DIFFERENTIAL-EFFECTS OF THE IMMUNOSUPPRESSANTS CYCLOSPORINE-A, FK506 AND KM2210 ON CYTOKINE GENE-EXPRESSION

Cyclosporin A (CsA) inhibited interleukin 2 (IL-2), IL-3, interferon g amma (IFN gamma), GM-CSF and tumor necrosis factor alpha (TNF alpha) m RNA expression in spleen cells stimulated with concavalin A (Con A) wh en determined by the semi-quantitative reverse transcription-polymeras e chain reaction (RT-PCR) method, FK506 which has a similar immunosupp ressive mechanism to that of CsA also showed the same inhibitory effec ts except for decreased IL-5 and IL-6 mRNA expression, In contrast, bo th CsA and FK506 enhanced transforming growth factor beta (TGF beta) a nd IL-1 beta mRNA expression, Another immunosuppressant KM2210 did not show any inhibitory effects on cytokine gene expression but rather en hanced IL-10, IL-6, TGF beta and IL-1 mRNA expression, thus suggesting that KM2210 has a completely different immunosuppressive mechanism fr om that of CsA and FK506. Anti-TFG beta 1 antibody abrogated the suppr ession by KM2210 of BALB/c anti-C3H/He mixed lymphocyte reaction (MLR) whereas this antibody did not abrogate the suppression by CsA and FK5 06 of BALB/c anti-C3H/He MLR. These results indicate that TGF beta is one of the major cytokines in KM2210 immunosuppression, in addition to IL-10, but not in immunosuppression by CsA and FK506.