title: LY294002 inhibits TLR3/4-mediated IFN-β production via inhibition of IRF3 activation with a PI3K-independent mechanism.
abstract: TLR3 and TLR4 utilize adaptor TRIF to activate interferon regulatory factor 3 (IRF3), resulting in interferon β (IFN-β) production to mediate anti-viral infection. In this report, we analyzed the effect of two known phosphatidylinositol 3-kinase (PI3K) inhibitors LY294002 and wortmannin on LPS- and poly(I:C)-induced IFN-β production in peritoneal macrophages. LY294002 inhibited LPS- and poly(I:C)-induced IFN-β transcription and secretion. In contrast, wortmannin could not inhibit IFN-β production. Furthermore, IRF3 transcriptional activation and binding to IFN-β promoter were found to be inhibited by LY294002. Therefore, our findings demonstrate LY294002 negatively regulates LPS- and poly(I:C)-induced IFN-β production through inhibition of IRF3 activation in a PI3K-independent manner.
authors.affiliation: Department of Immunology, Shandong University Medical School, Jinan, Shandong 250012, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.forename: Jianni
authors.initials: J
authors.lastname: Qi
authors.forename: Lijuan
authors.initials: L
authors.lastname: Wang
authors.forename: Meng
authors.initials: M
authors.lastname: Zhang
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.forename: Chengjiang
authors.initials: C
authors.lastname: Gao
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002867:Chromones / Q000378:metabolism / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D016899:Interferon-beta / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000378:metabolism / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011070:Poly I-C / Q000276:immunology / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta; D008070:Lipopolysaccharides; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011070:Poly I-C; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D000077191:Wortmannin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one