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Originally published In Press as doi:10.1074/jbc.M206883200 on September 16, 2002
J. Biol. Chem., Vol. 277, Issue 47, 45547-45557, November 22, 2002
Transforming Growth Factor- -Smad Signaling
Pathway Cooperates with NF- B to Mediate Nontypeable
Haemophilus influenzae-induced MUC2 Mucin
Transcription*
Hirofumi
Jono ,
Tsuyoshi
Shuto §,
Haidong
Xu ,
Hirofumi
Kai§,
David J.
Lim ,
James R.
Gum Jr.¶,
Young S.
Kim¶,
Shoji
Yamaoka ,
Xin-Hua
Feng**, and
Jian-Dong
Li 
From the Gonda Department of Cell and Molecular
Biology, House Ear Institute, and Department of Otolaryngology,
University of Southern California, Los Angeles, California 90057, the
§ Department of Molecular Medicine, 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, the
Department of Molecular Virology, Tokyo Medical and Dental
University, Tokyo 113-8519 Japan, and the ** Michael E. DeBakey Department of Surgery and Department of Molecular and Cellular
Biology, Baylor College of Medicine, Houston, Texas 77030
Transforming growth factor- (TGF- ) and
related factors are multifunctional cytokines that regulate diverse
cellular processes, including proliferation, differentiation,
apoptosis, and immune response. The involvement of TGF-
receptor-mediated signaling in bacteria-induced up-regulation of mucin,
a primary innate defensive response for mammalian airways, however,
still remains unknown. Here, we report that the bacterium nontypeable
Haemophilus influenzae (NTHi), an important human
respiratory pathogen, utilizes the TGF- -Smad signaling
pathway together with the TLR2-MyD88-TAK1-NIK-IKK / -I B pathway to mediate NF- B-dependent
MUC2 mucin transcription. The NTHi-induced TGF- receptor
Type II phosphorylation occurred at as early as 5 min. Pretreatment
of NTHi with TGF- neutralization antibody reduced up-regulation of
MUC2 transcription. Moreover, functional cooperation of
NF- B p65/p50 with Smad3/4 appears to positively mediate
NF- B-dependent MUC2 transcription. These
data are the first to demonstrate the involvement of TGF-
receptor-mediated signaling in bacteria-induced up-regulation of mucin
transcription, bring insights into the novel role of TGF- signaling
in bacterial pathogenesis, and may lead to new therapeutic intervention
of NTHi infections.
*
This work was supported in part by grants from the National
Institutes of Health (RO1-DC04562) (to J. D. L.), CA24321 (to Y. S. K. and J. G.) and GM63773 (to X.-H. F.), the Department of
Veterans Affairs Medical Research Service (to J. G. and Y. S. K.),
American Cancer Society Research Project Grant RPG-00214-01-CCG (to
X.-H. F.), and the Henry L. Guenther Foundation (to D. J. L. and
J. D. L.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The 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: the Gonda Dept. of
Cell and Molecular Biology, House Ear Inst., University of Southern
California, 2100 W. 3rd St., Los Angeles, CA 90057. Tel.: 213-273-8083;
Fax: 213-273-8088; E-mail: jdli@hei.org.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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Copyright © 2002 by the American Society for Biochemistry and Molecular Biology.
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