Bao Wenlei, Wang Yanfeng, Fu Yuting, Jia Xiaoyang, Li Jiaxin, Vangan Nyamtsengel, Bao Lili, Hao Huifang, Wang Zhigang
College of Life Science, Inner Mongolia University, Hohhot, China.
College of Life Science, Inner Mongolia University, Hohhot, China; College of Basic Medical Science, Inner Mongolia Medical University, Hohhot, China.
PLoS One. 2015 May 5;10(5):e0125910. doi: 10.1371/journal.pone.0125910. eCollection 2015.
Bacterial flagellin triggers inflammatory responses. Phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) regulate the production of pro- and anti-inflammatory cytokines that are induced by extrinsic antigens, but the function of mTORC1 in flagellin-induced inflammatory response is unknown. The purpose of this study was to examine the role and the mechanism of PI3K/Akt/mTOR pathway in flagellin-induced cytokine expression in mouse macrophages. We observed that flagellin upregulated TNF-α time- and dose-dependently. Flagellin stimulated rapid (<15 min) PI3K/Akt/mTOR phosphorylation that was mediated by TLR5. Inhibition of PI3K with LY294002 and wortmannin, and of mTORC1 with rapamycin decreased flagellin-induced TNF-α and IL-6 expression and cell proliferation. The activation of NF-κB p65 and STAT3 was regulated by mTORC1 via degradation of IκBα and phosphorylation of STAT3 in response to flagellin, respectively. Thus, the PI3K/Akt/mTORC1 pathway regulates the innate immune response to bacterial flagellin. Rapamycin is potential therapy that can regulate host defense against pathogenic infections.
细菌鞭毛蛋白可引发炎症反应。磷脂酰肌醇3激酶（PI3K）和雷帕霉素哺乳动物靶蛋白（mTOR）调节由外源性抗原诱导的促炎和抗炎细胞因子的产生，但mTORC1在鞭毛蛋白诱导的炎症反应中的功能尚不清楚。本研究的目的是探讨PI3K/Akt/mTOR信号通路在小鼠巨噬细胞中鞭毛蛋白诱导的细胞因子表达中的作用及机制。我们观察到鞭毛蛋白能时间和剂量依赖性地上调肿瘤坏死因子-α（TNF-α）。鞭毛蛋白刺激了由Toll样受体5（TLR5）介导的快速（<15分钟）PI3K/Akt/mTOR磷酸化。用LY294002和渥曼青霉素抑制PI3K，以及用雷帕霉素抑制mTORC1，可降低鞭毛蛋白诱导的TNF-α和白细胞介素-6（IL-6）表达及细胞增殖。mTORC1分别通过IκBα降解和STAT3磷酸化来调节鞭毛蛋白刺激下核因子κB p65（NF-κB p65）和信号转导子和转录激活子3（STAT3）的激活。因此，PI3K/Akt/mTORC1信号通路调节对细菌鞭毛蛋白的固有免疫反应。雷帕霉素是一种有潜力的疗法，可调节宿主对病原体感染的防御。
