A mechanism of suppression of TGF-beta/SMAD signaling by NF-kappa B/RelA.
A number of pathogenic and proinflammatory stimuli, and the transforming growth factor-beta (TGF-beta) exert opposing activities in cellular and immune responses. Here we show that the RelA subunit of nuclear factor kappaB (NF-kappaB/RelA) is necessary for the inhibition of TGF-beta-induced phosphorylation, nuclear translocation, and DNA binding of SMAD signaling complexes by tumor necrosis factor-alpha (TNF-alpha). The antagonism is mediated through up-regulation of Smad7 synthesis and induction of stable associations between ligand-activated TGF-beta receptors and inhibitory Smad7. Down-regulation of endogenous Smad7 by expression of antisense mRNA releases TGF-beta/SMAD-induced transcriptional responses from suppression by cytokine-activated NF-kappaB/RelA. Following stimulation with bacterial lipopolysaccharide (LPS), or the proinflammatory cytokines TNF-alpha and interleukin-1beta (IL-1beta, NF-kappaB/RelA induces Smad7 synthesis through activation of Smad7 gene transcription. These results suggest a mechanism of suppression of TGF-beta/SMAD signaling by opposing stimuli mediated through the activation of inhibitory Smad7 by NF-kappaB/RelA.
Bitzer
M
M
Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461 USA.
von Gersdorff
G
G
Liang
D
D
Dominguez-Rosales
A
A
Beg
A A
AA
Rojkind
M
M
Böttinger
E P
EP
D016475:3T3 Cells; D000818:Animals; D019556:COS Cells; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D008025:Ligases / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000502:physiology*; D051906:Smad7 Protein; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D004268:DNA-Binding Proteins; D016328:NF-kappa B; D018125:Receptors, Transforming Growth Factor beta; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D008025:Ligases; C028812:guanosine 3',5'-polyphosphate synthetases