Transforming growth factor-β-Smad signaling pathway cooperates with NF-κB to mediate nontypeable Haemophilus influenzae-induced MUC2 mucin transcription

Hirofumi Jono, Tsuyoshi Shuto, Haidong Xu, Hirofumi Kai, David J. Lim, James R. Gum, Young S. Kim, Shoji Yamaoka, Xin Hua Feng, Jian Dong Li

Research output: Contribution to journalArticle

85 Scopus citations

Abstract

Transforming growth factor-β (TGF-β) and related factors are multifunctional cytokines that regulate diverse cellular processes, including proliferation, differentiation, apoptosis, and immune response. The involvement of TGF-β 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-β-Smad signaling pathway together with the TLR2-MyD88-TAK1-NIK-IKKβ/γ-IκBα pathway to mediate NF-κB-dependent MUC2 mucin transcription. The NTHi-induced TGF-β receptor Type II phosphorylation occurred at as early as 5 min. Pretreatment of NTHi with TGF-β neutralization antibody reduced up-regulation of MUC2 transcription. Moreover, functional cooperation of NF-κB p65/p50 with Smad3/4 appears to positively mediate NF-κB-dependent MUC2 transcription. These data are the first to demonstrate the involvement of TGF-β receptor-mediated signaling in bacteria-induced up-regulation of mucin transcription, bring insights into the novel role of TGF-β signaling in bacterial pathogenesis, and may lead to new therapeutic intervention of NTHi infections.

Original languageEnglish (US)
Pages (from-to)45547-45557
Number of pages11
JournalJournal of Biological Chemistry
Volume277
Issue number47
DOIs
StatePublished - Nov 22 2002

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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