title: Hypoxia-inducible factor-1α (HIF1α) switches on transient receptor potential ankyrin repeat 1 (TRPA1) gene expression via a hypoxia response element-like motif to modulate cytokine release.
abstract: Transient receptor potential ankyrin repeat 1 (TRPA1) forms calcium (Ca(2+))- and zinc (Zn(2+))-permeable ion channels that sense noxious substances. Despite the biological and clinical importance of TRPA1, there is little knowledge of the mechanisms that lead to transcriptional regulation of TRPA1 and of the functional role of transcriptionally induced TRPA1. Here we show induction of TRPA1 by inflammatory mediators and delineate the underlying molecular mechanisms and functional relevance. In human fibroblast-like synoviocytes, key inflammatory mediators (tumor necrosis factor-α and interleukin-1α) induced TRPA1 gene expression via nuclear factor-κB signaling and downstream activation of the transcription factor hypoxia-inducible factor-1α (HIF1α). HIF1α unexpectedly acted by binding to a specific hypoxia response element-like motif and its flanking regions in the TRPA1 gene. The induced TRPA1 channels, which were intrinsically activated by endogenous hydrogen peroxide and Zn(2+), suppressed secretion of interleukin-6 and interleukin-8. The data suggest a previously unrecognized HIF1α mechanism that links inflammatory mediators to ion channel expression.
authors: Laboratory of Cellular Pharmacology, School of Pharmacy, Aichi-Gakuin University, 1-100 Kusumoto, Chikusa, Nagoya 464-8650, Japan.
authors: Noriyuki
authors: N
authors: Hatano
authors: Yuka
authors: Y
authors: Itoh
authors: Hiroka
authors: H
authors: Suzuki
authors: Yukiko
authors: Y
authors: Muraki
authors: Hidetoshi
authors: H
authors: Hayashi
authors: Kikuo
authors: K
authors: Onozaki
authors: Ian C
authors: IC
authors: Wood
authors: David J
authors: DJ
authors: Beech
authors: Katsuhiko
authors: K
authors: Muraki
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001483:Base Sequence; D002118:Calcium / Q000737:chemistry; D015220:Calcium Channels / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007249:Inflammation; D007473:Ion Channels / Q000737:chemistry; D051379:Mice; D008954:Models, Biological; D008957:Models, Genetic; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D015398:Signal Transduction; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000378:metabolism*; D015032:Zinc / Q000737:chemistry
chemical_list: D015220:Calcium Channels; D016207:Cytokines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007473:Ion Channels; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050051:Transient Receptor Potential Channels; D015032:Zinc; D002118:Calcium