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IL-10 mediation of activation-induced TH1 cell apoptosis and lymphoid dysfunction in polymicrobial sepsis.

机译：IL-10介导的细菌性败血症中激活诱导的TH1细胞凋亡和淋巴功能障碍。

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Recent studies suggest that increased activation-induced lymphocyte apoptosis (AICD) is detected in mouse splenocytes during polymicrobial sepsis which may contribute to lymphocyte immune dysfunction [i.e., decreased interleukin (IL-)2 and interferon-gamma (IFN-gamma) production] leading to the associated morbidity seen in those animals. Thus, we wanted to examine the hypothesis that immune suppressive agents, such as IL-4, IL-10 or prostaglandin E2(PGE2), known to be elevated in septic animals, also contribute to this increase in AICD. Here we demonstrate that the inclusion of monoclonal antibody (mAb) to IL-10, but not anti-IL-4 or ibuprofen (IBU), blunted this sepsis induced increase in splenocyte AICD. Additionally, septic mice deficient in the IL-10 gene product (-/-) showed neither an increase in AICD nor a loss of IL-2/IFN-gamma release capacity. Interestingly, mAb to IL-10 did not altered the extent of AICD in a Th2-cell line, but exogenous IL-10 did potentiate Th1-like cell line AICD. This was consistent with the finding that the increased AICD seen in septic mouse splenocytes was restricted largely to the CD4+ cells producing IL-2 (Th1-cells) and that mAb to IL-10 treatment suppressed this change. Furthermore, IL-10 appears to mediate its AICD effect by upregulation of the Fas receptor and Fas receptor signaling protein components, but not by altered expression of Bcl/Bax/Bad family members, in septic mouse splenocytes. To the extent that these processes contribute in a pathological fashion to the animal's capacity to survive sepsis we have previously observed that in vivo post-treatment of mice with mAb IL-10 markedly attenuated septic mortality. Collectively, these data indicate that in the septic mouse the Th2 cytokine IL-10 not only serves to actively induce Th1 lymphocyte immune dysfunction but also plays a role in their apoptotic depletion. These processes in turn appear to contribute to the animal's inability to ward off lethal septic challenge. Copyright 2001 Academic Press.
机译：最近的研究表明，在多菌败血症期间，小鼠脾细胞中检测到活化诱导的淋巴细胞凋亡（AICD）增加，这可能导致淋巴细胞免疫功能障碍[即白介素（IL-）2和干扰素-γ（IFN-γ）产生减少]导致在那些动物中看到的相关发病率。因此，我们希望检验一种假设，即在脓毒症动物中免疫抑制剂（例如IL-4，IL-10或前列腺素E2（PGE2））升高，也有助于AICD的增加。在这里，我们证明了针对IL-10的单克隆抗体（mAb）的加入，但对抗IL-4或布洛芬（IBU）的抑制却使这种败血症诱导的脾细胞AICD的增加变得钝化。此外，缺乏IL-10基因产物（-/-）的败血症小鼠既没有AICD的增加，也没有IL-2 /IFN-γ释放能力的丧失。有趣的是，针对IL-10的mAb不会改变Th2细胞系中AICD的程度，但是外源性IL-10确实增强了Th1类细胞系AICD的作用。这与以下发现是一致的：在脓毒症小鼠脾细胞中见到的AICD增加主要限于产生IL-2的CD4 +细胞（Th1细胞），而针对IL-10的mAb处理抑制了这种变化。此外，在脓毒症小鼠脾细胞中，IL-10似乎通过上调Fas受体和Fas受体信号蛋白成分来介导其AICD效应，而不是通过Bcl / Bax / Bad家族成员表达的改变而介导。在一定程度上，这些过程以病理方式对动物的脓毒症生存能力做出了贡献，我们先前已经观察到，用mAb IL-10对小鼠的体内后处理显着降低了败血症死亡率。总体而言，这些数据表明，在败血性小鼠中，Th2细胞因子IL-10不仅可主动诱导Th1淋巴细胞免疫功能障碍，而且在其凋亡减少中起作用。这些过程反过来又有助于动物抵御致死性败血症的挑战。版权所有2001，学术出版社。

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