMed

    Schmitz, H; Fromm, M; Bode, H; Scholz, P; Riecken, E O; Schulzke, J D

    1996-10-01

    Increased levels of tumor necrosis factor-alpha (TNF-alpha) have been found in, for example, inflammatory bowel disease (IBD) and human immunodeficiency virus (HIV) infection. To investigate a possible contribution of TNF-alpha to the pathogenesis of diarrhea in these diseases, ion transport of human distal colon was studied in the Ussing chamber in vitro. Serosal addition of TNF-alpha increased short-circuit current (Isc) of partially stripped tissues in a dose-dependent manner. Maximum Isc increase of 1.8 +/- 0.2 mumol.h-1.cm-2 was reached after 60 +/- 9 min at 200 ng/ml TNF-alpha. Bidirectional tracer flux measurements revealed that TNF-alpha induced an increase in 36 Cl serosal-to-mucosal flux, a decrease in 36Cl- mucosal-to-serosal flux, and a slight increase in K+ secretion indicated by an increased secretory 86Rb net flux. In the highly differentiated colonic epithelial cell line HT-29/B6, TNF-alpha had no effect on Isc, suggesting a mediation step located in the subepithelium. This supposition was supported by measurements on totally stripped human tissues, since removal of subepithelial layers by total stripping reduced the TNF-alpha effect by 40%. Experiments with tetrodotoxin (10(-6)M) indicated that the TNF-alpha effect was not mediated by the enteric nervous system. The specific 5-lipoxygenase blocker ICI-230487 (5 x 10(-8)M) also had no effect on TNF-alpha action. In contrast, inhibition of cyclooxygenase by indomethacin (10(-6)M inhibited the effect of TNF-alpha. Radioimmunoassay of prostaglandin E2 (PGE2) in the serosal bathing solution revealed an increase in PGE2 production/release after addition of TNF-alpha, which paralleled the Isc response. We conclude that TNF-alpha changed Cl- and K+ transport toward secretion in human colon. This effect was mediated by PGE2 produced by subepithelial cells. Thus TNF-alpha could be a mediator of diarrhea during intestinal inflammation, e.g., in IBD and HIV infection. PMID:8897887

  16. Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey

    PubMed Central

    Gupta, Subash C.; Kim, Ji Hye

    2012-01-01

    Although activity that induced tumor regression was observed and termed tumor necrosis factor (TNF) as early as the 1960s, the true identity of TNF was not clear until 1984, when Aggarwal and coworkers reported, for the first time, the isolation of 2 cytotoxic factors: one, derived from macrophages (molecular mass 17 kDa), was named TNF, and the second, derived from lymphocytes (20 kDa), was named lymphotoxin. Because the 2 cytotoxic factors exhibited 50% amino acid sequence homology and bound to the same receptor, they came to be called TNF-α and TNF-β. Identification of the protein sequences led to cloning of their cDNA. Based on sequence homology to TNF-α, now a total of 19 members of the TNF superfamily have been identified, along with 29 interacting receptors, and several molecules that interact with the cytoplasmic domain of these receptors. The roles of the TNF superfamily in inflammation, apoptosis, proliferation, invasion, angiogenesis, metastasis, and morphogenesis have been documented. Their roles in immunologic, cardiovascular, neurologic, pulmonary, and metabolic diseases are becoming apparent. TNF superfamily members are active targets for drug development, as indicated by the recent approval and expanding market of TNF blockers used to treat rheumatoid arthritis, psoriasis, Crohns disease, and osteoporosis, with a total market of more than US $20 billion. As we learn more about this family, more therapeutics will probably emerge. In this review, we summarize the initial discovery of TNF-α, and the insights gained regarding the roles of this molecule and its related family members in normal physiology and disease. PMID:22053109

  17. A phase II trial of recombinant tumor necrosis factor in patients with advanced colorectal carcinoma.

    PubMed

    Kemeny, N; Childs, B; Larchian, W; Rosado, K; Kelsen, D

    1990-08-15

    Sixteen previously treated (with only one prior regimen) patients with histologically proven metastatic or locally recurrent colorectal carcinoma were treated with recombinant tumor necrosis factor (rTNF) administered by 30-minute i.v. infusions twice daily for 5 consecutive days every other week for 8 weeks. Patients received 100 micrograms/m2 twice daily on day 1 of cycle 1 with escalation to 150 micrograms/m2 twice daily thereafter. Patients were concomitantly treated with indomethacin 25 mg every 6 hours and acetaminophen 650 mg every 4 hours to obviate fever and chills. Toxicities included: nausea/vomiting (69%), headache (25%), chills (69%), pain at tumor sites (63%), hypotension (31%), and hypertension (38%). Hematologic toxicity included leukopenia less than 2000 cells/mm3 (38%) and thrombocytopenia less than 100,000 cells/mm3 (13%). Liver function abnormalities occurred independently of the site or extent of metastatic disease and inconsistently in each treatment cycle. Four patients developed bilirubinemia greater than 2.5 x baseline values (range, 2.5 to 10.3 U/L); five patients had greater than 2.5 x elevations in alkaline phosphatase (range, 624 to 1663 U/L). Two patients developed retinal vein thrombosis in the absence of hemostatic abnormalities. In both instances, this complication occurred several weeks after completion of therapy. No objective responses were noted in 14 evaluable patients (95% confidence interval: 0 to 0.23). Three patients had stable disease for a median duration of 4.5 months. In conclusion, i.v. rTNF at this dose and schedule has no demonstrable antitumor efficacy. Twice-daily i.v. administration of this agent is associated with more hepatotoxicity than previously reported in trials using subcutaneous or once daily i.v. administration. Retinal vein thrombosis may be a late complication of i.v. rTNF at this dose and schedule. PMID:2386895

  18. Phase I evaluation of recombinant tumor necrosis factor given in combination with recombinant interferon-gamma.

    PubMed

    Smith, J W; Urba, W J; Clark, J W; Longo, D L; Farrell, M; Creekmore, S P; Conlon, K C; Jaffe, H; Steis, R G

    1991-10-01

    In light of in vitro and preclinical animal model data suggesting potential additive or synergistic antitumor effects from the combined use of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha), we conducted a phase I study employing escalating doses of each agent in 36 patients with solid tumors to determine the maximum tolerated dose (MTD). Patients were given an intramuscular (i.m.) injection of IFN-gamma, followed 5 min later by an i.m. injection of TNF-alpha, each agent in different sites, every other day for ten doses over 20 days. Patients received 10, 50, or 100 micrograms/m2 of each agent throughout the treatment course. No dose modifications were made. Patients suffering serious toxicity had therapy stopped and were considered to be off-study. All patients experienced fatigue, and 36% spent over half their time in bed on treatment days. Fever and chills were nearly universal. Mild to moderate elevations in serum transaminase levels were noted in 44% of patients, and 44% developed transient microscopic hematuria. Although 81% of patients had anorexia, only 17% of patients lost more than 3 kg of body wt during the 3 weeks of therapy. Because two of three patients receiving 100 micrograms/m2 of both agents developed serious toxicity (one fever greater than 105 degrees F, one thrombocytopenia 43,000/mm3), the MTD was established to be 100 micrograms/m2 of IFN-gamma plus 50 micrograms/m2 of TNF-alpha. The use of aspirin did not significantly alter the toxic effects of the agents. One patient with melanoma had a mixed response and one patient with mesothelioma transiently cleared his ascites of malignant cells. PMID:1790143

  19. Targeting the tumor necrosis factor-related apoptosis-inducing ligand path in neuroblastoma.

    PubMed

    Yang, Xuezhong; Thiele, Carol J

    2003-07-18

    The identification of the tumor necrosis factor (TNF) superfamily member TNF-related apoptosis-inducing ligand (TRAIL) a few years ago generated considerable enthusiasm for it as a potential cancer therapeutic agent. This is because TRAIL shows potent apoptosis inducing activity in a wide spectrum of transformed cell lines but not in cell lines derived from normal tissue origin. As the details in the signal transduction pathway of TRAIL-induced apoptosis are clarified, various defects of TRAIL pathway have been identified in TRAIL resistant cancer cells. Neuroblastoma is the most common extracranial solid tumor in children and those with a poor prognosis require more sensitive therapies. Unlike other cancer cells, most neuroblastoma cell lines are resistant to TRAIL induced apoptosis and the resistance correlates with caspase 8 deficiency, which is attributed to the methylation of the gene. Interferon (IFN)-gamma induces caspase 8 expression in most neuroblastoma cell lines regardless of the methylation status but fails to sensitize most NB to TRAIL. Further analysis indicates a TRAIL receptor deficiency contributes to TRAIL resistance in NB. Multiple lesions suggest that this path may play an important role in tumorigenesis and/ or evasion from therapies. Furthermore it indicates that the clinical application of TRAIL in NB will require a multi-modality approach. Important questions remain unanswered: How does IFN-gamma induce caspase 8 and why is the induction heterogeneous? How to stimulate the caspase 8 induction in cells that fail to respond to IFN-gamma? How to target other TRAIL pathway lesions with the clinically feasible approaches? PMID:12880973

  20. Wound healing potential of pterospermum acerifolium wild. With induction of tumor necrosis factor - α

    PubMed Central

    Senapati, Aswini Kumar; Giri, Ranjan Kumar; Panda, Dibya Sundar; Satyanarayan, Sremantula

    2011-01-01

    Pterospermum acerifolium, a well-known plant in Indian medicine possesses various therapeutic properties including healing properties and cytokine induction. Wound healing activity of ethanolic extract of P. acerifolium flower along with its effect on tumor necrosis factor-α (TNF-α) was assessed using excision model of wound repair in Wistar albino rats. After application of the P. acerifolium extract, rate of epithelization with an increase in wound contraction was observed. Animals tropically treated with 10% P. acerifolium extract in petroleum jelly, the wound healing process was observed faster as compared to control group which were treated with petroleum jelly alone. A significant accelerated healing was noticed in animals which were additionally prefed with 250mg/kg body weight of ethanolic P. acerifolium extract daily for 20 consecutive days along with the topical application 10% P. acerifolium extract. During wound healing phase TNF-α level was found to be up regulated by P. acerifolium treatment. Early wound healing may be pronounced due to P. acerifolium extract elevating TNF−α production PMID:24826024

  1. Inositol lipid metabolism in vasopressin stimulated hepatocytes from rats infused with tumor necrosis factor

    SciTech Connect

    Spitzer, J.A.; Rodriguez de Turco, E.B. )

    1989-05-30

    We studied the effect of i.v. infusion of human recombinant tumor necrosis factor alpha (rHuTNF alpha, Cetus, 15 micrograms/100 g bw over 3 h) on vasopressin (VP)-stimulated {sup 32}P-inositol lipid turnover and the release of {sup 3}H-inositol phosphates in isolated rat hepatocytes. The early VP-induced decrease (within 30 s) in {sup 32}P-phosphatidylinositol 4-phosphate and {sup 32}P-phosphatidylinositol 4,5-bisphosphate labeling was significantly reduced (-40%) and at the same time the uptake of {sup 32}P into phosphatidic acid was 50% lower than in saline-infused (matched control) rats. Within 5 min of VP-stimulation, lower {sup 32}P phosphatidylinositol (-40%) and higher {sup 32}P-phosphatidic acid (+30%) labeling were observed in rHuTNF alpha-infused rats. Infusion of rHuTNF alpha also affected the VP-induced release of {sup 3}H-inositol phosphates. The accumulation of {sup 3}H-inositol-labeled water soluble products was decreased by 25% and 17% at 30 s and 10 min, respectively. These data show that rHuTNF alpha mimics early perturbations induced by Escherichia coli endotoxin infusion in VP-stimulated inositol lipid metabolism in rat hepatocytes.

  2. Tuberculosis infection versus anti-tumor necrosis factor therapy: screening challenges in psoriatic patients

    PubMed Central

    Solovan, Caius; Chiticariu, Elena; Timofte, Adelina; Stoia-Djeska, Irina

    2012-01-01

    Objectives The aim of this study was to analyze the performance of the tuberculin skin test (TST) for screening and monitoring patients treated with anti-tumor necrosis factor agents, in a high-incidence area. Methods A 3-year retrospective study was carried out on 268 subjects. The study included 68 patients with moderate-to-severe psoriasis, screened for latent tuberculosis infection (LTBI) and subjects without psoriasis (100 adults and 100 children) with close contact with infected individuals. Results Positive tuberculin skin test (TST) results (induration >5 mm) were observed in 70.5% (48/68) of patients with psoriasis, higher than those observed in subjects with suspicion of tuberculosis or with close contact with infected individuals: 51% (51/100) in the adult group and 30% (30/100) in the children group. Conclusions These results show that the prevalence of LTBI evaluated with the TST in the psoriatic group is higher than in subjects without psoriasis. Limitation The positive reactions were not confirmed by other verification methods.

  3. Glucocorticoids Regulate Tristetraprolin Synthesis and Posttranscriptionally Regulate Tumor Necrosis Factor Alpha Inflammatory Signaling▿

    PubMed Central

    Smoak, Kathleen; Cidlowski, John A.

    2006-01-01

    Glucocorticoids are used to treat various inflammatory disorders, but the mechanisms underlying these actions are incompletely understood. The zinc finger protein tristetraprolin (TTP) destabilizes several proinflammatory cytokine mRNAs by binding to AU-rich elements within their 3′ untranslated regions, targeting them for degradation. Here we report that glucocorticoids induce the synthesis of TTP mRNA and protein in A549 lung epithelial cells and in rat tissues. Dexamethasone treatment leads to a sustained induction of TTP mRNA expression that is abrogated by RU486. Glucocorticoid induction of TTP mRNA is also blocked by actinomycin D but not by cycloheximide, suggesting a transcriptional mechanism which has been confirmed by transcription run-on experiments. The most widely characterized TTP-regulated gene is the AU-rich tumor necrosis factor alpha (TNF-α) gene. Dexamethasone represses TNF-α mRNA in A549 cells and decreases luciferase expression of a TNF-α 3′ untranslated region reporter plasmid in an orientation-dependent manner. Small interfering RNAs to TTP significantly prevent this effect, and a cell line stably expressing a short-hairpin RNA to TTP conclusively establishes that TTP is critical for dexamethasone inhibition of TNF-α mRNA expression. These studies provide the molecular evidence for glucocorticoid regulation of human TTP and reflect a novel inductive anti-inflammatory signaling pathway for glucocorticoids that acts via posttranscriptional mechanisms. PMID:16982682

  4. Safety of anti-tumor necrosis factor therapy during pregnancy in patients with inflammatory bowel disease.

    PubMed

    Androulakis, Ioannis; Zavos, Christos; Christopoulos, Panagiotis; Mastorakos, George; Gazouli, Maria

    2015-12-21

    Treatment of inflammatory bowel disease has significantly improved since the introduction of biological agents, such as infliximab, adalimumab, certolizumab pegol, and golimumab. The Food and Drug Administration has classified these factors in category B, which means that they do not demonstrate a fetal risk. However, during pregnancy fetuses are exposed to high anti-tumor necrosis factor (TNF) levels that are measurable in their plasma after birth. Since antibodies can transfer through the placenta at the end of the second and during the third trimesters, it is important to know the safety profile of these drugs, particularly for the fetus, and whether maintaining relapse of the disease compensates for the potential risks of fetal exposure. The limited data available for the anti-TNF drugs to date have not demonstrated any significant adverse outcomes in the pregnant women who continued their therapy from conception to the first trimester of gestation. However, data suggest that anti-TNFs should be discontinued during the third trimester, as they may affect the immunological system of the newborn baby. Each decision should be individualized, based on the distinct characteristics of the patient and her disease. Considering all the above, there is a need for more clinical studies regarding the effect of anti-TNF therapeutic agents on pregnancy outcomes. PMID:26715803

  5. Curcumin half analog modulates interleukin-6 and tumor necrosis factor-alpha in inflammatory bowel disease

    PubMed Central

    Kondamudi, Phani Krishna; Kovelamudi, Hemalatha; Nayak, Pawan G.; Rao, Mallikarjuna Chamallamudi; Shenoy, Rekha Raghuveer

    2015-01-01

    Background: The present study was aimed at examining the effect of dehydrozingerone (DHZ), half analogue of curcumin which is the active constituent of turmeric (Curcuma longa) in the di-nitrochlorobenzene (DNCB) induced model for inflammatory bowel disease (IBD). Materials and Methods: Male Wistar rats (200–220 g) were divided into four groups (n = 6). Chemical induction of IBD was done by sensitizing with 300 µL of 20 g/L of DNCB (in acetone) onto the nape of rats for 14 days followed by intra-colonic instillation of 250 µL of DNCB (0.1% DNCB in 50% alcohol) solution on day 15. Rats in Group 1 (normal control) and Group 2 (DNCB control) were treated with vehicle. Rats in Group 3 were treated with DHZ (100 mg/kg, p.o.; 8 days) and Group 4 animals were treated with sulfasalazine (SS) (100 mg/kg, p.o.; 8 days). On 24th day, the rats were killed, colon removed and the macroscopic, biochemical, and histopathological evaluations were performed. Results: The levels of myeloperoxidase, thiobarbituric acid reactive substrate, and nitrite increased significantly (P < 0.05) in the DNCB group whereas reduced significantly in the DHZ and SS treated groups. Serum nitrite levels were found to be insignificant between the different groups. Interleukin-6, tumor necrosis factor-alpha level was significantly high in the DNCB group. Conclusion: These findings show that DHZ can be a promising molecule for the treatment of IBD. PMID:26664018

  6. Control of Mycobacterial Infections in Mice Expressing Human Tumor Necrosis Factor (TNF) but Not Mouse TNF.

    PubMed

    Olleros, Maria L; Chavez-Galan, Leslie; Segueni, Noria; Bourigault, Marie L; Vesin, Dominique; Kruglov, Andrey A; Drutskaya, Marina S; Bisig, Ruth; Ehlers, Stefan; Aly, Sahar; Walter, Kerstin; Kuprash, Dmitry V; Chouchkova, Miliana; Kozlov, Sergei V; Erard, François; Ryffel, Bernard; Quesniaux, Valérie F J; Nedospasov, Sergei A; Garcia, Irene

    2015-09-01

    Tumor necrosis factor (TNF) is an important cytokine for host defense against pathogens but is also associated with the development of human immunopathologies. TNF blockade effectively ameliorates many chronic inflammatory conditions but compromises host immunity to tuberculosis. The search for novel, more specific human TNF blockers requires the development of a reliable animal model. We used a novel mouse model with complete replacement of the mouse TNF gene by its human ortholog (human TNF [huTNF] knock-in [KI] mice) to determine resistance to Mycobacterium bovis BCG and M. tuberculosis infections and to investigate whether TNF inhibitors in clinical use reduce host immunity. Our results show that macrophages from huTNF KI mice responded to BCG and lipopolysaccharide similarly to wild-type macrophages by NF-κB activation and cytokine production. While TNF-deficient mice rapidly succumbed to mycobacterial infection, huTNF KI mice survived, controlling the bacterial burden and activating bactericidal mechanisms. Administration of TNF-neutralizing biologics disrupted the control of mycobacterial infection in huTNF KI mice, leading to an increased bacterial burden and hyperinflammation. Thus, our findings demonstrate that human TNF can functionally replace murine TNF in vivo, providing mycobacterial resistance that could be compromised by TNF neutralization. This new animal model will be helpful for the testing of specific biologics neutralizing human TNF. PMID:26123801

  7. Molecular Basis for Defining the Pineal Gland and Pinealocytes as Targets for Tumor Necrosis Factor

    PubMed Central

    Carvalho-Sousa, Claudia Emanuele; da Silveira Cruz-Machado, Sanseray; Tamura, Eduardo Koji; Fernandes, Pedro A. C. M.; Pinato, Luciana; Muxel, Sandra M.; Cecon, Erika; Markus, Regina P.

    2011-01-01

    The pineal gland, the gland that translates darkness into an endocrine signal by releasing melatonin at night, is now considered a key player in the mounting of an innate immune response. Tumor necrosis factor (TNF), the first pro-inflammatory cytokine to be released by an inflammatory response, suppresses the translation of the key enzyme of melatonin synthesis (arylalkylamine-N-acetyltransferase, Aanat). Here, we show that TNF receptors of the subtype 1 (TNF-R1) are expressed by astrocytes, microglia, and pinealocytes. We also show that the TNF signaling reduces the level of inhibitory nuclear factor kappa B protein subtype A (NFKBIA), leading to the nuclear translocation of two NFKB dimers, p50/p50, and p50/RelA. The lack of a transactivating domain in the p50/p50 dimer suggests that this dimer is responsible for the repression of Aanat transcription. Meanwhile, p50/RelA promotes the expression of inducible nitric oxide synthase (iNOS) and the production of nitric oxide, which inhibits adrenergically induced melatonin production. Together, these data provide a mechanistic basis for considering pinealocytes a target of TNF and reinforce the idea that the suppression of pineal melatonin is one of the mechanisms involved in mounting an innate immune response. PMID:22654792

  8. Tumor necrosis factor-{alpha} enhances IL-15-induced natural killer cell differentiation

    SciTech Connect

    Lee, Jiwon; Lee, Suk Hyung; Shin, Nara; Jeong, Mira; Kim, Mi Sun; Kim, Mi Jeong; Yoon, Suk Ran; Chung, Jin Woong; Kim, Tae-Don; Choi, Inpyo

    2009-09-04

    The differentiation of natural killer (NK) cells is regulated by various factors including soluble growth factors and transcription factors. Here, we have demonstrated that tumor necrosis factor-{alpha} (TNF-{alpha}) is a positive regulator of NK cell differentiation. TNF-{alpha} augmented the IL-15-induced expression of NK1.1 and CD122 in mature NK cells, and TNF-{alpha} alone also induced NK cell maturation as well as IL-15. TNF-{alpha} also increased IFN-{gamma} production in NK cells in the presence of IL-15. Meanwhile, mRNA expression of several transcription factors, including T-bet and GATA-3, was increased by the addition of TNF-{alpha} and IL-15. In addition, TNF-{alpha} increased nuclear factor-kappa B (NF-{kappa}B) activity in NK cells and inhibition of NF-{kappa}B impeded TNF-{alpha}-enhanced NK cell maturation. Overall, these data suggest that TNF-{alpha} significantly increased IL-15-driven NK cell differentiation by increasing the expression of transcription factors that play crucial roles in NK cell maturation and inducing the NF-{kappa}B activity.

  9. Varicella zoster meningitis complicating combined anti-tumor necrosis factor and corticosteroid therapy in Crohn's disease.

    PubMed

    Ma, Christopher; Walters, Brennan; Fedorak, Richard N

    2013-06-01

    Opportunistic viral infections are a well-recognized complication of anti-tumor necrosis factor (TNF) therapy for inflammatory bowel disease (IBD). Cases of severe or atypical varicella zoster virus infection, both primary and latent reactivation, have been described in association with immunosuppression of Crohn's disease (CD) patients. However, central nervous system varicella zoster virus infections have been rarely described, and there are no previous reports of varicella zoster virus meningitis associated with anti-TNF therapy among the CD population. Here, we present the case of a 40-year-old male with severe ileocecal-CD who developed a reactivation of dermatomal herpes zoster after treatment with prednisone and adalimumab. The reactivation presented as debilitating varicella zoster virus meningitis, which was not completely resolved despite aggressive antiviral therapy with prolonged intravenous acyclovir and subsequent oral valacyclovir. This is the first reported case of opportunistic central nervous system varicella zoster infection complicating anti-TNF therapy in the CD population. This paper also reviews the literature on varicella zoster virus infections of immunosuppressed IBD patients and the importance of vaccination prior to initiation of anti-TNF therapy. PMID:23745038

  10. Demyelinizing Neurological Disease after Treatment with Tumor Necrosis Factor-α Antagonists

    PubMed Central

    Bruè, Claudia; Mariotti, Cesare; Rossiello, Ilaria; Saitta, Andrea; Giovannini, Alfonso

    2016-01-01

    Purpose Demyelinizing neurological disease is a rare complication after treatment with tumor necrosis factor (TNF)α antagonists. We report on a case of multiple sclerosis after TNFα antagonist treatment and discuss its differential diagnosis. Methods This is an observational case study. Results A 48-year-old male was referred to Ophthalmology in January 2015 for an absolute scotoma in the superior quadrant of the visual field in his right eye. Visual acuity was 20/50 in the right eye and 20/20 in the left. Fundus examination was unremarkable bilaterally. Spectral domain optical coherence tomography revealed a normal macular retina structure. Visual field examination revealed a superior hemianopsia in the right eye. Head magnetic resonance imaging showed findings compatible with optic neuritis. The visual evoked potentials confirmed the presence of optic neuritis. The patient had been under therapy with adalimumab since January 2014, for Crohn's disease. Suspension of adalimumab was recommended, and it was substituted with tapered deltacortene, from 1 mg/kg/day. After 1 month, the scotoma was resolved completely. Conclusions TNFα antagonists can provide benefit to patients with inflammatory autoimmune diseases. However, they can also be associated with severe adverse effects. Therefore, adequate attention should be paid to neurological abnormalities in patients treated with TNFα antagonists. PMID:27504093