THE PROTECTIVE ROLE OF ENDOGENOUSLY SYNTHESIZED NITRIC-OXIDE IN STAPHYLOCOCCAL-ENTEROTOXIN B-INDUCED SHOCK IN MICE

Nitric oxide (NO) synthesis during experimental endotoxemia has been s hown to have both deleterious and beneficial effects. In the present s tudy, we analyzed the in vivo production and the regulatory role of NO in the shock syndrome induced by staphylococcal enterotoxin B (SEB) i n mice. First, we found that intraperitoneal administration of 100 mu g SEB in BALB/c mice induced a massive synthesis of NO as indicated by high serum levels of nitrite (NO2-) and nitrate (NO3-) peaking 16 h a fter SEB injection. The inhibition of NO2- and NO3- release in mice in jected with anti-tumor necrosis factor (TNF) and/or anti-interferon ga mma (IFN-gamma) monoclonal antibody (mAb) before SEB challenge reveale d that both cytokines were involved in SEB-induced NO overproduction. In vitro experiments indicated that NO synthase (NOS) inhibition by N- nitro-L-arginine methyl ester (L-NAME) enhanced IFN-gamma and TNF prod uction by splenocytes in response to SEB. A similar effect was observe d in vivo as treatment of mice with L-NAME resulted in increased IFN-g amma and TNF serum levels 24 h after SEB challenge, together with pers istent expression of corresponding cytokine mRNA in spleen. The prolon ged production of inflammatory cytokines in mice receiving L-NAME and SEB was associated with a 95% mortality rate within 96 h, whereas all mice survived injections of SEB or L-NAME alone. Both TNF and IFN-gamm a were responsible for the lethality induced by SEB in L-NAME-treated mice as shown by the protection provided by simultaneous administratio n of anti-IFN-gamma and anti-TNF mAbs. We conclude the SEB induces NO synthesis in vivo and that endogenous NO has protective effects in thi s model of T cell-dependent shock by downregulating IFN-gamma and TNF production.