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.