The Role of Cytotoxic T-Lymphocyte Associated Antigen 4 (CTLA4) +49A/G and Tumor Necrosis Factor Alpha (TNF-α) -308G/A Polymorphism in the Development of Celiac Disease in Jordanian Patients

ABSTRACTMice 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-α) in the development of toxin-mediated renal disease in mice. Mice pretreated with TNF-α 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-α administration succumbed more quickly than mice given Stx1 alone. Increased lethality in mice treated with Stx1 followed by TNF-α 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-α pretreatment group, although we noted a sparing of renal function when TNF-α was administered before toxin. Compared to that of treatment with Stx1 alone, treatment with TNF-α after toxin altered the renal cytokine profile so that the expression of proinflammatory cytokines TNF-α and interleukin-1β (IL-1β) increased, and the expression of the anti-inflammatory cytokine IL-10 decreased. Increased lethality in mice treated with Stx1 followed by TNF-α 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-α is a candidate interventional strategy blocking disease progression, while TNF-α production after intoxication exacerbates disease.

Download Full-text

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

Molecular and Cellular Biology ◽

10.1128/mcb.00287-06 ◽

2007 ◽

Vol 27 (5) ◽

pp. 1771-1783 ◽

Cited By ~ 38

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.

Download Full-text

Substitution of methionine 435 with leucine, isoleucine, and serine in tumor necrosis factor alpha converting enzyme inactivates ectodomain shedding activity

Biochemistry and Cell Biology ◽

10.1139/o06-179 ◽

2007 ◽

Vol 85 (1) ◽

pp. 141-149 ◽

Cited By ~ 13

Author(s):

Liliana Pérez ◽

John E. Kerrigan ◽

Xiaojin Li ◽

Huizhou Fan

Keyword(s):

Growth Factor ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Ectodomain Shedding ◽

Converting Enzyme ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Factor Alpha ◽

Necrosis Factor

Tumor necrosis factor alpha (TNF-α) converting enzyme (TACE) is a zinc metalloprotease that has emerged as a general sheddase, which is responsible for ectodomain release of numerous membrane proteins, including the proinflammatory cytokine TNF-α, the leukocyte adhesin l-selectin and epidermal growth factor receptor ligand-transforming growth factor α (TGF-α), and related family members. Structurally, TACE belongs to a large clan of proteases, designated the metzincins, because TACE possesses a conserved methionine (Met435), frequently referred to as the met-turn residue, in its active site. A vital role of this residue in the function of TACE is supported by the fact that cells expressing the M435I TACE variant are defective in ectodomain shedding. However, the importance of Met435 in TACE appears to be uncertain, since another metzincin, matrix metalloprotease-2, has been found to be enzymatically fully active with either leucine or serine in place of its met-turn residue. We constructed TACE mutants with leucine or serine in place of Met435 to further examine the role of the met-turn residue in TACE-mediated ectodomain cleavage. Similar to the M435I TACE mutant, both the M435L and M435S constructs are defective in cleaving transmembrane TNF-α, TGF-α, and l-selectin. Comparative modeling and dynamic computation detected structural perturbations, which resulted in higher energy, in the catalytic zinc complexes of the Met435 TACE mutants compared with that in the wild-type enzyme. Thus, Met435 serves to maintain the stability of the catalytic center of TACE for the hydrolysis of peptide bonds in substrates.

Download Full-text

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

Journal of the Egyptian Society of Parasitology ◽

10.12816/0010849 ◽

2015 ◽

Vol 45 (1) ◽

pp. 47-60 ◽

Cited By ~ 3

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

Download Full-text

Role of Tumor Necrosis Factor Alpha in Development of Immunity against Cryptosporidium parvum Infection

Infection and Immunity ◽

10.1128/iai.00195-06 ◽

2006 ◽

Vol 74 (7) ◽

pp. 4379-4382 ◽

Cited By ~ 17

Author(s):

I-Sarah Lean ◽

Sonia Lacroix-Lamandé ◽

Fabrice Laurent ◽

Vincent McDonald

Keyword(s):

Tumor Necrosis Factor ◽

Cryptosporidium Parvum ◽

Tumor Necrosis ◽

Necrosis Factor Alpha ◽

Parasite Invasion ◽

Tnf Α ◽

Factor Alpha ◽

Redundant Role ◽

Necrosis Factor

ABSTRACT Tumor necrosis factor (TNF-α) significantly reduced Cryptosporidium parvum development in a murine enterocyte cell line, and a key mechanism of action appeared to be inhibition of parasite invasion. However, TNF-α-deficient mice controlled infection as effectively as wild-type mice. This suggests that TNF-α might have only a redundant role for establishing immunity against C. parvum.

Download Full-text

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

Infection and Immunity ◽

10.1128/iai.69.11.6651-6659.2001 ◽

2001 ◽

Vol 69 (11) ◽

pp. 6651-6659 ◽

Cited By ~ 76

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.

Download Full-text

The Role of Tumor Necrosis Factor-alpha (TNF-α) in Skeletal Muscle Regeneration

Journal of Histochemistry & Cytochemistry ◽

10.1177/002215540104900807 ◽

2001 ◽

Vol 49 (8) ◽

pp. 989-1001 ◽

Cited By ~ 95

Author(s):

Rachel A. Collins ◽

Miranda D. Grounds

Keyword(s):

Skeletal Muscle ◽

Tumor Necrosis Factor ◽

Muscle Regeneration ◽

Tumor Necrosis ◽

Necrosis Factor Alpha ◽

Tissue Sections ◽

Tnf Α ◽

Factor Alpha ◽

Necrosis Factor

The role of tumor necrosis factor-alpha (TNF-α), an important mediator of the inflammatory response after injury, was investigated in regenerating skeletal muscle. The pattern of expression of TNF-α during muscle regeneration was examined by immunohistochemistry in tissue sections of crush-injured or transplanted muscle autografts and in primary cultures of adult skeletal muscle. TNF-α was highly expressed in injured myofibers, inflammatory cells, endothelial cells, fibroblasts, and mast cells. Myoblasts and myotubes also expressed TNF-α in primary muscle cultures and tissue sections. The essential role of TNF-α and its homologue lymphotoxin-alpha (LT-α) during muscle regeneration was assessed by basic histology in TNF-α(–) and TNF-α(-/-)/LT-α(-/-) mice. No difference was apparent in the onset or pattern of muscle regeneration (i.e., inflammatory response, activation and fusion of myoblasts) between the two strains of null mice or between nulls and normal control mice. However, both strains of null mice appeared more prone to bystander damage of host muscle and regeneration distant from the site of injury/transplantation. Although expression of TNF-α may play an important role in muscle regeneration, the studies in the null mice show that redundancy within the cytokine system (or some other response) can effectively compensate for the absence of TNF-α in vivo. (J Histochem Cytochem 49:989–1001, 2001)

Download Full-text