TRAF6 Mediates IL-1b/LPS-Induced Suppression of TGF-b Signaling through Its Interaction with the Type III TGF-b Receptor

Transforming growth factor-b1 (TGF-b1) is an important anti-inflammatory cytokine that modulates and resolves inflammatory responses. Recent studies have demonstrated that inflammation enhances neoplastic risk and potentiates tumor progression. In the evolution of cancer, pro-inflammatory cytokines such as IL-1b must overcome the anti-inflammatory effects of TGF-b to boost pro-inflammatory responses in epithelial cells. Here we show that IL-1b or Lipopolysaccharide (LPS) suppresses TGF-b-induced anti-inflammatory signaling in a NF-kB-independent manner. TRAF6, a key molecule in IL-1b signaling, mediates this suppressive effect through interaction with the type III TGF-b receptor (TbRIII), which is TGF-b-dependent and requires type I TGF-b receptor (TbRI) kinase activity. TbRI phosphorylates TbRIII at residue S829, which promotes the TRAF6/TbRIII interaction and consequent sequestration of TbRIII from the TbRII/TbRI complex. Our data indicate that IL-1b enhances the pro-inflammatory response by suppressing TGF-bsignaling through TRAF6