Synergistic induction of nuclear factor-kappaB by transforming growth factor-beta and tumour necrosis factor-alpha is mediated by protein kinase A-dependent RelA acetylation.
The TGF-beta (transforming growth factor-beta) pathway represents an important signalling pathway involved in regulating diverse biological processes, including cell proliferation, differentiation and inflammation. Despite the critical role for TGF-beta in inflammatory responses, its role in regulating NF-kappaB (nuclear factor-kappaB)-dependent inflammatory responses still remains unknown. In the present study we show that TGF-beta1 synergizes with proinflammatory cytokine TNF-alpha (tumour necrosis factor-alpha) to induce NF-kappaB activation and the resultant inflammatory response in vitro and in vivo. TGF-beta1 synergistically enhances TNF-alpha-induced NF-kappaB DNA binding activity via induction of RelA acetylation. Moreover, synergistic enhancement of TNF-alpha-induced RelA acetylation and DNA-binding activity by TGF-beta1 is mediated by PKA (protein kinase A). Thus the present study reveals a novel role for TGF-beta in inflammatory responses and provides new insight into the regulation of NF-kappaB by TGF-beta signalling.
Ishinaga
Hajime
H
Department of Microbiology & Immunology, University of Rochester Medical Center, Rochester, NY 14642, U.S.A.
Jono
Hirofumi
H
Lim
Jae Hyang
JH
Komatsu
Kensei
K
Xu
Xiangbin
X
Lee
Jiyun
J
Woo
Chang-Hoon
CH
Xu
Haidong
H
Feng
Xin-Hua
XH
Chen
Lin-Feng
LF
Yan
Chen
C
Li
Jian-Dong
JD
D000107:Acetylation / Q000187:drug effects; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D016328:NF-kappa B; D051996:Transcription Factor RelA; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; D017868:Cyclic AMP-Dependent Protein Kinases