Ayala A, Chung C S, Song G Y, Chaudry I H
Center for Surgical Research and Department of Surgery, Brown University School of Medicine and Rhode Island Hospital, Providence, RI 02903, USA.
Cytokine. 2001 Apr 7;14(1):37-48. doi: 10.1006/cyto.2001.0848.
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.
近期研究表明，在多微生物败血症期间，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[即白细胞介素（IL-）-2和干扰素-γ（IFN-γ）产生减少]，进而导致这些动物出现相关的发病率。因此，我们想要检验这样一个假设，即免疫抑制剂，如IL-4、IL-10或前列腺素E2（PGE2），已知在败血症动物中水平升高，也会导致AICD的增加。在此我们证明，加入抗IL-10单克隆抗体（mAb），而非抗IL-4或布洛芬（IBU），可减弱败血症诱导的脾细胞AICD增加。此外，缺乏IL-10基因产物（-/-）的败血症小鼠既未出现AICD增加，也未丧失IL-2/IFN-γ释放能力。有趣的是，抗IL-10 mAb并未改变Th2细胞系中AICD的程度，但外源性IL-10确实增强了Th1样细胞系的AICD。这与以下发现一致，即败血症小鼠脾细胞中增加的AICD主要局限于产生IL-2的CD4+细胞（Th1细胞），且抗IL-10 mAb处理可抑制这种变化。此外，在败血症小鼠脾细胞中，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，而不是通过改变Bcl/Bax/Bad家族成员的表达。就这些过程以病理方式影响动物在败血症中的生存能力而言，我们之前观察到，用抗IL-10 mAb对小鼠进行体内治疗后，可显著降低败血症死亡率。总体而言，这些数据表明，在败血症小鼠中，Th2细胞因子IL-10不仅有助于积极诱导Th1淋巴细胞免疫功能障碍，还在其凋亡性消耗中发挥作用。反过来，这些过程似乎导致动物无法抵御致命的败血症挑战。
