MAPK p38 antagonism as a novel method of inhibiting lymphoid immune suppression in polymicrobial sepsis.
MAPK p38 antagonism as a novel method of inhibiting lymphoid immune suppression in polymicrobial sepsis.
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DOI：
10.1152/ajpcell.2001.281.2.c662
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发表时间：
2001-08
期刊：
影响因子：
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通讯作者：
G. Y. Song;C. Chung;Irshad H. Chaudry;Alfred Ayala
中科院分区：
文献类型：
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作者：
G. Y. Song;C. Chung;Irshad H. Chaudry;Alfred Ayala
尽管研究表明，在败血症期间，从Th1应答到Th2应答的转变有助于显著抑制细胞介导的免疫，但其发生的机制尚不清楚。鉴于丝裂原活化蛋白激酶（MAPK） p38在免疫细胞的活化和功能中起着关键作用，本研究的目的是确定MAPK p38活化在多微生物脓毒症中所见的免疫功能障碍中的作用。为此，采用盲肠结扎穿刺法（CLP）诱导C3H/HeN雄性小鼠多微生物脓毒症。clp后24 h收集脾脏淋巴细胞和纯化的T细胞，用特异性MAPK p38抑制剂SB-203580预处理，然后用针对T细胞标记物CD3的单克隆抗体刺激。结果表明，CLP后，白细胞介素(IL)-2的释放明显降低，而免疫抑制介质IL-10的释放以及IL-10和IL-4的mRNA水平升高。抑制MAPK p38可抑制体外IL-10水平以及IL-10和IL-4基因表达，同时恢复IL-2的释放。为了确定这些体外发现是否可以转化为体内环境，小鼠在clp后12小时给予100 mg SB-203580/kg体重或生理盐水载体（腹腔内）。体外淋巴细胞反应性检查表明，与体外发现一样，脓毒症小鼠Th1反应性恢复。根据我们最近的发现，延迟体内SB-203580治疗也提高了CLP后的生存率，我们认为这些结果不仅说明了MAPK p38在脓毒症中诱导免疫抑制剂的作用，而且表明在脓毒症的初始促炎状态后给药SB-203580可以显著预防脓毒症的发病率。
Although studies indicate that a shift from a Th1 to a Th2 response contributes to a marked suppression of cell-mediated immunity during sepsis, the mechanism by which this occurs remains unknown. Given that the mitogen-activated protein kinase (MAPK) p38 plays a critical role in the activation and function of immune cells, the aim of this study was to determine the contribution of MAPK p38 activation to the immune dysfunction seen in polymicrobial sepsis. To study this, polymicrobial sepsis was induced in C3H/HeN male mice by cecal ligation and puncture (CLP). Splenic lymphocytes and purified T cells were harvested 24 h post-CLP, pretreated with the specific MAPK p38 inhibitor SB-203580, and then stimulated with a monoclonal antibody against the T cell marker CD3. The results indicate that interleukin (IL)-2 release is markedly depressed while the release of the immunosuppressive mediator, IL-10, as well as mRNA levels of IL-10 and IL-4, are augmented after CLP. Inhibition of MAPK p38 suppressed in vitro IL-10 levels as well as IL-10 and IL-4 gene expression while restoring the release of IL-2. To determine whether these in vitro findings could be translated to an in vivo setting, mice were given 100 mg of SB-203580/kg body wt or saline vehicle (intraperitoneal) at 12 h post-CLP. Examination of ex vivo lymphocyte responsiveness indicated that, as with the in vitro finding, septic mouse Th1 responsiveness was restored. In light of our recent finding that delayed in vivo SB-203580 treatment also improved survival after CLP, we believe that these results not only illustrate the role of MAPK p38 in the induction of immunosuppressive agents in sepsis but demonstrate that SB-203580 administration after the initial proinflammatory state of sepsis significantly prevents the morbidity from sepsis.