A Failure of Transforming Growth Factor-[beta]1 Negative Regulation Maintains Sustained NF-[kappa]B Activation in Gut Inflammation

Immunologically mediated tissue damage in the gut is associated with increased production of proinflammatory cytokines, which activate the transcription factor NF-[kappa]B in a variety of different cell types. The mechanisms/factors that negatively regulate NF-[kappa]B in the human gut and the pathw...

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Bibliographic Details
Published in:The Journal of biological chemistry 2004-02, Vol.279 (6), p.3925-3932
Main Authors: Monteleone, G, Mann, J, Monteleone, I, Vavassori, P, Bremner, R, Fantini, M, Blanco, G N, Tersigni, R, Alessandroni, L, Mann, D, Pallone, F, MacDonald, T T
Format: Article
Language:English
Subjects:
lamina propria
Smad7 protein
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Summary:Immunologically mediated tissue damage in the gut is associated with increased production of proinflammatory cytokines, which activate the transcription factor NF-[kappa]B in a variety of different cell types. The mechanisms/factors that negatively regulate NF-[kappa]B in the human gut and the pathways leading to the sustained NF-[kappa]B activation in gut inflammation remain to be identified. Pretreatment of normal human intestinal lamina propria mononuclear cells (LPMC) with transforming growth factor-[beta]1 (TGF-[beta]1) resulted in a marked suppression of TNF-[alpha]-induced NF-[kappa]B p65 accumulation in the nucleus, NF-[kappa]B binding DNA activity, and NF-[kappa]B- dependent gene activation. TGF-[beta]1 also increased I[kappa]B[alpha] transcripts and protein in normal LPMC. In marked contrast, treatment of LPMC from patients with inflammatory bowel disease with TGF-[beta]1 did not reduce TNF-induced NF-[kappa]B activation due to the overexpression of Smad7. Indeed inhibiting Smad7 by specific antisense oligonucleotides increased I[kappa]B[alpha] expression and reduced NF-[kappa]B p65 accumulation in the nucleus. This effect was due to endogenous TGF-[beta]1. TGF-[beta]1 directly stimulated I[kappa]B[alpha] promoter transcriptional activity in gut fibroblasts in vitro, and overexpression of Smad7 blocked this effect. These data show that TGF-[beta]1 is a negative regulator of NF-[kappa]B activation in the gut and that Smad7 maintains high NF-[kappa]B activity in gut inflammation by blocking TGF-[beta]1 signaling.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M303654200