TY  - JOUR
A1  - Rudloff, Ina
A1  - Bachmann, Malte
A1  - Pfeilschifter, Josef
A1  - Mühl, Heiko
T1  - Mechanisms of rapid induction of interleukin-22 in activated T cells and its modulation by cyclosporin a
T2  - Journal of biological chemistry
N2  - 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 αCD3 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 IκB kinase (IKK) complex activation, the IKKα/β 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 IKKα impaired IL22 gene expression. Data presented suggest that NF-AT, CREB, and IKKα 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.
KW  - Cytokines Induction
KW  - Gene Regulation
KW  - Immunosuppression
KW  - Inflammation
KW  - Interleukin
KW  - T Cell Biology
KW  - Cyclosporin A
KW  - Interleukin-22
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/76648
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-766485
SN  - 0021-9258
VL  - 287.2012
IS  - 7
SP  - 4531
EP  - 4543
PB  - American Society for Biochemistry and Molecular Biology Publications
CY  - Bethesda, Md
ER  -