Tumor necrosis factor alpha-mediated toxic shock in Trypanosoma cruzi-infected interleukin 10-deficient mice
Tumor necrosis factor alpha-mediated toxic shock in Trypanosoma cruzi-infected interleukin 10-deficient mice
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DOI：
10.1128/iai.68.7.4075-4083.2000
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发表时间：
2000-07-01
影响因子：
3.1
通讯作者：
Brombacher, F
中科院分区：
文献类型：
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作者：
Hölscher, C;Mohrs, M;Brombacher, F
利用白细胞介素-10（IL-10）-缺陷（IL-10（-/-））小鼠，先前的研究揭示了感染克氏锥虫后的病理性免疫应答，其与CD 4（+）T细胞和促炎细胞因子的过度产生有关。Cruzi感染的IL-10-/-小鼠表现出减少的寄生虫血症，伴随着γ干扰素（IFN-γ）、IL-12和活性氮中间体的全身释放增加以及肿瘤坏死因子α（TNF-α）的过度产生。尽管有这种早期抵抗，IL-10（-/-）小鼠在感染后第三周内死亡，而所有对照小鼠在急性感染后存活。濒死小鼠的临床表现包括体重减轻、体温过低、低血糖、高钾血症和血液中肝源性酶增加以及肝坏死和血管内凝血，表明可能由全身TNF-α过度产生介导的中毒性休克样综合征。事实上，全身TNF-α的高产生与死亡率显著相关，濒死小鼠在血液中TNF-α浓度极高时死亡。用TNF-α抗血清治疗可减轻T. cruzi感染的IL-10（-/-）小鼠的存活时间显著延长;小鼠在感染后第四周死亡，再次显示了全身TNF-α浓度升高与死亡时间之间的显著相关性。由于升高的血清IL-12和IFN-γ浓度不受抗血清给药的影响，这些研究表明TNF-α是这种中毒性休克综合征的直接介质。总之，在实验诱导的恰加斯病期间内源性IL-10的诱导似乎对于反调节过度促炎细胞因子反应导致TNF-α介导的中毒性休克至关重要。
Using interleukin-10 (IL-10)-deficient (IL-10(-/-)) mice, previous studies revealed a pathological immune response after infection with Trypanosoma cruzi that is associated with CD4(+) T cells and overproduction of proinflammatory cytokines, In this study we further investigate the pathology and potential mediators for the mortality in infected animals, T. cruzi-infected IL-10-/- mice showed reduced parasitemia accompanied by increased systemic release of gamma interferon (IFN-gamma), IL-12, and reactive nitrogen intermediates and over-production of tumor necrosis factor alpha (TNF-alpha). Despite this early resistance, IL-10(-/-) mice died within the third week of infection, whereas all control mice survived acute infection. The clinical manifestation with weight loss, hypothermia, hypoglycemia, hyperkalemia, and increased liver-derived enzymes in the blood together with hepatic necrosis and intravascular coagulation in moribund mice indicated a toxic shock-like syndrome, possibly mediated by the systemic TNF-alpha overproduction. Indeed, high production of systemic TNF-alpha significantly correlated with mortality, and moribund mice died with critically high TNF-alpha concentrations in the blood. Consequent treatment with and TNF-alpha antiserum attenuated pathological changes in T. cruzi-infected IL-10(-/-) mice acid significantly prolonged survival; the mice died during the fourth week postinfection, again with a striking correlation between regaining high systemic TNF-alpha concentrations and the time of death. Since elevated serum IL-12 and IFN-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 experimentally induced Chagas' disease seems to be crucial for counterregulating an overshooting proinflammatory cytokine response resulting in TNF-alpha-mediated toxic shock.