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

Transforming growth factor-beta (TGF-beta) family members are multifunctional growth factors involved in regulating diverse biological processes. Despite the critical role for TGF-beta in regulating cell proliferation, differentiation, migration and development, its role in regulating NF-kappa B-dependent inflammatory response still remains unclear. Here, we show that TGF-beta 1 induces acetylation of NF-kappa B p65 subunit to synergistically enhance bacterium non-typeable Haemophilus influenzae-induced NF-kappa B activation and inflammatory response in vitro and in vivo. The TGF-beta 1-induced acetylation of p65 is mediated via a Smad3/4-PKA-p300-dependent signaling pathway. Acetylation of p65 at lysine 221 by TGF-b1 is critical for synergistic enhancement of bacteria-induced DNA-binding activity, NF-kappa B activation, NF-kappa B-dependent transcription of TNF-beta and IL-1 beta and interstitial polymorphonuclear neutrophil infiltration in vitro and in vivo. These studies provide new insights into the novel regulation of NF-kappa B by TGF-beta signaling.