TY - JOUR
T1 - Transforming growth factor-β-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
AU - Jono, Hirofumi
AU - Xu, Haidong
AU - Kai, Hirofumi
AU - Lim, David J.
AU - Kim, Young S.
AU - Feng, Xin Hua
AU - Li, Jian Dong
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2003/7/25
Y1 - 2003/7/25
N2 - In contrast to the extensive studies on the role of transforming growth factor-β (TGF-β) in regulating cell proliferation, differentiation, and apoptosis over the past decade, relatively little is known about the exact role of TGF-β signaling in regulating host response in infectious diseases. Most of the recent studies have suggested that TGF-β 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-β 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-β regulates host primary innate defensive responses, such as up-regulation of mucin, in the airway epithelial cells. Moreover, how the TGF-β-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 pathway. Activation of TGF-β-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-β signaling in attenuating host primary innate defensive responses and enhance our understanding of the signaling mechanism underlying the cross-talk between TGF-β-Smad signaling pathway and the p38 MAPK pathway.
AB - In contrast to the extensive studies on the role of transforming growth factor-β (TGF-β) in regulating cell proliferation, differentiation, and apoptosis over the past decade, relatively little is known about the exact role of TGF-β signaling in regulating host response in infectious diseases. Most of the recent studies have suggested that TGF-β 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-β 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-β regulates host primary innate defensive responses, such as up-regulation of mucin, in the airway epithelial cells. Moreover, how the TGF-β-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 pathway. Activation of TGF-β-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-β signaling in attenuating host primary innate defensive responses and enhance our understanding of the signaling mechanism underlying the cross-talk between TGF-β-Smad signaling pathway and the p38 MAPK pathway.
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U2 - 10.1074/jbc.M301773200
DO - 10.1074/jbc.M301773200
M3 - Article
C2 - 12734193
AN - SCOPUS:0042847362
VL - 278
SP - 27811
EP - 27819
JO - The Journal of biological chemistry
JF - The Journal of biological chemistry
SN - 0021-9258
IS - 30
ER -