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HIF-1 Is Up-Regulated in Activated Mast Cells by a Process That Involves Calcineurin and NFAT¹

Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland

Mast cells play important roles in many pathological conditions where local hypoxia is observed, including asthma, rheumatic diseases, and certain types of cancer. Here, we investigated how expression of the hypoxia-inducible factor 1, subunit gene (HIF1A), is regulated in mast cells. The product of HIF1A is hypoxia-inducible factor 1 (HIF-1), is a major nuclear transcription factor modulating gene expression in response to hypoxic conditions. We observed that under hypoxic conditions, exposure of mast cells to ionomycin and substance P resulted in significant up-regulation of HIF1A expression as compared with resting mast cells incubated under identical conditions. The ionomycin-mediated increase in HIF-1 protein levels was sensitive to the transcription inhibitor actinomycin D and to inhibitors of calcineurin, cyclosporin A (CsA), and FK506. The increased HIF-1 protein level was paralleled by a severalfold increase in HIF-1 mRNA that could be also inhibited with actinomycin D and CsA. The HIF1A promoter activity was significantly increased in ionomycin-activated mast cells, and the promoter activity could be inhibited by CsA and FK506. Furthermore, in situ mutagenesis experiments showed that the ionomycin-mediated HIF1A promoter activity depends on a conservative NFAT-binding site. Thus, accumulation of HIF-1 in activated mast cells requires up-regulation of HIF1A gene transcription and depends on the calcineurin-NFAT signaling pathway.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by the Ministry of Science and Higher Education Grant 2 P05A 089 26.

² Address correspondence and reprint requests to Dr. Jaroslaw Dastych, Institute of Medical Biology Polish Academy of Sciences, Lodowa 106 Strasse, 93-232 Lodz, Poland. E-mail address: jdastych{at}cbm.pan.pl

³ Abbreviations used in this paper: HIF-1, hypoxia-inducible transcription factor 1; HIF-1, hypoxia-inducible transcription factor 1; HRE, hypoxia-responsive element; HIF1A, hypoxia-inducible factor 1, subunit (basic helix-loop-helix transcription factor) gene; CaN, calcineurin; CsA, cyclosporine A; ActD, actinomycin D; ChIP, chromatin immunoprecipitation.