Suntaek Hong
1, Seunghwan Lim
1, Allen G Li
2, Chan Lee
1, Youn Sook Lee
3, Eun-Kyung Lee
3, Seok Hee Park
3, Xiao-Jing Wang
2 & Seong-Jin Kim
1, 4
1 Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20892-50551, USA.
2 Departments of Dermatology and Otolaryngology, Oregon Health & Science University, Portland, Oregon 97239-2999, USA.
3 Department of Pathology, Inha University College of Medicine and Inha Research Institute of Medical Sciences, Incheon 400-712, Korea.
4 Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon 406-840, Korea.
Transforming growth factor-
1 (TGF-
1) regulates inflammation and can inhibit activation of the transcription factor NF-
B in certain cell types. Here we show that the TGF-
-induced signaling protein Smad7 bound to TAB2 and TAB3, which are adaptors that link the kinase TAK1 to \''upstream\'' regulators in the proinflammatory tumor necrosis factor (TNF) signaling pathway. Smad7 thereby promoted TGF-
-mediated anti-inflammatory effects. The formation of Smad7-TAB2 and Smad7-TAB3 complexes resulted in the suppression of TNF signaling through the adaptors TRAF2, TAB2 and/or TAB3, and TAK1. Furthermore, expression of a transgene encoding Smad7 in mouse skin suppressed inflammation and NF-
B nuclear translocation substantially and disrupted the formation of endogenous TRAF2-TAK1-TAB2 and TRAF2-TAK1-TAB3 complexes. Thus, Smad7 is a critical mediator of TGF-
signals that block proinflammatory TNF signals.