REGULATION OF LIPOPOLYSACCHARIDE-INDUCED TUMOR-NECROSIS-FACTOR PRODUCTION BY CYCLOSPORINE-A IN MICE PRIMED WITH MURAMYL DIPEPTIDE

The effect of cyclosporin A (CsA) on tumor necrosis factor (TNF) or in terleukin-6 (IL-6) production was evaluated in vivo in primed or unpri med mice challenged with lipopolysaccharide (LPS). Both pretreatment w ith BCG infection or with muramyl dipeptide (MDP) prior to LPS challen ge resulted in an increase in the cytokine bioactivity level in the bl ood. CsA administration inhibited the TNF production. In unprimed mice , either normal or sensitized to LPS lethality by galactosamine treatm ent, a marked decrease in the cytokine level was observed after inject ion of CsA. After adrenalectomy, the yield of both TNF and IL-6 follow ing LPS injection was markedly elevated but decreased by CsA administr ation. Ex vivo experiments have shown that the inhibitory effect of Cs A could be demonstrated at the level of macrophages from mice previous ly given the drug. If mice had received MDP, in vitro responses of cel ls to LPS were enhanced but again CsA decreased the mRNA expression an d protein secretion.