Transforming growth factor-beta-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.
In contrast to the extensive studies on the role of transforming growth factor-beta (TGF-beta) in regulating cell proliferation, differentiation, and apoptosis over the past decade, relatively little is known about the exact role of TGF-beta signaling in regulating host response in infectious diseases. Most of the recent studies have suggested that TGF-beta 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-beta 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-beta regulates host primary innate defensive responses, such as up-regulation of mucin, in the airway epithelial cells. Moreover, how the TGF-beta-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-beta-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-beta signaling in attenuating host primary innate defensive responses and enhance our understanding of the signaling mechanism underlying the cross-talk between TGF-beta-Smad signaling pathway and the p38 MAPK pathway.
Gonda Department of Cell and Molecular Biology, House Ear Institute, University of Southern California, Los Angeles, California 90057, USA.
Hirofumi
H
Jono
Haidong
H
Xu
Hirofumi
H
Kai
David J
DJ
Lim
Young S
YS
Kim
Xin-Hua
XH
Feng
Jian-Dong
JD
Li
D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D054638:Dual Specificity Phosphatase 1; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005799:Genes, Dominant; D006193:Haemophilus influenzae / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D055271:Mucin 5AC; D009077:Mucins / Q000096:biosynthesis* / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C524678:MUC5AC protein, human; D055271:Mucin 5AC; D009077:Mucins; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D008156:Luciferases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D017027:Protein Tyrosine Phosphatases