Mechanisms of rapid induction of interleukin-22 in activated T cells and its modulation by cyclosporin A

Ina Rudloff, Malte Bachmann, Josef Pfeilschifter, Heiko Muhl

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10 Citations (Scopus)

Abstract

IL-22 is an immunoregulatory cytokine displaying pathological functions in models of autoimmunity like experimental psoriasis. Understanding molecular mechanisms driving IL-22, together with knowledge on the capacity of current immunosuppressive drugs to target this process, may open an avenue to novel therapeutic options. Here, we sought to characterize regulation of human IL22 gene expression with focus on the established model of Jurkat T cells. Moreover, effects of the prototypic immunosuppressant cyclosporin A (CsA) were investigated. We report that IL-22 induction by TPA/A23187 (T/A) or alphaCD3 is inhibited by CsA or related FK506. Similar data were obtained with peripheral blood mononuclear cells or purified CD3(+) T cells. IL22 promoter analysis (-1074 to +156 bp) revealed a role of an NF-AT (-95/-91 nt) and a CREB (-194/-190 nt) binding site for gene induction. Indeed, binding of CREB and NF-ATc2, but not c-Rel, under the influence of T/A to those elements could be proven by ChIP. Because CsA has the capability to impair IkappaB kinase (IKK) complex activation, the IKKalpha/beta inhibitor IKKVII was evaluated. IKKVII likewise reduced IL-22 induction in Jurkat cells and peripheral blood mononuclear cells. Interestingly, transfection of Jurkat cells with siRNA directed against IKKalpha impaired IL22 gene expression. Data presented suggest that NF-AT, CREB, and IKKalpha contribute to rapid IL22 gene induction. In particular the crucial role of NF-AT detected herein may form the basis of direct action of CsA on IL-22 expression by T cells, which may contribute to therapeutic efficacy of the drug in autoimmunity.
Original languageEnglish
Pages (from-to)4531 - 4543
Number of pages13
JournalThe Journal of Biological Chemistry
Volume287
Issue number7
DOIs
Publication statusPublished - 2012
Externally publishedYes

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