A novel role for IkappaB kinase (IKK) alpha and IKKbeta in ERK-dependent up-regulation of MUC5AC mucin transcription by Streptococcus pneumoniae.
Epithelial cells represent the first line of host innate defense against invading microbes by elaborating a range of molecules involved in pathogen clearance. In particular, epithelial mucins facilitate the mucociliary clearance by physically trapping inhaled microbes. Up-regulation of mucin production thus represents an important host innate defense response against invading microbes. How mucin is induced in upper respiratory Streptococcus pneumoniae infections is unknown. In this study, we show that pneumolysin is required for up-regulation of MUC5AC mucin via TLR4-dependent activation of ERK in human epithelial cells in vitro and in mice in vivo. Interestingly, a "second wave" of ERK activation appears to be important in mediating MUC5AC induction. Moreover, IkappaB kinase (IKK) alpha and IKKbeta are distinctly involved in MUC5AC induction via an ERK1-dependent, but IkappaBalpha-p65- and p100-p52-independent, mechanism, thereby revealing novel roles for IKKs in mediating up-regulation of MUC5AC mucin by S. pneumoniae.
Ha
Unhwan
U
Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Lim
Jae Hyang
JH
Jono
Hirofumi
H
Koga
Tomoaki
T
Srivastava
Amit
A
Malley
Richard
R
Pagès
Gilles
G
Pouysségur
Jacques
J
Li
Jian-Dong
JD
D000818:Animals; D001426:Bacterial Proteins; D001980:Bronchi / Q000166:cytology; D002478:Cells, Cultured; D004847:Epithelial Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000502:physiology*; D007113:Immunity, Innate; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D055271:Mucin 5AC; D009077:Mucins / Q000235:genetics*; D013296:Streptococcus pneumoniae / Q000276:immunology*; D013301:Streptolysins; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics*
D001426:Bacterial Proteins; C524678:MUC5AC protein, human; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; D009077:Mucins; D013301:Streptolysins; C032290:plY protein, Streptococcus pneumoniae; D051550:I-kappa B Kinase; D048052:Mitogen-Activated Protein Kinase 3