TGF-β induces p65 acetylation to enhance bacteria-induced NF-κB activation

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Abstract
Transforming growth factor‐β (TGF‐β) family members are multifunctional growth factors involved in regulating diverse biological processes. Despite the critical role for TGF‐β in regulating cell proliferation, differentiation, migration and development, its role in regulating NF‐κB‐dependent inflammatory response still remains unclear. Here, we show that TGF‐β1 induces acetylation of NF‐κB p65 subunit to synergistically enhance bacterium nontypeable Haemophilus influenzae‐induced NF‐κB activation and inflammatory response in vitro and in vivo. The TGF‐β1‐induced acetylation of p65 is mediated via a Smad3/4‐PKA‐p300‐dependent signaling pathway. Acetylation of p65 at lysine 221 by TGF‐β1 is critical for synergistic enhancement of bacteria‐induced DNA‐binding activity, NF‐κB activation, NF‐κB‐dependent transcription of TNF‐α and IL‐1β and interstitial polymorphonuclear neutrophil infiltration in vitro and in vivo. These studies provide new insights into the novel regulation of NF‐κB by TGF‐β signaling.