mTORC1 Regulates Flagellin-Induced Inflammatory Response in Macrophages.
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.
College of Life Science, Inner Mongolia University, Hohhot, China.
Wenlei
W
Bao
College of Life Science, Inner Mongolia University, Hohhot, China.
Yanfeng
Y
Wang
College of Life Science, Inner Mongolia University, Hohhot, China.
Yuting
Y
Fu
College of Life Science, Inner Mongolia University, Hohhot, China.
Xiaoyang
X
Jia
College of Life Science, Inner Mongolia University, Hohhot, China.
Jiaxin
J
Li
College of Life Science, Inner Mongolia University, Hohhot, China.
Nyamtsengel
N
Vangan
College of Life Science, Inner Mongolia University, Hohhot, China; College of Basic Medical Science, Inner Mongolia Medical University, Hohhot, China.
Lili
L
Bao
College of Life Science, Inner Mongolia University, Hohhot, China.
Huifang
H
Hao
College of Life Science, Inner Mongolia University, Hohhot, China.
Zhigang
Z
Wang
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D002867:Chromones / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005408:Flagellin / Q000378:metabolism* / Q000494:pharmacology; D005786:Gene Expression Regulation; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D046912:Multiprotein Complexes / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D051198:Toll-Like Receptor 5 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D002867:Chromones; D016207:Cytokines; D009025:Morpholines; D046912:Multiprotein Complexes; D016328:NF-kappa B; D000081082:Phosphoinositide-3 Kinase Inhibitors; D050796:STAT3 Transcription Factor; D051198:Toll-Like Receptor 5; D014409:Tumor Necrosis Factor-alpha; D005408:Flagellin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases