Smad6 negatively regulates interleukin 1-receptor-Toll-like receptor signaling through direct interaction with the adaptor Pellino-1.
Transforming growth factor-beta1 (TGF-beta1) 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-beta-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-1beta treatment. Blockade of IRAK1-Pellino-1-TRAF6 signaling prevented degradation of the inhibitor IkappaBalpha and subsequent nuclear translocation of transcription factor NF-kappaB and thus expression of proinflammatory genes. 'Knockdown' of endogenous Smad6 expression by RNA interference reduced anti-inflammatory activity mediated by TGF-beta1 or the TGF-beta family member BMP-4. Thus Smad6 is a critical mediator of the TGF-beta-BMP pathway that mediates anti-inflammatory activity and negatively regulates IL-1R-Toll-like receptor signals.
Choi
Kyung-Chul
KC
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.
Lee
Youn Sook
YS
Lim
Seunghwan
S
Choi
Hyo Kyoung
HK
Lee
Chang-Hun
CH
Lee
Eun-Kyung
EK
Hong
Suntaek
S
Kim
In-Hoo
IH
Kim
Seong-Jin
SJ
Park
Seok Hee
SH
D021581:Active Transport, Cell Nucleus; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation / Q000276:immunology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034622:RNA Interference; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D015398:Signal Transduction; D051905:Smad6 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048029:TNF Receptor-Associated Factor 6 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
D019485:Bone Morphogenetic Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009687:Nuclear Proteins; D017472:Receptors, Interleukin-1; C497802:SMAD6 protein, human; D051905:Smad6 Protein; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; D016212:Transforming Growth Factor beta; D000072000:NF-KappaB Inhibitor alpha; C485959:PELI1 protein, human; D044767:Ubiquitin-Protein Ligases; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases