title: Transforming growth factor-beta -Smad signaling pathway cooperates with NF-kappa B to mediate nontypeable Haemophilus influenzae-induced MUC2 mucin transcription.
abstract: Transforming growth factor-beta (TGF-beta) and related factors are multifunctional cytokines that regulate diverse cellular processes, including proliferation, differentiation, apoptosis, and immune response. The involvement of TGF-beta 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-beta-Smad signaling pathway together with the TLR2-MyD88-TAK1-NIK-IKKbeta/gamma-IkappaBalpha pathway to mediate NF-kappaB-dependent MUC2 mucin transcription. The NTHi-induced TGF-beta receptor Type II phosphorylation occurred at as early as 5 min. Pretreatment of NTHi with TGF-beta neutralization antibody reduced up-regulation of MUC2 transcription. Moreover, functional cooperation of NF-kappaB p65/p50 with Smad3/4 appears to positively mediate NF-kappaB-dependent MUC2 transcription. These data are the first to demonstrate the involvement of TGF-beta receptor-mediated signaling in bacteria-induced up-regulation of mucin transcription, bring insights into the novel role of TGF-beta signaling in bacterial pathogenesis, and may lead to new therapeutic intervention of NTHi infections.
authors.affiliation: Gonda Department of Cell and Molecular Biology, House Ear Institute, University of Southern California, Los Angeles, California 90057, USA.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Jono
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shuto
authors.forename: Haidong
authors.initials: H
authors.lastname: Xu
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kai
authors.forename: David J
authors.initials: DJ
authors.lastname: Lim
authors.forename: James R
authors.initials: JR
authors.lastname: Gum
authors.forename: Young S
authors.initials: YS
authors.lastname: Kim
authors.forename: Shoji
authors.initials: S
authors.lastname: Yamaoka
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Feng
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation / Q000378:metabolism; D019898:Autocrine Communication; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D029721:Drosophila Proteins; D005786:Gene Expression Regulation; D005798:Genes, Bacterial; D017930:Genes, Reporter; D006193:Haemophilus influenzae / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D008954:Models, Biological; D055262:Mucin-2; D009077:Mucins / Q000235:genetics* / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D012703:Serotyping; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D008562:Membrane Glycoproteins; D055262:Mucin-2; D009077:Mucins; D053594:Myeloid Differentiation Factor 88; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D051785:Smad Proteins; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D000097782:NF-kappaB-Inducing Kinase; C524625:MUC2 protein, human; C507779:MYD88 protein, human; C000606204:NFKBIA protein, human; C490515:NR2C2 protein, human; C495342:TLR2 protein, human; C496559:CHUK protein, human; C496560:IKBKB protein, human; C496565:IKBKE protein, human