IFN-γ is a master regulator of endotoxin shock syndrome in mice primed with heat-killed Propionibacterium acnes
IFN-γ is a master regulator of endotoxin shock syndrome in mice primed with heat-killed Propionibacterium acnes
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DOI：
10.1093/intimm/dxp122
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发表时间：
2010-03-01
影响因子：
4.4
通讯作者：
Nakanishi, Kenji
中科院分区：
文献类型：
--
作者：
Kawa, Kosuke;Tsutsui, Hiroko;Nakanishi, Kenji
内毒素休克综合征的主要临床表现是高凝、低体温、全身炎症反应和休克。如前所述，用热灭活痤疮丙酸杆菌致敏的小鼠对LPS诱导肿瘤坏死因子（TNF）-α和TNF-α引发致死性休克的作用高度敏感。在这里，我们研究了痤疮丙酸杆菌诱导的LPS和TNF-α致敏的机制，以及随后用LPS或TNF-α攻击后个体症状的发展。痤疮丙酸杆菌致敏的野生型（WT）小鼠，而不是幼稚小鼠，表现出高凝状态，血浆中凝血酶-抗凝血酶复合物和抗纤溶纤溶酶原激活物抑制剂1水平升高，体温过低，全身炎症反应和LPS或TNF-α攻击后的高死亡率。据报道痤疮丙酸杆菌处理诱导T（h）1和T（h）17细胞发育。痤疮丙酸杆菌致敏的Il 12 p40（-/-）和Ifn γ（-/-）小鼠，而不是Il 17 A（-/-）小鼠，在LPS或TNF-α攻击后逃避所有这些症状/体征，表明IL-12-IFN-γ轴对于LPS和TNF-α的致敏性是必需的。此外，就在LPS攻击之前阻断IFN-γ可以防止痤疮丙酸杆菌致敏的WT小鼠发生内毒素休克综合征。这些结果表明IFN-γ对内毒素休克的发展是必需的，并提示其作为治疗感染性休克的有效治疗靶点。
Hyper-coagulation, hypothermia, systemic inflammatory responses and shock are major clinical manifestations of endotoxin shock syndrome in human. As previously reported, mice primed with heat-killed Propionibacterium acnes are highly susceptible to the action of LPS to induce tumour necrosis factor (TNF)-alpha and to that of TNF-alpha to trigger lethal shock. Here we investigated the mechanisms underlying the P. acnes-induced sensitization to LPS and TNF-alpha and the development of individual symptoms after subsequent challenge with LPS or TNF-alpha. Propionibacterium acnes-primed wild-type (WT) mice, but not naive mice, exhibited hyper-coagulation with elevated levels of thrombin-antithrombin complexes and anti-fibrinolytic plasminogen activator inhibitor 1 in their plasma, hypothermia, systemic inflammatory responses and high mortality rate after LPS or TNF-alpha challenge. Propionibacterium acnes treatment reportedly induces both T(h)1 and T(h)17 cell development. Propionibacterium acnes-primed Il12p40(-/-) and Ifn gamma(-/-) mice, while not Il17A(-/-) mice, evaded all these symptoms/signs upon LPS or TNF-alpha challenge, indicating essential requirement of IL-12-IFN-gamma axis for the sensitization to LPS and TNF-alpha. Furthermore, IFN-gamma blockade just before LPS challenge could prevent P. acnes-primed WT mice from endotoxin shock syndrome. These results demonstrated requirement of IFN-gamma to the development of endotoxin shock and suggested it as a potent therapeutic target for the treatment of septic shock.