Kyung-Chul Choi1, 5, Youn Sook Lee1, 2, 5, Seunghwan Lim3, Hyo Kyoung Choi1, Chang-Hun Lee4, Eun-Kyung Lee1, 2, Suntaek Hong3, In-Hoo Kim4, Seong-Jin Kim3 & Seok Hee Park1, 2
1 Department of Pathology, Inha University College of Medicine and Inha Research Institute for Medical Sciences, Inha University College of Medicine by BK-21 Project, Incheon 400-712, Republic of Korea.
2 Center for Advanced Medical Education, Inha University College of Medicine by BK-21 Project, Incheon 400-712, Republic of Korea.
3 Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, National Institute of Health, Bethesda, Maryland 20892, USA.
4 Research Institute, National Cancer Center, Goyang, Gyeonggi 411-769, Republic of Korea.
5 These authors contributed equally to this work.
Transforming growth factor-ß1 (TGF-ß1) is a potent cytokine with pleiotropic effects, including anti-inflammatory activity. Here we show that the signaling protein Smad6 bound to Pellino-1, an adaptor protein of mammalian interleukin 1 receptor (IL-1R)-associated kinase 1 (IRAK1), and thereby promoted TGF-ß-mediated anti-inflammatory effects. Smad6-Pellino-1 interaction abrogated signaling mediated by a complex of IRAK1, Pellino-1 and adaptor protein TRAF6 that formed after stimulation by IL-1ß treatment. Blockade of IRAK1-Pellino-1-TRAF6 signaling prevented degradation of the inhibitor IĸBa and subsequent nuclear translocation of transcription factor NF-ĸB and thus expression of proinflammatory genes. ''Knockdown'' of endogenous Smad6 expression by RNA interference reduced anti-inflammatory activity mediated by TGF-ß1 or the TGF-ß family member BMP-4. Thus Smad6 is a critical mediator of the TGF-ß-BMP pathway that mediates anti-inflammatory activity and negatively regulates IL-1R-Toll-like receptor signals.