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

Nat Immunol. 2006 Oct;7(10):1057-65. doi: 10.1038/ni1383. Epub 2006 Sep 3.


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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Bone Morphogenetic Proteins / metabolism
  • Cells, Cultured
  • Humans
  • I-kappa B Proteins / metabolism
  • Inflammation / immunology*
  • Interleukin-1 Receptor-Associated Kinases / metabolism
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / metabolism*
  • RNA Interference
  • Receptors, Interleukin-1 / metabolism*
  • Signal Transduction
  • Smad6 Protein / antagonists & inhibitors
  • Smad6 Protein / genetics
  • Smad6 Protein / metabolism*
  • TNF Receptor-Associated Factor 6 / antagonists & inhibitors
  • TNF Receptor-Associated Factor 6 / metabolism
  • Toll-Like Receptors / metabolism*
  • Transforming Growth Factor beta / metabolism*
  • Ubiquitin-Protein Ligases


  • Bone Morphogenetic Proteins
  • I-kappa B Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Nuclear Proteins
  • Receptors, Interleukin-1
  • SMAD6 protein, human
  • Smad6 Protein
  • TNF Receptor-Associated Factor 6
  • Toll-Like Receptors
  • Transforming Growth Factor beta
  • NF-KappaB Inhibitor alpha
  • PELI1 protein, human
  • Ubiquitin-Protein Ligases
  • IRAK1 protein, human
  • Interleukin-1 Receptor-Associated Kinases