A mechanism of suppression of TGF-beta/SMAD signaling by NF-kappa B/RelA

A number of pathogenic and proinflammatory stimuli, and the transforming gr owth factor-beta (TGF-beta) exert opposing activities in cellular and immun e responses. Here we show that the RelA subunit of nuclear factor kappa B ( NF-kappa B/RelA) is necessary for the inhibition of TGF-beta-induced phosph orylation, nuclear translocation, and DNA binding of SMAD signaling complex es by tumor necrosis factor-alpha (TNF-alpha). The antagonism is mediated t hrough up-regulation of Smad7 synthesis and induction of stable association s between ligand-activated TGF-beta receptors and inhibitory Smad7. Down-re gulation of endogenous Smad7 by expression of antisense mRNA releases TGF-b eta/SMAD-induced transcriptional responses from suppression by cytokine-act ivated NF-kappa B/RelA. Following stimulation with bacterial lipopolysaccha ride (LPS), or the proinflammatory cytokines TNF-alpha and interleukin-l be ta (IL-1 beta, NF-kappa B/RelA induces Smad7 synthesis through activation o f Smad7 gene transcription. These results suggest a mechanism of suppressio n of TGF-beta/SMAD signaling by opposing stimuli mediated through the activ ation of inhibitory Smad7 by NF-kappa B/RelA.