TGF-beta induces p65 acetylation to enhance bacteria-induced NF-kappaB 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-kappaB-dependent inflammatory response still remains unclear. Here, we show that TGF-beta1 induces acetylation of NF-kappaB p65 subunit to synergistically enhance bacterium nontypeable Haemophilus influenzae-induced NF-kappaB activation and inflammatory response in vitro and in vivo. The TGF-beta1-induced acetylation of p65 is mediated via a Smad3/4-PKA-p300-dependent signaling pathway. Acetylation of p65 at lysine 221 by TGF-beta1 is critical for synergistic enhancement of bacteria-induced DNA-binding activity, NF-kappaB activation, NF-kappaB-dependent transcription of TNF-alpha and IL-1beta and interstitial polymorphonuclear neutrophil infiltration in vitro and in vivo. These studies provide new insights into the novel regulation of NF-kappaB by TGF-beta signaling.
Ishinaga
Hajime
H
Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Jono
Hirofumi
H
Lim
Jae Hyang
JH
Kweon
Soo-Mi
SM
Xu
Haodong
H
Ha
Un-Hwan
UH
Xu
Haidong
H
Koga
Tomoaki
T
Yan
Chen
C
Feng
Xin-Hua
XH
Chen
Lin-Feng
LF
Li
Jian-Dong
JD
D000107:Acetylation; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D006192:Haemophilus Infections / Q000378:metabolism*; D006193:Haemophilus influenzae; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D008156:Luciferases; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D051900:Smad3 Protein / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D051900:Smad3 Protein; D051996:Transcription Factor RelA; D016212:Transforming Growth Factor beta; D008156:Luciferases