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 ligand, cis-N-cyclohexyl-N-ethyl-3-(3-chloro-4-cyclohexyl-phenyl) propen-2-ylamine hydrochloride (SR 31747), elicited a suppressive effect on immune responses through the sigma receptor expressed on lymphocytes. Here the effect of SR 31747 on the proinflammatory cytokine production by endotoxin-activated macrophages is examined. In vivo, SR 31747 dramatically blocked lipopolysaccharide-induced production of interleukin (IL)-1, IL-6 and tumor necrosis factor-alpha in a dose-dependent manner (ED50, 2 mg/kg). Whereas SR 31747 suppression was not observed in vitro on lipopolysaccharide-induced IL-6 by macrophages, sera from SR 31747-treated animals displayed a strong inhibitory activity. It was shown that this effect could be completely reversed by the steroid receptor antagonist, mifepristone, which suggests that SR 31747 probably abrogated monokine production through an indirect mechanism that involves endogenous corticosteroids. This conclusion was supported by in vivo experiments that showed that 1) ablation of corticosteroids by use of mifepristone or adrenalectomy suppressed the effect of SR 31747 and 2) administration of SR 31747 induced an enhancement of the corticosterone level. It was also shown that this molecule improved the survival of animals with endotoxinic shock as a result of monokine inhibition. The combination of immunosuppression, previously described, along with anti-inflammatory properties makes SR 31747 a novel attractive molecule for therapeutic applications such as autoimmune diseases in which both immune and inflammatory disorders are involved.