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Hypoxia-inducible factor induction by tumour necrosis factor in normoxic cells requires receptor-interacting protein-dependent nuclear factor kappa B activation.

ABSTRACT: Tumour necrosis factor alpha (TNF-alpha) binds to its receptor (TNFR1) and activates both death- and inflammation/survival-related signalling pathways. The inflammation and survival-related signalling cascade results in the activation of the transcription factor, nuclear factor kappa B (NF-kappa B) and requires recruitment of receptor-interacting protein (RIP) to TNFR1. The indispensable role of RIP in TNF-induced NF-kappa B activation has been demonstrated in RIP(-/-) mice and in cell lines derived from such mice. In the present study, we show that the TNF-alpha-induced accumulation of hypoxia-inducible factor 1 alpha (HIF-1 alpha) protein in normoxic cells is RIP-dependent. Exposing fibroblasts derived from RIP(-/-) mice to either cobalt or PMA resulted in an equivalent HIF-1 alpha induction to that seen in RIP(+/+) fibroblasts. In contrast, RIP(-/-) cells were unable to induce HIF-1 alpha in response to TNF-alpha. Further, transient transfection of NIH 3T3 cells with an NF-kappa B super-repressor plasmid (an inhibitor of NF-kappa B activation) also prevented HIF-1 alpha induction by TNF-alpha. Surprisingly, although HIF-1 alpha mRNA levels remained unchanged after induction by TNF, induction of HIF-1 alpha protein by the cytokine was completely blocked by pretreatment with the transcription inhibitors actinomycin D and 5,6-dichlorobenzimidazole riboside. Finally, TNF failed to induce both HIF-1 alpha, made resistant to von Hippel-Lindau (VHL), and wild-type HIF-1 alpha transfected into VHL(-/-) cells. These results indicate that HIF-1 alpha induction by TNF-alpha in normoxic cells is mediated by protein stabilization but is nonetheless uniquely dependent on NF-kappa B-driven transcription. Thus the results describe a novel mechanism of HIF-1 alpha up-regulation and they identify HIF-1 alpha as a unique component of the NF-kappa B-mediated inflammatory/survival response.

SUBMITTER: Jung Y

PROVIDER: S-EPMC1223232 | biostudies-other | 2003 Mar

REPOSITORIES: biostudies-other

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Project description:BackgroundThe humoral system is activated and various cytokines are released due to infections in tissues and traumatic damage. Nuclear factor-kappa B dimers are encoded by nuclear factor-kappa B genes and regulate transcription of several crucial proteins of inflammation such as tumour necrosis factor-alpha.AimsTo investigate the possible effect of polymorphisms on tumour necrosis factor-alpha serum levels with clinical and prognostic parameters of sepsis by determining the nuclear factor-kappa B-1-94 ins/del ATTG and tumour necrosis factor-alpha (-308 G/A) gene polymorphisms and tumour necrosis factor-alpha serum levels.Study designCase-control study.MethodsSeventy-two patients with sepsis and 104 healthy controls were included in the study. In order to determine the polymorphisms of nuclear factor-kappa B-1-94 ins/del ATTG and tumour necrosis factor-alpha (-308 G/A), polymerase chain reaction-restriction fragment length polymorphism analysis was performed and serum tumour necrosis factor-alpha levels were determined using an enzyme-linked immunosorbent assay.ResultsWe observed no significant differences in tumour necrosis factor-alpha serum levels between the study groups. In the patient group, an increase in the tumour necrosis factor-alpha serum levels in patients carrying the tumour necrosis factor-alpha (-308 G/A) A allele compared to those without the A allele was found to be statistically significant. Additionally, an increase in the tumour necrosis factor-alpha serum levels in patients carrying tumour necrosis factor-alpha (-308 G/A) AA genotype compared with patients carrying the AG or GG genotypes was statistically significant. No significant differences were found in these 2 polymorphisms between the patient and control groups (p>0.05).ConclusionOur results showed the AA genotype and the A allele of the tumour necrosis factor-alpha (-308 G/A) polymorphism may be used as a predictor of elevated tumour necrosis factor-alpha levels in patients with sepsis.

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Hypoxia-inducible factor induction by tumour necrosis factor in normoxic cells requires receptor-interacting protein-dependent nuclear factor kappa B activation.

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