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

Mi La Cho, Ji Hyeon Ju, Kyoung Woon Kim, Young Mee Moon, Seon Yeong Lee, So Youn Min, Young Gyu Cho, Hyun Sook Kim, Kyung Su Park, Chong Hyeon Yoon, Sang Heon Lee, Sung Hwan Park, Ho Youn Kim

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52 Scopus citations

Abstract

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-κB 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-κB 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-κB signal pathway for IL-15-induced IL-17 production. CSA down-regulated the phosphorylation of Akt and IκB. CSA inhibited binding of NF-κB 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-κB pathway in CD4+ T cells, which is possible mechanism of CSA in treating RA as NF-κB targeting strategy.

Original languageEnglish (US)
Pages (from-to)88-96
Number of pages9
JournalImmunology Letters
Volume108
Issue number1
DOIs
StatePublished - Jan 15 2007

Keywords

  • CD4 T cells
  • Cyclosporine A
  • IL-15
  • IL-17
  • NF-κB
  • PI3K
  • Rheumatoid arthritis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Cho, M. L., Ju, J. H., Kim, K. W., Moon, Y. M., Lee, S. Y., Min, S. Y., Cho, Y. G., Kim, H. S., Park, K. S., Yoon, C. H., Lee, S. H., Park, S. H., & Kim, H. Y. (2007). Cyclosporine A inhibits IL-15-induced IL-17 production in CD4+ T cells via down-regulation of PI3K/Akt and NF-κB. Immunology Letters, 108(1), 88-96. https://doi.org/10.1016/j.imlet.2006.11.001