Tumour necrosis factor-α suppresses the hypoxic response by NF-κB-dependent induction of inhibitory PAS domain protein in PC12 cells

Kenji Goryo, Satoru Torii, Ken Ichi Yasumoto, Kazuhiro Sogawa

    Research output: Contribution to journalArticlepeer-review

    13 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)311-318
    Number of pages8
    JournalJournal of biochemistry
    Volume150
    Issue number3
    DOIs
    Publication statusPublished - 2011 Sep 1

    Keywords

    • HIF-1
    • IPAS
    • NF-κB
    • TNF-α
    • hypoxic response

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology

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