The effect of immunosuppressant FK506 on hepatic function of graft

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Studies were performed to determine whether the immunosuppressants FK506 and cyclosporin A directly influence gene expression of inducible nitric oxide synthase by IL-1β in hepatocytes. Methods : Primary cultures of rat hepatocytes were treated with IL-1β in the presence and absence of FK506 or cyclosporin A. Release of nitrite into culture medium, levels of inducible nitric oxide synthase protein and mRNA, and activation of NF-κB were compared with the two drugs. Results : IL-1β increased levels of inducible nitric oxide synthase protein and inducible nitric oxide synthase mRNA, as well as nitric oxide production, in the cultured hepatocytes. NF-κB, an important transcription factor in inducible nitric oxide synthase gene expression in response to inflammation, also appeared in the nuclear fraction of hepatocytes after addition of IL-1β. FK506 markedly inhibited the nitric oxide formation, inducible nitric oxide synthase protein synthesis and inducible nitric oxide synthase mRNA expression induced by IL-1β, but cyclosporin A had no effects. Furthermore, FK506 inhibited NF-κB activation and decreased mRNA levels of the p50/p65 subunits of NF-κB. Conclusions : These results demonstrate that FK506, but not cyclosporin A, inhibits the induction of inducible nitric oxide synthase expression during NF-κB activation