Cyclosporine A inhibits IL-15-induced IL-17 production in CD4+ T cells via down-regulation of PI3K/Akt and NF-κB

Cyclosporine A (CSA) has various biological effects on T cells, including inhibition of interleukin (IL)-15-induced IL-17 production in CD4(+) T cells from patients with rheumatoid arthritis (RA). However, the mechanism underlying this effect is not fully understood. Here, we tried to investigate the mechanism of CSA to inhibit IL-17 production induced by IL-15 in CD4(+) T cells. Synovial fluid and serum levels of IL-15 and IL-17 were determined by ELISA. CD4(+) T cells from RA patients were treated with IL-15 in the presence of CSA or several signal inhibitors. The concentration of IL-17 in culture supernatants was measured by ELISA and IL-17 mRNA expression was determined by RT-PCR. NF-kappa B binding activity for IL-17 transcription was assessed by electrophoretic mobility shift assay. IL-15 induced IL-17 production by CD4(+) T cells in dose-and time-dependent manner. IL-15-stimulated IL-17 production and mRNA expression were inhibited by CSA in CD4(+) T cells. Moreover PI3K/Akt inhibitor, NF-kappa B inhibitor, and FK506 significantly inhibited IL-15-induced IL-17 production in CD4(+) T cells. Inhibition studies revealed the requirement of PI3K/Akt and NF-kappa B signal pathway for IL-15-induced IL-17 production. CSA down-regulated the phosphorylation of Akt and I kappa B. CSA-inhibited binding of NF-kappa B to IL-17 promoter. The inhibitory effect of CSA on IL-15 induced IL-17 production partially depended on the increase in IL-10, since neutralizing anti-IL-10 antibodies were able to partially reverse this inhibition. CSA inhibits IL-17 production by CD4(+) T cells and this effect is mediated by IL-15-activated NF-kappa B pathway in CD4(+) T cells, which is possible mechanism of CSA in treating RA as NF-kappa B targeting strategy. (c) 2006 Elsevier B.V. All rights reserved.