IN-VIVO INHIBITION OF ENDOTOXIN-INDUCED PRO-INFLAMMATORY CYTOKINES PRODUCTION BY THE SIGMA-LIGAND SR-31747

In previous studies, the authors demonstrated that the new sigma ligan d, l-3-(3-chloro-4-cyclohexyl-phenyl)propen-2-ylamine hydrochloride (S R 31747), elicited a suppressive effect on immune responses through th e sigma receptor expressed on lymphocytes. Here the effect of SR 31747 on the proinflammatory cytokine production by endotoxin-activated mac rophages is examined. In vivo, SR 31747 dramatically blocked lipopolys accharide-induced production of interleukin (IL)-1, IL-6 and tumor nec rosis factor-alpha in a dose-dependent manner (ED(50), 2 mg/kg). Where as SR 31747 suppression was not observed in vitro on lipopolysaccharid e-induced IL-6 by macrophages, sera from SR 31747-treated animals disp layed a strong inhibitory activity. It was shown that this effect coul d be completely reversed by the steroid receptor antagonist, mifeprist one, which suggests that SR 31747 probably abrogated monokine producti on through an indirect mechanism that involves endogenous corticostero ids. This conclusion was supported by in vivo experiments that showed that 1) ablation of corticosteroids by use of mifepristone or adrenale ctomy suppressed the effect of SR 31747 and 2) administration of SR 31 747 induced an enhancement of the corticosterone level. it was also sh own that this molecule improved the survival of animals with endotoxin ic shock as a result of monokine inhibition. The combination of immuno suppression, previously described, along with anti-inflammatory proper ties makes SR 31747 a novel attractive molecule for therapeutic applic ations such as autoimmune diseases in which both immune and inflammato ry disorders are involved.