Transcription Factor HIF-1α Controls Expression of the Cytokine IL-22 in CD4 T Cells

IL-22 is expressed by activated lymphocytes and is important in modulation of tissue responses during inflammation. The cytokine induces proliferative and antiapoptotic pathways in epithelial cells allowing enhanced cell survival. This can have positive effects, such as in the maintenance of epithelial barriers in the gastrointestinal tract, but also negative effects, such as contributing to colorectal tumorigenesis. Because IL-22 can be dual-natured, we hypothesized that its biological activity should be tightly regulated to limit IL-22 expression to the sites of inflammation. One such environmental cue could be low oxygen, which often accompanies inflammation. We show that in CD4 T cells IL-22 expression is upregulated in hypoxia. The Il22 promoter contains a putative conserved hypoxic response element suggesting that the transcription factor HIF-1 alpha may influence IL-22 expression. Differentiation in the presence of dimethyloxallyl glycine, a stabilizer of HIF-1 alpha at normoxia, increased IL-22 expression. Using HIF-1 alpha-deficient CD4 T cells, we show that hypoxic IL-22 upregulation is dependent on HIF-1 alpha. These findings have implications on the regulation of Il22 gene expression and the presence of the cytokine in different inflammatory environments.