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Originally published In Press as doi:10.1074/jbc.M301773200 on May 6, 2003
J. Biol. Chem., Vol. 278, Issue 30, 27811-27819, July 25, 2003
Transforming Growth Factor- -Smad Signaling Pathway Negatively Regulates Nontypeable Haemophilus influenzae-induced MUC5AC Mucin Transcription via Mitogen-activated Protein Kinase (MAPK) Phosphatase-1-dependent Inhibition of p38 MAPK*
Hirofumi Jono  ,
Haidong Xu ,
Hirofumi Kai  ,
David J. Lim ,
Young S. Kim ¶,
Xin-Hua Feng || and
Jian-Dong Li **
From the
Gonda Department of Cell and Molecular
Biology, House Ear Institute, and the Department of Otolaryngology, University
of Southern California, Los Angeles, California 90057, the
Department of Molecular Medicine, Graduate
School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973,
Japan, the ¶Gastrointestinal Research Laboratory,
Veterans Affairs Medical Center and Department of Medicine, University of
California, San Francisco, California 94143, and the
||Michael E. DeBakey Department of Surgery and
Department of Molecular and Cellular Biology, Baylor College of Medicine,
Houston, Texas 77030
In contrast to the extensive studies on the role of transforming growth
factor- (TGF-) in regulating cell proliferation, differentiation,
and apoptosis over the past decade, relatively little is known about the exact
role of TGF- signaling in regulating host response in infectious
diseases. Most of the recent studies have suggested that TGF- inhibits
macrophage activation during infections with pathogens such as Trypanosoma
cruzi and Leishmania, thereby favoring virulence. In certain
situations, however, there is also evidence that TGF- has been
correlated with enhanced resistance to microbes such as Candida
albicans, thus benefiting the host. Despite these distinct observations
that mainly focused on macrophages, little is known about how TGF-
regulates host primary innate defensive responses, such as up-regulation of
mucin, in the airway epithelial cells. Moreover, how the TGF--Smad
signaling pathway negatively regulates p38 mitogen-activated protein kinase
(MAPK), a key pathway mediating host response to bacteria, still remains
largely unknown. Here we show that nontypeable Haemophilus
influenzae, a major human bacterial pathogen of otitis media and chronic
obstructive pulmonary diseases, strongly induces up-regulation of
MUC5AC mucin via activation of the Toll-like receptor
2-MyD88-dependent p38 path-way. Activation of TGF--Smad signaling,
however, leads to down-regulation of p38 by inducing MAPK phophatase-1,
thereby acting as a negative regulator for MUC5AC induction. These
studies may bring new insights into the novel role of TGF- signaling in
attenuating host primary innate defensive responses and enhance our
understanding of the signaling mechanism underlying the cross-talk between
TGF--Smad signaling pathway and the p38 MAPK pathway.
Received for publication, February 19, 2003
, and in revised form, May 3, 2003.
* This work was supported by National Institutes of Health Grants DC004562,
DC005843, and HL070293 (to J. D. L.), CA24321 (to Y. S. K. and J. G.), and
GM63773 (to X.-H. F.) and a grant from the Department of Veterans Affairs
Medical Research Service (to J. G. and Y. S. K.). 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.
**
To whom correspondence should be addressed: House Ear Inst., 2100 West Third
St., Los Angeles, CA 90057. E-mail:
jdli{at}hei.org.
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Copyright © 2003 by the American Society for Biochemistry and Molecular Biology.
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