title: IL-13 dampens human airway epithelial innate immunity through induction of IL-1 receptor-associated kinase M.
abstract: BACKGROUND
  Impaired airway mucosal immunity can contribute to increased respiratory tract infections in asthmatic patients, but the involved molecular mechanisms have not been fully clarified. Airway epithelial cells serve as the first line of respiratory mucosal defense to eliminate inhaled pathogens through various mechanisms, including Toll-like receptor (TLR) pathways. Our previous studies suggest that impaired TLR2 function in T(H)2 cytokine-exposed airways might decrease immune responses to pathogens and subsequently exacerbate allergic inflammation. IL-1 receptor-associated kinase M (IRAK-M) negatively regulates TLR signaling. However, IRAK-M expression in airway epithelium from asthmatic patients and its functions under a T(H)2 cytokine milieu remain unclear.
  
  
  OBJECTIVE
  We sought to evaluate the role of IRAK-M in IL-13-inhibited TLR2 signaling in human airway epithelial cells.
  
  
  METHODS
  We examined IRAK-M protein expression in epithelia from asthmatic patients versus that in normal airway epithelia. Moreover, IRAK-M regulation and function in modulating innate immunity (eg, TLR2 signaling) were investigated in cultured human airway epithelial cells with or without IL-13 stimulation.
  
  
  RESULTS
  IRAK-M protein levels were increased in asthmatic airway epithelium. Furthermore, in primary human airway epithelial cells, IL-13 consistently upregulated IRAK-M expression, largely through activation of phosphoinositide 3-kinase pathway. Specifically, phosphoinositide 3-kinase activation led to c-Jun binding to human IRAK-M gene promoter and IRAK-M upregulation. Functionally, IL-13-induced IRAK-M suppressed airway epithelial TLR2 signaling activation (eg, TLR2 and human β-defensin 2), partly through inhibiting activation of nuclear factor κB.
  
  
  CONCLUSIONS
  Our data indicate that epithelial IRAK-M overexpression in T(H)2 cytokine-exposed airways inhibits TLR2 signaling, providing a novel mechanism for the increased susceptibility of infections in asthmatic patients.
authors.affiliation: Department of Medicine, National Jewish Health and the University of Colorado Denver, Denver, CO 80206, USA.
authors.forename: Qun
authors.initials: Q
authors.lastname: Wu
authors.forename: Di
authors.initials: D
authors.lastname: Jiang
authors.forename: Sean
authors.initials: S
authors.lastname: Smith
authors.forename: Jyoti
authors.initials: J
authors.lastname: Thaikoottathil
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Martin
authors.forename: Russell P
authors.initials: RP
authors.lastname: Bowler
authors.forename: Hong Wei
authors.initials: HW
authors.lastname: Chu
mesh_terms: D001249:Asthma / Q000276:immunology*; D002478:Cells, Cultured; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D053592:Interleukin-1 Receptor-Associated Kinases / Q000096:biosynthesis*; D018793:Interleukin-13 / Q000276:immunology / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: D018793:Interleukin-13; D016328:NF-kappa B; D034741:RNA, Small Interfering; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D019869:Phosphatidylinositol 3-Kinases; C507771:IRAK3 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; D048031:JNK Mitogen-Activated Protein Kinases