Tumor necrosis factor alpha-mediated toxic shock in Trypanosoma cruzi-infected interleukin 10-deficient mice

Using interleukin-10 (IL-10)-deficient (IL-10(-/-)) mice, previous studies revealed a pathological immune response after infection with Trypanosoma cr uzi that is associated with CD4(+) T cells and overproduction of proinflamm atory cytokines, In this study we further investigate the pathology and pot ential mediators for the mortality in infected animals, T. cruzi-infected I L-10-/- mice showed reduced parasitemia accompanied by increased systemic r elease of gamma interferon (IFN-gamma), IL-12, and reactive nitrogen interm ediates and over-production of tumor necrosis factor alpha (TNF-alpha). Des pite this early resistance, IL-10(-/-) mice died within the third week of i nfection, whereas all control mice survived acute infection. The clinical m anifestation with weight loss, hypothermia, hypoglycemia, hyperkalemia, and increased liver-derived enzymes in the blood together with hepatic necrosi s and intravascular coagulation in moribund mice indicated a toxic shock-li ke syndrome, possibly mediated by the systemic TNF-alpha overproduction. In deed, high production of systemic TNF-alpha significantly correlated with m ortality, and moribund mice died with critically high TNF-alpha concentrati ons in the blood. Consequent treatment with and TNF-alpha antiserum attenua ted pathological changes in T. cruzi-infected IL-10(-/-) mice acid signific antly prolonged survival; the mice died during the fourth week postinfectio n, again with a striking correlation between regaining high systemic TNF-al pha concentrations and the time of death. Since elevated serum IL-12 and IF N-gamma concentrations were not affected by the administration of antiserum , these studies suggest that TNF-alpha is the direct mediator of this toxic shock syndrome. In conclusion, induction of endogenous IL-10 during experi mentally induced Chagas' disease seems to be crucial for counterregulating an overshooting proinflammatory cytokine response resulting in TNF-alpha-me diated toxic shock.