title: The transforming growth factor-beta-Smad3/4 signaling pathway acts as a positive regulator for TLR2 induction by bacteria via a dual mechanism involving functional cooperation with NF-kappaB and MAPK phosphatase 1-dependent negative cross-talk with p38 MAPK.
abstract: The transforming growth factor beta (TGF-beta) pathway represents an important signaling pathway involved in the regulation of diverse biological processes, including cell proliferation, differentiation, and apoptosis. Despite the known role of TGF-betaR-mediated signaling in suppressing immune response, its role in regulating human Toll-like receptors (TLRs), key host defense receptors that recognize invading bacterial pathogens, however, remains unknown. Here, we show for the first time that TGF-betaR-Smad3/4 signaling pathway acts as a positive regulator for TLR2 induction by bacterium nontypeable Hemophilus influenzae (NTHi) in vitro and in vivo. The positive regulation of TLR2 induction by TGF-betaR is mediated via a dual mechanism involving distinct signaling pathways. One mechanism involves functional cooperation between the TGF-betaR-Smad3/4 pathway and NF-kappaB pathway. Another involves MAP kinase phosphatase 1 (MKP-1)-dependent inhibition of p38 MAPK, a known negative regulator for TLR2 induction. Moreover, we showed that TbetaR-mediated signaling is probably activated by NTHi-derived TGF-beta mimicry molecule via an autocrine-independent mechanism. Thus, our study provides new insights into the role of TGF-beta signaling in positively regulating host defense response by tightly controlling the expression level of TLR2 during bacterial infections and may lead to new therapeutic strategies for modulating host defense and inflammatory response.
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York 14642; Gonda Department of Cell and Molecular Biology, House Ear Institute, University of Southern California, Los Angeles, California 90057.
authors.forename: Fumi
authors.initials: F
authors.lastname: Mikami
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York 14642; Gonda Department of Cell and Molecular Biology, House Ear Institute, University of Southern California, Los Angeles, California 90057.
authors.forename: Jae Hyang
authors.initials: JH
authors.lastname: Lim
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York 14642; Gonda Department of Cell and Molecular Biology, House Ear Institute, University of Southern California, Los Angeles, California 90057.
authors.forename: Hajime
authors.initials: H
authors.lastname: Ishinaga
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York 14642; Gonda Department of Cell and Molecular Biology, House Ear Institute, University of Southern California, Los Angeles, California 90057.
authors.forename: Un-Hwan
authors.initials: UH
authors.lastname: Ha
authors.affiliation: Gonda Department of Cell and Molecular Biology, House Ear Institute, University of Southern California, Los Angeles, California 90057.
authors.forename: He
authors.initials: H
authors.lastname: Gu
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York 14642; Gonda Department of Cell and Molecular Biology, House Ear Institute, University of Southern California, Los Angeles, California 90057.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Koga
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York 14642; Gonda Department of Cell and Molecular Biology, House Ear Institute, University of Southern California, Los Angeles, California 90057.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Jono
authors.affiliation: Department of Molecular Medicine, Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kai
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York 14642; Gonda Department of Cell and Molecular Biology, House Ear Institute, University of Southern California, Los Angeles, California 90057. Electronic address: Jian-Dong_Li@urmc.rochester.edu.
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Li
mesh_terms: D001419:Bacteria / Q000472:pathogenicity*; D001424:Bacterial Infections / Q000276:immunology; D054638:Dual Specificity Phosphatase 1; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D007109:Immunity; D016328:NF-kappa B / Q000502:physiology; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000502:physiology; D020239:Receptor Cross-Talk; D015398:Signal Transduction / Q000502:physiology*; D051900:Smad3 Protein / Q000378:metabolism; D051901:Smad4 Protein / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D016328:NF-kappa B; D051900:Smad3 Protein; D051901:Smad4 Protein; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D017027:Protein Tyrosine Phosphatases