Staphylococcal enterotoxin B (SEB), a bacterial superantigen, activates the immune system resulting in a burst of pro- and anti-inflammatory cytokines. A central anti-inflammatory mediator in this process is IL-10. Using IL-10-deficient C57BL/6 (IL-10 KO) mice, we studied the role of endogenous IL-10 in the regulation of the immune response to SEB. SEB (100 microg) induced the release of IL-10 in control C57BL/6 [IL-10 wild type (WT)] mice, but not in their IL-10 KO counterparts. SEB-evoked plasma levels of TNF-alpha, IL-1beta, IL-2, IL-6, IL-12 and IFN-gamma were significantly higher in the IL-10 KO mice than in the WT animals. The release of macrophage inflammatory proteins-1alpha and -2 was also enhanced in the IL-10 KO mice. Further, upon SEB challenge, mice deficient in IL-10 produced higher levels of nitric oxide than the WT animals. IL-10 deficiency resulted in a marked enhancement of the SEB-induced apoptosis of thymocytes. Finally, IL-10 KO mice were more susceptible to SEB-induced lethal shock than their WT controls. These results show that IL-10 plays an important immunoregulatory role in the response to a superantigenic stimulus, by dampening of the shock-inducing inflammatory response and early activation-induced cell death elicited by SEB.