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

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.