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B Kinase (IKK) 
and IKK
in ERK-Dependent Up-Regulation of MUC5AC Mucin Transcription by Streptococcus pneumoniae1
* Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642;
Gonda Department of Cell and Molecular Biology, House Ear Institute, University of Southern California, Los Angeles, CA 90057;
Children’s Hospital, Harvard Medical School, Boston, MA 02115; and
Institute of Signaling, Developmental Biology and Cancer Research, Nice, France
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, I
B kinase (IKK) 
and IKK
are distinctly involved in MUC5AC induction via an ERK1-dependent, but IB-p65- and p100-p52-independent, mechanism, thereby revealing novel roles for IKKs in mediating up-regulation of MUC5AC mucin by S. pneumoniae.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by National Institutes of Health Grants DC004562 and DC005843 (to J.-D.L.), AI067737 and AI057784 (to R.M.), Training Grants DC008703 (to U.H.) and AI07061 (to A.S.), and a grant from the Ligue Nationale Contre le Cancer "Eqipes Labellisées" (to G.P. and J.P.).
2 U.H. and J.H.L. contributed equally.
3 Address correspondence and reprint requests to Dr. Jian-Dong Li, Department of Microbiology and Immunology, University of Rochester Medical Center, Box 672, 601 Elmwood Avenue, Rochester, NY 14642. E-mail address: Jian-Dong_Li{at}urmc.rochester.edu
4 Abbreviations used in this paper: IKK, IB kinase; IRAK1, IL-1R-associated kinase 1; TRAF6, TNFR-associated factor 6; EGF, epidermal growth factor; WT, wild type; Ply mt, pneumolysin-deficient mutant; LDH, lactate dehydrogenase; NHBE, primary human bronchial epithelial; MEF, mouse embryonic fibroblast; DN, dominant negative; TK, thymidine kinase; siRNA, small-interfering RNA; Q-PCR, quantitative PCR; NTHi, nontypeable Haemophilus influenzae; Tpl2, tumor progression locus 2; ELK, Ets-like transcription factor.
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  T. Koga, J. H. Lim, H. Jono, U. H. Ha, H. Xu, H. Ishinaga, S. Morino, X. Xu, C. Yan, H. Kai, et al. Tumor Suppressor Cylindromatosis Acts as a Negative Regulator for Streptococcus pneumoniae-induced NFAT Signaling J. Biol. Chem., May 2, 2008; 283(18): 12546 - 12554. [Abstract] [Full Text] [PDF]
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