IL-22 plays an important role in tissue repair and inflammatory responses, and is implicated in the pathogenesis of psoriasis, ulcerative colitis, as well as liver and pancreas damage. The molecular mechanisms of its regulation have been actively studied. Here, we show that the differential regulation of IL-22 expression in CD4(+) T cells by IL-6 and IL-27 was detected rapidly after stimulation. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays demonstrated that both STATI and STAT3 directly bind to the STAT responsive elements (SRE) of the IL-22 promoter, and the balance between activated STAT3 and STATI determines IL-22 promoter activities. We further show that the heterozygous mutation of the STATI gene results in elevated levels of IL-22 production and induces much severer skin inflammation in an imiquimod (IMQ)-induced murine psoriasis model. Together, our results reveal a novel regulatory mechanism of IL-22 expression by STATI through directly antagonizing STAT3, and the importance of the balance between STAT3 and STAT1 in IL-22 regulation and psoriasis pathogenesis. (C) 2018 Elsevier Inc. All rights reserved.