title: Cyclosporine differentially regulates interleukin-10, interleukin-15, and tumor necrosis factor a production by rheumatoid synoviocytes.
abstract: OBJECTIVE
  To determine the direct effect of cyclosporin A (CSA) on the production of cytokines by rheumatoid synovial fibroblasts.
  
  
  METHODS
  Fibroblast-like synoviocytes (FLS) were prepared from the synovial tissues of patients with rheumatoid arthritis and cultured in the presence of CSA. The production of interleukin-10 (IL-10), IL-15, and tumor necrosis factor a (TNFalpha) by FLS was measured in culture supernatants by enzyme-linked immunosorbent assay. The expression of IL-10, IL-15, and TNFalpha messenger RNA (mRNA) in FLS was determined by polymerase chain reaction (PCR).
  
  
  RESULTS
  CSA (1-1,000 ng/ml) increased the production of IL-10, but decreased in a dose-dependent manner the levels of IL-15 and TNFalpha that were spontaneously secreted from FLS. CSA also potently inhibited the production of IL-15 and TNFalpha stimulated with interferon-gamma, IL-1beta, or lipopolysaccharide. The inhibitory effect of CSA on IL-15 and TNFalpha production depended on the increase in IL-10, since neutralizing anti-IL-10 antibodies were able to partially reverse this inhibition. In a semiquantitative PCR, CSA increased IL-10 mRNA expression but strongly suppressed IL-1beta-induced IL-15 and TNFalpha mRNA expression, indicating that the production of these cytokines by CSA was regulated at the transcriptional level. Results with the calcineurin inhibitor FK-506, but not with the immunosuppressant rapamycin, were similar to those with CSA. Agonists of cAMP displayed an additive effect on the changes produced in the IL-10, IL-15, and TNFalpha levels by CSA, while a cAMP antagonist almost completely abrogated the effect of CSA, suggesting that cAMP is the major intracellular signal that mediates cytokine regulation by CSA.
  
  
  CONCLUSIONS
  These results suggest that CSA differentially regulates the production of cytokines by rheumatoid synoviocytes via a cAMP-dependent pathway.
authors.affiliation: The Center for Rheumatic Diseases in Kang-Nam St. Mary's Hospital, Catholic University of Korea, Seoul.
authors.forename: Mi-La
authors.initials: ML
authors.lastname: Cho
authors.forename: Wan-Uk
authors.initials: WU
authors.lastname: Kim
authors.forename: So-Youn
authors.initials: SY
authors.lastname: Min
authors.forename: Do-June
authors.initials: DJ
authors.lastname: Min
authors.forename: Jun-Ki
authors.initials: JK
authors.lastname: Min
authors.forename: Sang-Heon
authors.initials: SH
authors.lastname: Lee
authors.forename: Sung-Hwan
authors.initials: SH
authors.lastname: Park
authors.forename: Chul-Soo
authors.initials: CS
authors.lastname: Cho
authors.forename: Ho-Youn
authors.initials: HY
authors.lastname: Kim
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000963:Antimetabolites / Q000494:pharmacology; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D003994:Bucladesine / Q000494:pharmacology; D065095:Calcineurin Inhibitors; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics* / Q000276:immunology; D016048:Dideoxyadenosine / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D019409:Interleukin-15 / Q000235:genetics / Q000276:immunology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D013583:Synovial Membrane / Q000166:cytology*; D016559:Tacrolimus / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D000963:Antimetabolites; D018501:Antirheumatic Agents; D065095:Calcineurin Inhibitors; D016207:Cytokines; D007166:Immunosuppressive Agents; D019409:Interleukin-15; D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D016048:Dideoxyadenosine; D003994:Bucladesine; D016572:Cyclosporine; D000242:Cyclic AMP; D015056:1-Methyl-3-isobutylxanthine; D016559:Tacrolimus