Interruption of macrophage-derived IL-27(p28) production by IL-10 during sepsis requires STAT3 but not SOCS3.
Interruption of macrophage-derived IL-27(p28) production by IL-10 during sepsis requires STAT3 but not SOCS3.
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DOI：
10.4049/jimmunol.1302280
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发表时间：
2014-12-01
期刊：
影响因子：
--
通讯作者：
Ward PA
中科院分区：
文献类型：
--
作者：
Bosmann M;Russkamp NF;Strobl B;Roewe J;Balouzian L;Pache F;Radsak MP;van Rooijen N;Zetoune FS;Sarma JV;Núñez G;Müller M;Murray PJ;Ward PA
严重脓毒症和脓毒性休克是世界范围内发病率和死亡率的主要原因。预防相关炎症促进脓毒症不良结局的发展和进展。异源二聚体白细胞介素-27（IL-27; p28/EBI 3）的作用与脓毒症的自然病程有关，而脓毒症中IL-27基因表达和释放调控的分子机制尚不清楚。在这份报告中，我们研究了调节IL-27的p28亚基在盲肠结扎和穿孔后的内毒素休克和多微生物败血症的事件。IL-27（p28）的中和抗体在脓毒症期间改善了C57 BL/6小鼠的存活率，限制了细胞因子释放并降低了细菌负荷。IL-27信号转导的遗传破坏增强了巨噬细胞的呼吸爆发。使用脾切除小鼠或氯膦酸盐脂质体治疗的实验表明，脾中的巨噬细胞可能是脓毒症期间IL-27（p28）的重要来源。在TLR 4激活的巨噬细胞培养物中，F4/80+ CD 11b +IL-27（p28）+细胞的频率随着IL-10的加入而降低。IL-10拮抗IL-27（p28）的MyD 88依赖性和TRIF依赖性释放。Tie 2-Cre/STAT 3flox巨噬细胞中STAT 3的基因缺失完全中断了TLR 4激活后IL-10对IL-27（p28）的抑制。相比之下，在Tie 2-Cre/SOCS 3flox巨噬细胞中，IL-10保持完全活性以抑制IL-27（p28），同时缺失SOCS 3。抗体阻断IL-10受体或IL-10遗传缺陷导致内毒素休克和多微生物败血症中IL-27（p28）浓度升高3-5倍。我们的研究确定IL-10是感染相关炎症过程中IL-27（p28）产生的关键抑制因子。这些发现可能有助于对脓毒症期间不利的IL-27（p28）释放进行有益的操纵。
Severe sepsis and septic shock are leading causes of morbidity and mortality worldwide. Infection-associated inflammation promotes the development and progression of adverse outcomes in sepsis. The effects of heterodimeric Interleukin-27 (IL-27; p28/EBI3) have been implicated in the natural course of sepsis, while the molecular mechanisms underlying regulation of gene expression and release of IL-27 in sepsis are poorly understood. In this report we studied the events regulating the p28 subunit of IL-27 in endotoxic shock and polymicrobial sepsis following cecal ligation and puncture. Neutralizing antibodies to IL-27(p28) improved survival rates, confined cytokine release and reduced bacterial burden in C57BL/6 mice during sepsis. Genetic disruption of IL-27 signaling enhanced the respiratory burst of macrophages. Experiments using splenectomized mice or treatment with clodronate liposomes suggested macrophages in the spleen may be a significant source of IL-27(p28) during sepsis. In cultures of TLR4-activated macrophages, the frequency of F4/80+CD11b+IL-27(p28)+ cells was reduced with addition of IL-10. IL-10 antagonized both MyD88-dependent and TRIF-dependent release of IL-27(p28). Genetic deletion of STAT3 in Tie2-Cre/STAT3flox macrophages completely interrupted the inhibition of IL-27(p28) by IL-10 after TLR4-activation. In contrast, IL-10 remained fully active to suppress IL-27(p28) with deletion of SOCS3 in Tie2-Cre/SOCS3flox macrophages. Blockade of the IL-10 receptor by antibody or genetic deficiency of IL-10 resulted in 3-5-fold higher concentrations of IL-27(p28) in endotoxic shock and polymicrobial sepsis. Our studies identify IL-10 as a critical suppressing factor for IL-27(p28) production during infection-associated inflammation. These findings may be helpful for a beneficial manipulation of adverse IL-27(p28) release during sepsis.
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DOI：
10.1084/jem.20100410
发表时间：
2011-01-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Cox JH;Kljavin NM;Ramamoorthi N;Diehl L;Batten M;Ghilardi N
通讯作者：
Ghilardi N
影响因子：
15.3
作者：
Liu, Jianguo;Guan, Xiuqin;Ma, Xiaojing
通讯作者：
Ma, Xiaojing
影响因子：
120.7
作者：
Boomer, Jonathan S.;To, Kathleen;Chang, Kathy C.;Takasu, Osamu;Osborne, Dale F.;Walton, Andrew H.;Bricker, Traci L.;Jarman, Stephen D., II;Kreisel, Daniel;Krupnick, Alexander S.;Srivastava, Anil;Swanson, Paul E.;Green, Jonathan M.;Hotchkiss, Richard S.
通讯作者：
Hotchkiss, Richard S.
影响因子：
32.4
作者：
Pflanz, S;Timans, JC;Kastelein, RA
通讯作者：
Kastelein, RA
影响因子：
32.4
作者：
Hamano, S;Himeno, K;Yoshida, H
通讯作者：
Yoshida, H