title: Lithium attenuates IFN-β production and antiviral response via inhibition of TANK-binding kinase 1 kinase activity.
abstract: Lithium salt is a widely used glycogen synthase kinase-3β inhibitor and effective drug for the treatment of psychiatric diseases. However, the effects of lithium in innate immune responses, especially in cellular antiviral responses, are unknown. In this study, we show that lithium chloride attenuates LPS-, polyinosinic-polycytidylic acid-, and Sendai virus-induced IFN-β production and IFN regulatory factor 3 activation in macrophages in a glycogen synthase kinase-3β-independent manner. The ability of the lithium to inhibit IFN-β production was confirmed in vivo, as mice treated with lithium chloride exhibited decreased levels of IFN-β upon Sendai virus infection. In vitro kinase assay demonstrates that lithium suppresses TANK-binding kinase 1 kinase activity. Consistently, lithium significantly enhanced the replication of vesicular stomatitis virus in vitro and in vivo. Severe infiltration of monocytes and tissue damage were observed in the lungs of control mice, compared with lithium-treated mice after virus infection. Our findings suggest lithium as an inhibitor of TANK-binding kinase 1 and potential target for the intervention of diseases with uncontrolled IFN-β production. Furthermore, lithium attenuates host defense to virus infection and may cause severely adverse effects in clinical applications.
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Xueying
authors.initials: X
authors.lastname: Zhao
authors.forename: Meng
authors.initials: M
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.forename: Chengjiang
authors.initials: C
authors.lastname: Gao
mesh_terms: D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D016899:Interferon-beta / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides; D018021:Lithium Chloride / Q000378:metabolism / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology; D011070:Poly I-C; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D010253:Respirovirus Infections / Q000276:immunology*; D029082:Sendai virus / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D050838:Interferon Regulatory Factor-3; D008070:Lipopolysaccharides; D034741:RNA, Small Interfering; D016899:Interferon-beta; C498588:Tbk1 protein, mouse; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D017346:Protein Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride; D011070:Poly I-C