TRAF6 mediates IL-1ß/LPS-induced suppression of TGF-ß signaling through its interaction with the type III TGF-ß receptor.

ABSTRACT

Transforming growth factor-ß1 (TGF-ß1) 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-1ß must overcome the anti-inflammatory effects of TGF-ß to boost pro-inflammatory responses in epithelial cells. Here we show that IL-1ß or Lipopolysaccharide (LPS) suppresses TGF-ß-induced anti-inflammatory signaling in a NF-κB-independent manner. TRAF6, a key molecule in IL-1ß signaling, mediates this suppressive effect through interaction with the type III TGF-ß receptor (TßRIII), which is TGF-ß-dependent and requires type I TGF-ß receptor (TßRI) kinase activity. TßRI phosphorylates TßRIII at residue S829, which promotes the TRAF6/TßRIII interaction and consequent sequestration of TßRIII from the TßRII/TßRI complex. Our data indicate that IL-1ß enhances the pro-inflammatory response by suppressing TGF-ß signaling through TRAF6-mediated sequestration of TßRIII, which may be an important contributor to the early stages of tumor progression.