Transcription Factor HIF-1α Controls Expression of the Cytokine IL-22 in CD4 T Cells
Transcription Factor HIF-1α Controls Expression of the Cytokine IL-22 in CD4 T Cells
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DOI：
10.4049/jimmunol.1600250
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发表时间：
2016-10-01
影响因子：
4.4
通讯作者：
Zenewicz, Lauren A.
中科院分区：
文献类型：
--
作者：
Budda, Scott A.;Girton, Alanson;Zenewicz, Lauren A.
IL-22由活化的淋巴细胞表达，并且在炎症期间调节组织反应中是重要的。细胞因子诱导上皮细胞中的增殖和抗凋亡途径，从而提高细胞存活率。这可能有积极的影响，如在维持胃肠道上皮屏障，但也有负面影响，如有助于结直肠肿瘤的发生。由于IL-22可以是双重性质的，我们假设其生物活性应该受到严格调控，以限制IL-22在炎症部位的表达。一个这样的环境线索可能是低氧，这通常伴随着炎症。我们发现，在CD 4 T细胞中，IL-22的表达在缺氧中上调。IL-22启动子含有一个保守的缺氧反应元件，提示转录因子HIF-1 α可能影响IL-22的表达。在二甲基氧烯丙基甘氨酸（一种常氧下HIF-1 α的稳定剂）存在下的分化增加了IL-22的表达。使用HIF-1 α缺陷的CD 4 T细胞，我们表明缺氧IL-22上调依赖于HIF-1 α。这些发现对IL 22基因表达的调节和细胞因子在不同炎症环境中的存在具有影响。
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.