Transforming growth factor-beta -Smad signaling pathway cooperates with NF-kappa B to mediate nontypeable Haemophilus influenzae-induced MUC2 mucin transcription

J Biol Chem. 2002 Nov 22;277(47):45547-57. doi: 10.1074/jbc.M206883200. Epub 2002 Sep 16.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Antigens, Differentiation / metabolism
  • Autocrine Communication
  • Cell Line
  • DNA-Binding Proteins / metabolism*
  • Drosophila Proteins*
  • Gene Expression Regulation*
  • Genes, Bacterial
  • Genes, Reporter
  • Haemophilus influenzae / genetics
  • Haemophilus influenzae / metabolism*
  • Humans
  • I-kappa B Kinase
  • I-kappa B Proteins / metabolism
  • Membrane Glycoproteins / metabolism
  • Models, Biological
  • Mucin-2
  • Mucins / genetics*
  • Mucins / metabolism
  • Myeloid Differentiation Factor 88
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • NF-kappaB-Inducing Kinase
  • Promoter Regions, Genetic
  • Protein Serine-Threonine Kinases / metabolism
  • Receptors, Cell Surface / metabolism
  • Receptors, Immunologic / metabolism
  • Receptors, Steroid / metabolism
  • Receptors, Thyroid Hormone / metabolism
  • Serotyping
  • Signal Transduction / physiology*
  • Smad Proteins
  • Toll-Like Receptor 2
  • Toll-Like Receptors
  • Trans-Activators / metabolism*
  • Transcription, Genetic
  • Transforming Growth Factor beta / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, Differentiation
  • DNA-Binding Proteins
  • Drosophila Proteins
  • I-kappa B Proteins
  • MUC2 protein, human
  • MYD88 protein, human
  • Membrane Glycoproteins
  • Mucin-2
  • Mucins
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • NFKBIA protein, human
  • NR2C2 protein, human
  • Receptors, Cell Surface
  • Receptors, Immunologic
  • Receptors, Steroid
  • Receptors, Thyroid Hormone
  • Smad Proteins
  • TLR2 protein, human
  • Toll-Like Receptor 2
  • Toll-Like Receptors
  • Trans-Activators
  • Transforming Growth Factor beta
  • NF-KappaB Inhibitor alpha
  • Protein Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human