Adverse functions of IL-17A in experimental sepsis
Adverse functions of IL-17A in experimental sepsis
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DOI：
10.1096/fj.07-105221
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发表时间：
2008-07-01
期刊：
影响因子：
4.8
通讯作者：
Ward, Peter A.
中科院分区：
文献类型：
--
作者：
Flierl, Michael A.;Rittirsch, Daniel;Ward, Peter A.
IL-17 A是由多种细胞产生的促炎细胞因子。在本研究中，我们研究了IL-17 A在盲肠结扎穿孔（CLP）诱导的小鼠脓毒症中的作用。IL-17 A水平，上升的时间依赖性在CLP后的血浆中，不受影响的情况下，α β T细胞或中性粒细胞。形成鲜明对比的是，γ δ T细胞敲除或γ δ T细胞耗尽的小鼠在CLP后显示基线IL-17 A血浆水平。通过两种不同的抗体中和IL-17 A改善了脓毒症（存活率从近似10%到接近60%）。出乎意料的是，抗体治疗是保护性的，即使在CLP后抗IL-17 A的施用延迟长达12小时。IL-17 A阻断的这些保护作用与菌血症水平的显著降低以及血浆中全身促炎细胞因子和趋化因子的显著降低相关。在IL-17 A的共同存在下，小鼠腹腔巨噬细胞与脂多糖（LPS）的体外孵育显著增加了这些细胞的TNF-α、IL-1 β和IL-6的产生。这些数据表明，在实验性脓毒症期间，γ δ T细胞衍生的IL-17 A促进高水平的促炎介质和菌血症，导致致死率提高。IL-17 A可能是脓毒症潜在的治疗靶点。
IL-17A is a proinflammatory cytokine produced by a variety of cells. In the current study, we examined the role of IL-17A in sepsis induced in mice by cecal ligation and puncture (CLP). IL-17A levels, which rose time-dependently in plasma after CLP, were not affected in the absence of alpha beta T cells or neutrophils. In sharp contrast, gamma delta T cell-knockout or gamma delta T cell-depleted mice displayed baseline IL-17A plasma levels after CLP. Neutralization of IL-17A by two different antibodies improved sepsis (survival from similar to 10% to nearly 60%). Unexpectedly, antibody treatment was protective, even when administration of anti-IL-17A was delayed for up to 12 h after CLP. These protective effects of IL-17A blockade were associated with substantially reduced levels of bacteremia together with significant reductions of systemic proinflammatory cytokines and chemokines in plasma. In vitro incubation of mouse peritoneal macrophages with lipopolysaccharide (LPS) in the copresence of IL-17A substantially increased the production of TNF-alpha, IL-1 beta, and IL-6 by these cells. These data suggest that, during experimental sepsis, gamma delta T cell-derived IL-17A promotes high levels of proinflammatory mediators and bacteremia, resulting in enhanced lethality. IL-17A may be a potential therapeutic target in sepsis.