Smad6 negatively regulates interleukin 1-receptor–Toll-like receptor signaling through direct interaction with the adaptor Pellino-1

Kyung-Chul Choi^1, 5, Youn Sook Lee^1, 2, 5, Seunghwan Lim³, Hyo Kyoung Choi¹, Chang-Hun Lee⁴, Eun-Kyung Lee^1, 2, Suntaek Hong³, In-Hoo Kim⁴, Seong-Jin Kim³ & Seok Hee Park^1, 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-1 (TGF-1) 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--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-1 treatment. Blockade of IRAK1–Pellino-1–TRAF6 signaling prevented degradation of the inhibitor IB and subsequent nuclear translocation of transcription factor NF-B and thus expression of proinflammatory genes. 'Knockdown' of endogenous Smad6 expression by RNA interference reduced anti-inflammatory activity mediated by TGF-1 or the TGF- family member BMP-4. Thus Smad6 is a critical mediator of the TGF-–BMP pathway that mediates anti-inflammatory activity and negatively regulates IL-1R–Toll-like receptor signals.

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