title: MAPK kinase 3 potentiates Chlamydia HSP60-induced inflammatory response through distinct activation of NF-κB.
abstract: Chlamydia pneumonia (C. pneumonia) remains one of the leading causes of bacterial pneumonia and has been implicated in the pathogenesis of some inflammation-related diseases, such as asthma, chronic obstructive pulmonary disease, and vascular diseases. Heat shock protein 60 is one of the pathogenic components of C. pneumonia that is closely associated with the inflammatory disorders. However, the molecular basis for the immunopathologic property of chlamydial heat shock protein (cHSP60) has not been elucidated. In this article, we report that MAPK kinase 3 (MKK3) is essential for cHSP60-induced lung inflammation, because MKK3-knockout mice displayed significantly reduced lung neutrophil accumulation and decreased production of proinflammatory mediators, correlating with the alleviated inflammatory response in lung tissues. Mechanistically, p38 kinase was selectively activated by MKK3 in response to cHSP60 and activated NF-κB by stimulating the nuclear kinase, mitogen- and stress-activated protein kinase 1. The specific knockdown of mitogen- and stress-activated protein kinase 1 in macrophages resulted in a defective phosphorylation of NF-κB/RelA at Ser(276) but had no apparent effect on RelA translocation. Furthermore, TGF-β-activated kinase 1 was found to relay the signal to MKK3 from TLR4, the major receptor that sensed cHSP60 in the initiation of the inflammatory response. Thus, we establish a critical role for MKK3 signaling in cHSP60 pathology and suggest a novel mechanism underlying C. pneumonia-associated inflammatory disorders.
authors.affiliation: Department of Basic Medical Science, Key Laboratory of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Kang
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Zhe
authors.initials: Z
authors.lastname: Lu
authors.forename: Hangjie
authors.initials: H
authors.lastname: Ying
authors.forename: Hang
authors.initials: H
authors.lastname: Zhang
authors.forename: Wen
authors.initials: W
authors.lastname: Ding
authors.forename: Cuili
authors.initials: C
authors.lastname: Wang
authors.forename: Liyun
authors.initials: L
authors.lastname: Shi
mesh_terms: D000818:Animals; D002460:Cell Line; D018834:Chaperonin 60 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D023521:Chlamydophila Infections / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D016993:Chlamydophila pneumoniae / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D004306:Dose-Response Relationship, Immunologic; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism* / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D018834:Chaperonin 60; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3