The multifunctional TGF-β cytokine regulates a variety of biological functions of cellular proliferation, apoptosis, differentiation, and immune regulation. A number of data indicate that alterations of TGF-β signaling in pathological conditions cau...
The multifunctional TGF-β cytokine regulates a variety of biological functions of cellular proliferation, apoptosis, differentiation, and immune regulation. A number of data indicate that alterations of TGF-β signaling in pathological conditions cause a variety of human diseases, including cancer, inflammation, and tissue fibrosis. Among signal transducers involved in TGF-β signaling pathway, much attention has recently been paid to inhibitory Smads(I-Smads), Smad6 and Smad7, since Smad-mediated signals induced by TGF-β have been tightly regulated by negative feedback mechanisms via I-Smads. Here we demonstrate that Smad6, one of I-Smads, act as a critical mediator of the TGF-β program of anti-inflammatory activity which negatively regulates Interleukin-1 receptor(IL-1R)/Toll-like receptor(TLR) signals via direct interaction of Smad6 with Pellino-1 protein. Furthermore, we also show several evidences that Smad7, another I-Smad, suppressed TNF-alpha-induced NF-ĸB activation. Thus we define the novel functions of I-Smad proteins acting as anti-inflammatory mediators.