title: Tumour necrosis factor-α suppresses the hypoxic response by NF-κB-dependent induction of inhibitory PAS domain protein in PC12 cells.
abstract: Inflammation is often accompanied by hypoxia. However, crosstalk between signalling pathways activated by inflammation and signalling events that control adaptive response to hypoxia is not fully understood. Here we show that exposure to tumour necrosis factor-α (TNF-α) activates expression of the inhibitory PAS domain protein (IPAS) to suppress the hypoxic response caused by hypoxia-inducible factor (HIF)-1 and HIF-2 in rat pheochromocytoma PC12 cells but not in human hepatoma Hep3B cells. This induction of IPAS was dependent on the nuclear factor-κB (NF-κB) pathway and attenuated hypoxic induction of HIF-1 target genes such as tyrosine hydroxylase (TH) and vascular endothelial growth factor (VEGF). HIF-dependent reporter activity in hypoxia was also decreased following TNF-α treatment. Knockdown of IPAS mRNA by small interfering RNA (siRNA) restored the TNF-α-suppressed hypoxic response. These results indicate that TNF-α is a cell-type specific suppressor of HIFs and suggest a novel crosstalk between stimulation by inflammatory mediators and HIF-dependent hypoxic response.
authors.affiliation: Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Sendai 980-8578, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Goryo
authors.forename: Satoru
authors.initials: S
authors.lastname: Torii
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Yasumoto
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Sogawa
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D000860:Hypoxia / Q000235:genetics*; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics; D007249:Inflammation / Q000235:genetics; D053858:Metabolic Networks and Pathways; D016328:NF-kappa B / Q000378:metabolism; D016716:PC12 Cells; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D013312:Stress, Physiological; D014157:Transcription Factors / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051793:Hypoxia-Inducible Factor 1; D016328:NF-kappa B; D034741:RNA, Small Interfering; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D014446:Tyrosine 3-Monooxygenase; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C424683:Hif3a protein, rat