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

Transient receptor potential ankyrin repeat 1 (TRPA1) forms calcium (Ca2+)- and zinc (Zn2+)-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-alpha and interleukin-1 alpha) induced TRPA1 gene expression via nuclear factor-kappa B signaling and downstream activation of the transcription factor hypoxia-inducible factor-1 alpha (HIF1 alpha). HIF1 alpha 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 Zn2+, suppressed secretion of interleukin-6 and interleukin-8. The data suggest a previously unrecognized HIF1 alpha mechanism that links inflammatory mediators to ion channel expression.