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首页> 外文期刊>American Journal of Physiology >MAPK p38 antagonism as a novel method of inhibiting lymphoid immune suppression in polymicrobial sepsis.
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MAPK p38 antagonism as a novel method of inhibiting lymphoid immune suppression in polymicrobial sepsis.

机译：MAPK p38拮抗作用是一种抑制微生物败血症中淋巴样免疫抑制的新方法。

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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.
机译：尽管研究表明败血症期间从Th1应答转变为Th2应答可明显抑制细胞介导的免疫，但这种机制的发生机制仍然未知。鉴于有丝分裂原激活的蛋白激酶（MAPK）p38在免疫细胞的激活和功能中起着关键作用，因此本研究的目的是确定MAPK p38激活对在败血症中发现的免疫功能障碍的影响。为了研究这一点，通过盲肠结扎和穿刺（CLP）在C3H / HeN雄性小鼠中诱发了败血症。 CLP后24小时收获脾淋巴细胞和纯化的T细胞，用特异性MAPK p38抑制剂SB-203580预处理，然后用抗T细胞标记CD3的单克隆抗体刺激。结果表明，CLP后白介素（IL）-2的释放显着降低，而免疫抑制介质IL-10的释放以及IL-10和IL-4的mRNA水平增加。 MAPK p38的抑制抑制了体外IL-10水平以及IL-10和IL-4基因的表达，同时恢复了IL-2的释放。为了确定这些体外发现是否可以转化为体内设置，在CLP后12小时给小鼠服用100 mg SB-203580 / kg体重或生理盐水（腹膜内）。体外淋巴细胞反应性的检查表明，与体外发现一样，败血性小鼠Th1反应性得以恢复。根据我们最近的发现，延迟的SB-203580体内治疗还可以改善CLP后的存活率，我们相信这些结果不仅说明MAPK p38在脓毒症诱导免疫抑制剂中的作用，而且证明了SB-203580在脓毒症后给药败血症的初始促炎状态显着预防了败血症的发病率。

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