Studies on the Role of Tumor Necrosis Factor- Alpha ( Tnf-Α ) in Hepatocytes Induced Apoptosis in Vaccinated , Schistosoma Mansoni-Challenged Mice

2015 ◽  
Vol 45 (1) ◽  
pp. 47-60 ◽  
Author(s):  
Samia E. Etewa ◽  
Naglaa F. Abd El-Aal ◽  
Sara A. Abdelrahman ◽  
Eman H. Abd El Bary ◽  
Mahmoud A. El-Shafei
Keyword(s):  
Tumor Necrosis Factor ◽  
Schistosoma Mansoni ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Induced Apoptosis ◽  
Necrosis Factor

scholarly journals Tumor Necrosis Factor Alpha-Induced Apoptosis Requires p73 and c-ABL Activation Downstream of RB Degradation

2004 ◽  
Vol 24 (10) ◽  
pp. 4438-4447 ◽  
Author(s):  
B. Nelson Chau ◽  
Tung-Ti Chen ◽  
Yisong Y. Wan ◽  
James DeGregori ◽  
Jean Y. J. Wang
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Abl Tyrosine Kinase ◽  
Tnf Α ◽  
Factor Alpha ◽  
Induced Apoptosis ◽  
Necrosis Factor

ABSTRACT The retinoblastoma protein (RB) suppresses cell proliferation and apoptosis. We have previously shown that RB degradation is required for tumor necrosis factor alpha (TNF-α) to induce apoptosis. We show here the identification of two apoptotic effectors, i.e., c-ABL tyrosine kinase and p73, which are activated by TNF-α following RB degradation. In cells expressing a degradation-resistant RB protein (RB-MI), TNF-α does not activate c-ABL. RB-MI also inhibits TNF-α-mediated activation of p73. Genetic deletion and pharmacological inhibition of c-ABL or p73 diminish the apoptotic response to TNF-α in human cell lines and mouse fibroblasts. Thymocytes isolated from RbMI/MI , Abl −/−, or p73 −/− mice are resistant to TNF-α-induced apoptosis compared to their wild-type counterparts. This is in contrast to p53 −/− thymocytes, which exhibit a wild-type level of apoptosis in response to TNF-α. Thus, c-ABL and p73 contribute to apoptosis induced by TNF-α, in addition to their role in promoting DNA damage-associated cell death.

scholarly journals Role of Cytochrome c in Apoptosis: Increased Sensitivity to Tumor Necrosis Factor Alpha Is Associated with Respiratory Defects but Not with Lack of Cytochrome c Release

2007 ◽  
Vol 27 (5) ◽  
pp. 1771-1783 ◽  
Author(s):  
Uma D. Vempati ◽  
Francisca Diaz ◽  
Antoni Barrientos ◽  
Sonoko Narisawa ◽  
Abdul M. Mian ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Oxidative Phosphorylation ◽  
Tumor Necrosis ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Increased Sensitivity ◽  
Factor Alpha ◽  
Induced Apoptosis ◽  
Necrosis Factor

ABSTRACT Although the role of cytochrome c in apoptosis is well established, details of its participation in signaling pathways in vivo are not completely understood. The knockout for the somatic isoform of cytochrome c caused embryonic lethality in mice, but derived embryonic fibroblasts were shown to be resistant to apoptosis induced by agents known to trigger the intrinsic apoptotic pathway. In contrast, these cells were reported to be hypersensitive to tumor necrosis factor alpha (TNF-α)-induced apoptosis, which signals through the extrinsic pathway. Surprisingly, we found that this cell line (CRL 2613) respired at close to normal levels because of an aberrant activation of a testis isoform of cytochrome c, which, albeit expressed at low levels, was able to replace the somatic isoform for respiration and apoptosis. To produce a bona fide cytochrome c knockout, we developed a mouse knockout for both the testis and somatic isoforms of cytochrome c. The mouse was made viable by the introduction of a ubiquitously expressed cytochrome c transgene flanked by loxP sites. Lung fibroblasts in which the transgene was deleted showed no cytochrome c expression, no respiration, and resistance to agents that activate the intrinsic and to a lesser but significant extent also the extrinsic pathways. Comparison of these cells with lines with a defective oxidative phosphorylation system showed that cells with defective respiration have increased sensitivity to TNF-α-induced apoptosis, but this process was still amplified by cytochrome c. These studies underscore the importance of oxidative phosphorylation and apoptosome function to both the intrinsic and extrinsic apoptotic pathways.

scholarly journals Bid-Independent Mitochondrial Activation in Tumor Necrosis Factor Alpha-Induced Apoptosis and Liver Injury

2006 ◽  
Vol 27 (2) ◽  
pp. 541-553 ◽  
Author(s):  
Xiaoyun Chen ◽  
Wen-Xing Ding ◽  
Hong-Min Ni ◽  
Wentao Gao ◽  
Ying-Hong Shi ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Liver Injury ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Necrosis Factor Alpha ◽  
Apoptosis Pathway ◽  
Tnf Α ◽  
Factor Alpha ◽  
Induced Apoptosis ◽  
Necrosis Factor

ABSTRACT The death receptor apoptosis pathway is intimately connected with the mitochondrial apoptosis pathway. Bid is a BH3-only pro-death Bcl-2 family protein and is the major molecule linking the two pathways. Bid-mediated mitochondrial activation occurs early and is responsible for the prompt progress of tumor necrosis factor alpha (TNF-α)-induced apoptosis. However, in both cultured cells and animal models of TNF-α-induced injury, later-phase Bid-independent mitochondrial activation could be demonstrated. Consequently, bid-deficient mice are still susceptible to endotoxin-induced liver injury and mortality. Notably, embryonic hepatocyte apoptosis and lethality caused by TNF-α in the absence of p65relA cannot be rescued by the simultaneous deletion of bid. Further studies indicate that multiple mechanisms including reactive oxygen species, JNK, and permeability transition are critically involved in Bid-independent mitochondrial activation. Inhibition of these events suppresses TNF-α-induced mitochondrial activation and apoptosis in bid-deficient cells. These findings thus indicate that there are at least two sets of mechanisms of mitochondrial activation upon TNF-α stimulation. While the Bid-mediated mechanism is rapid and potent, the Bid-independent mechanism progresses gradually and involves multiple players. The critical involvement of Bid-independent mitochondrial activation in TNF-α-induced apoptosis demands the intervention of TNF-α-mediated tissue injury via multiple avenues.

scholarly journals No Evidence for a Major Effect of Tumor Necrosis Factor Alpha Gene Polymorphisms in Periportal Fibrosis Caused by Schistosoma mansoni Infection

2003 ◽  
Vol 71 (10) ◽  
pp. 5456-5460 ◽  
Author(s):  
Carole Eboumbou Moukoko ◽  
Nasureldin El Wali ◽  
O. K. Saeed ◽  
Qurashi Mohamed-Ali ◽  
Jean Gaudart ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
Tumor Necrosis Factor ◽  
Schistosoma Mansoni ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Major Effect ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT Hepatic periportal fibrosis (PPF), associated with portal hypertension, is a major pathological consequence of infections with Schistosoma mansoni and Schistosoma japonicum. Indeed, affected subjects may die from portal hypertension. Previous studies have indicated that tumor necrosis factor alpha (TNF-α) may aggravate fibrosis. We therefore investigated whether PPF was associated with certain polymorphisms of the TNF-α gene. Four polymorphisms (TNF-α −376 G/A, −308 G/A, −238 G/A, and +488 G/A) were investigated in two Sudanese populations living in an area in which S. mansoni is endemic. These polymorphisms were analyzed for 105 Sudanese subjects with various grades of PPF, from mild to advanced; all subjects were from two neighboring villages (Taweela and Umzukra). They were then analyzed for 70 subjects with advanced liver disease and for 345 matched controls from the Gezira region. We found no evidence of associations between these four polymorphisms and PPF in both of these studies. Thus, these four polymorphisms, two of which (TNF-α −376 and −308) were found to increase TNF-α gene transcription, are unlikely to have a major effect on PPF progression in these populations. However, this result does not exclude the possibility that these polymorphisms have a minor effect on PPF development.

scholarly journals Critical Role for Tumor Necrosis Factor Alpha in Controlling the Number of Lumenal Pathogenic Bacteria and Immunopathology in Infectious Colitis

2001 ◽  
Vol 69 (11) ◽  
pp. 6651-6659 ◽  
Author(s):  
Nathalie S. Gonçalves ◽  
Marjan Ghaem-Maghami ◽  
Giovanni Monteleone ◽  
Gad Frankel ◽  
Gordon Dougan ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Interleukin 12 ◽  
Necrosis Factor Alpha ◽  
Infectious Colitis ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT Infection of mice with the intestinal bacterial pathogenCitrobacter rodentium results in colonic mucosal hyperplasia and a local Th1 inflammatory response similar to that seen in mouse models of inflammatory bowel disease. In these latter models, and in patients with Crohn's disease, neutralization of tumor necrosis factor alpha (TNF-α) is of therapeutic benefit. Since there is no information on the role of TNF-α in either immunity to noninvasive bacterial pathogens or on the role of TNF-α in the immunopathology of infectious colitis, we investigated C. rodentiuminfection in TNFRp55−/− mice. In TNFRp55−/−mice, there were higher colonic bacterial burdens, but the organisms were cleared at the same rate as C57BL/6 mice, showing that TNF-α is not needed for protective antibacterial immunity. The most striking feature of infection in TNFRp55−/−mice, however, was the markedly enhanced pathology, with increased mucosal weight and thickness, increased T-cell infiltrate, and a markedly greater mucosal Th1 response. Interleukin-12 p40 transcripts were markedly elevated in C. rodentium-infected TNFRp55−/− mice, and this was associated with enhanced mucosal STAT4 phosphorylation. TNF-α is not obligatory for protective immunity to C. rodentium in mice; however, it appears to play some role in downregulating mucosal pathology and Th1 immune responses.

scholarly journals The Absence of NF-κB-Mediated Inhibition of c-Jun N-Terminal Kinase Activation Contributes to Tumor Necrosis Factor Alpha-Induced Apoptosis

2002 ◽  
Vol 22 (24) ◽  
pp. 8571-8579 ◽  
Author(s):  
Fangming Tang ◽  
Guilin Tang ◽  
Jialing Xiang ◽  
Qing Dai ◽  
Marsha R. Rosner ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Biological Activities ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Induced Apoptosis ◽  
Jnk Activation ◽  
Necrosis Factor

ABSTRACT The proinflammatory cytokine tumor necrosis factor alpha (TNF-α) regulates immune responses, inflammation, and programmed cell death (apoptosis). TNF-α exerts its biological activities by activating multiple signaling pathways, including IκB kinase (IKK), c-Jun N-terminal protein kinase (JNK), and caspases. IKK activation inhibits apoptosis through the transcription factor NF-κB, whose target genes include those that encode inhibitors of both caspases and JNK. Despite activation of the antiapoptotic IKK/NF-κB pathway, TNF-α is able to induce apoptosis in cells sensitive to it, such as human breast carcinoma MCF-7 and mouse fibroblast LM cells. The molecular mechanism underlying TNF-α-induced apoptosis is incompletely understood. Here we report that in TNF-α-sensitive cells activation of the IKK/NF-κB pathway fails to block TNF-α-induced apoptosis, although its inactivation still promotes TNF-α-induced apoptosis. Interestingly, TNF-α-induced apoptosis is suppressed by inhibition of the JNK pathway but promoted by its activation. Furthermore, activation of JNK by TNF-α was transient in TNF-α-insensitive cells but prolonged in sensitive cells. Conversion of JNK activation from prolonged to transient suppressed TNF-α-induced apoptosis. Thus, absence of NF-κB-mediated inhibition of JNK activation contributes to TNF-α-induced apoptosis.

scholarly journals Tumor Necrosis Factor Alpha-Induced Interleukin-8 Production via NF-κB and Phosphatidylinositol 3-Kinase/Akt Pathways Inhibits Cell Apoptosis in Human Hepatocytes

2002 ◽  
Vol 70 (11) ◽  
pp. 6294-6301 ◽  
Author(s):  
Yosuke Osawa ◽  
Masahito Nagaki ◽  
Yoshiko Banno ◽  
David A. Brenner ◽  
Takahiko Asano ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Growth Inhibition ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Phosphatidylinositol 3 Kinase ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Induced Apoptosis ◽  
Necrosis Factor

ABSTRACT Tumor necrosis factor alpha (TNF-α) not only induces apoptotic signals but also causes antiapoptotic and regenerative responses in the liver. However, the molecular mechanism(s) of the latter events remains unclear. In the present study, we examined TNF-α-induced genes in Hc human normal (unsensitized) hepatocytes by cDNA microarray analysis. Interleukin-8 (IL-8) induction was the most pronounced of the upregulated genes. The IL-8 protein level was also increased. IL-8 belongs to the ELR-CXC chemokine family and appears to exert mitogenic and antiapoptotic functions in other cell systems. IL-8 expression by TNF-α was inhibited when two survival signals, nuclear factor κB (NF-κB) and phosphatidylinositol 3-kinase (PI3K)/Akt, were inhibited by a mutant form of inhibitor of NF-κB (IκB); by dominant negative (kinase-dead) Akt; or by treatment with LY 294002, an inhibitor of PI3K. TNF-α induced apoptosis in Hc cells that were sensitized by inhibition of NF-κB and PI3K activation. IL-8 administration protected mice against concanavalin A-induced hepatitis in vivo. IL-8 also rescued the sensitized Hc cells, at least in part, from TNF-α-induced apoptosis in vitro. TNF-α inhibited DNA synthesis in unsensitized Hc cells in the absence of serum. Exogenous IL-8 reversed, though anti-IL-8 neutralization antibody enhanced, growth inhibition by TNF-α. These results indicate that IL-8, the production of which is stimulated by TNF-α, inhibits apoptosis of sensitized hepatocytes and releases normal (unsensitized) hepatocytes from growth inhibition induced by TNF-α.

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