INTERLEUKIN-12 IS CRITICAL FOR INDUCTION OF NITRIC OXIDE-MEDIATED IMMUNOSUPPRESSION FOLLOWING VACCINATION OF MICE WITH ATTENUATED SALMONELLA-TYPHIMURIUM

Studies from our laboratory have shown that infection of mice with an attenuated strain of Salmonella typhimurium causes a marked suppressio n in the capacity of splenocytes to generate an in vitro plaque-formin g cell (PFC) response to sheep erythrocytes. The suppression has been shown to be mediated by mature, adherent macrophages (M phi s) and non adherent, precursor M phi s. Nitric oxide has been identified as the s uppressor factor. The present study investigated the role of interleuk in-12 (IL-12) in the generation of nitric oxide-mediated immunosuppres sion in this model. Salmonella inoculation resulted in marked suppress ion of PFC responses and high levels of nitrite production. When mice were treated with anti-IL-12 prior to inoculation, nitrite levels in s plenocyte cultures were reduced by 75% and the suppression of PFC resp onses,vas prevented. The nonadherent splenocyte fraction from Salmonel la-inoculated mice, which contains precursor M phi s and is weakly imm unosuppressive, was treated with IL-12 in vitro. IL-12 augmented the c apacity of this fraction to suppress PFC responses by normal splenocyt es in a coculture system. Additionally, IL-12 induced nitrite and gamm a interferon (IFN-gamma) production in a dose-dependent manner. Treatm ent with anti-IFN-gamma blocked nitrite production and suppression, in dicating that IFN-gamma is an important intermediary in the pathway of IL-12-induced immunosuppression. These results indicate that IL-12 is critical for the induction of nitric oxide-mediated immunosuppression following S. typhimurium inoculation and, through its ability to stim ulate IFN-gamma production, can induce nitric oxide-producing suppress or M phi s.