Immunologically mediated tissue damage in the gut is associated with increased production of proinflammatory cytokines, which activate the transcription factor NF-kappaB in a variety of different cell types. The mechanisms/factors that negatively regulate NF-kappaB in the human gut and the pathways leading to the sustained NF-kappaB activation in gut inflammation remain to be identified. Pretreatment of normal human intestinal lamina propria mononuclear cells (LPMC) with transforming growth factor-beta1 (TGF-beta1) resulted in a marked suppression of TNF-alpha-induced NF-kappaB p65 accumulation in the nucleus, NF-kappaB binding DNA activity, and NF-kappaB-dependent gene activation. TGF-beta1 also increased IkappaBalpha transcripts and protein in normal LPMC. In marked contrast, treatment of LPMC from patients with inflammatory bowel disease with TGF-beta1 did not reduce TNF-induced NF-kappaB activation due to the overexpression of Smad7. Indeed inhibiting Smad7 by specific antisense oligonucleotides increased IkappaBalpha expression and reduced NF-kappaB p65 accumulation in the nucleus. This effect was due to endogenous TGF-beta1. TGF-beta1 directly stimulated IkappaBalpha promoter transcriptional activity in gut fibroblasts in vitro, and overexpression of Smad7 blocked this effect. These data show that TGF-beta1 is a negative regulator of NF-kappaB activation in the gut and that Smad7 maintains high NF-kappaB activity in gut inflammation by blocking TGF-beta1 signaling.

Monteleone, G., Mann, J., Monteleone, I., Vavassori, P., Bremner, R., Fantini, M.c., et al. (2004). A failure of transforming growth factor-beta1 negative regulation maintains sustained NF-kappaB activation in gut inflammation. THE JOURNAL OF BIOLOGICAL CHEMISTRY, 279(6), 3925-3932 [10.1074/jbc.M303654200].

A failure of transforming growth factor-beta1 negative regulation maintains sustained NF-kappaB activation in gut inflammation

MONTELEONE, GIOVANNI;MONTELEONE, IVAN;FANTINI, MASSIMO CLAUDIO;DEL VECCHIO BLANCO, GIOVANNA;PALLONE, FRANCESCO;
2004-02-06

Abstract

Immunologically mediated tissue damage in the gut is associated with increased production of proinflammatory cytokines, which activate the transcription factor NF-kappaB in a variety of different cell types. The mechanisms/factors that negatively regulate NF-kappaB in the human gut and the pathways leading to the sustained NF-kappaB activation in gut inflammation remain to be identified. Pretreatment of normal human intestinal lamina propria mononuclear cells (LPMC) with transforming growth factor-beta1 (TGF-beta1) resulted in a marked suppression of TNF-alpha-induced NF-kappaB p65 accumulation in the nucleus, NF-kappaB binding DNA activity, and NF-kappaB-dependent gene activation. TGF-beta1 also increased IkappaBalpha transcripts and protein in normal LPMC. In marked contrast, treatment of LPMC from patients with inflammatory bowel disease with TGF-beta1 did not reduce TNF-induced NF-kappaB activation due to the overexpression of Smad7. Indeed inhibiting Smad7 by specific antisense oligonucleotides increased IkappaBalpha expression and reduced NF-kappaB p65 accumulation in the nucleus. This effect was due to endogenous TGF-beta1. TGF-beta1 directly stimulated IkappaBalpha promoter transcriptional activity in gut fibroblasts in vitro, and overexpression of Smad7 blocked this effect. These data show that TGF-beta1 is a negative regulator of NF-kappaB activation in the gut and that Smad7 maintains high NF-kappaB activity in gut inflammation by blocking TGF-beta1 signaling.
6-feb-2004
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/12 - GASTROENTEROLOGIA
English
Con Impact Factor ISI
Active Transport, Cell Nucleus; NF-kappa B; Tumor Necrosis Factor-alpha; Recombinant Proteins; DNA-Binding Proteins; Humans; Transcriptional Activation; Transforming Growth Factor beta1; Cells, Cultured; Crohn Disease; I-kappa B Proteins; Smad7 Protein; Transcription Factor RelA; Inflammation Mediators; Transforming Growth Factor beta; Gene Expression Regulation; Oligodeoxyribonucleotides, Antisense; Trans-Activators; Signal Transduction
Monteleone, G., Mann, J., Monteleone, I., Vavassori, P., Bremner, R., Fantini, M.c., et al. (2004). A failure of transforming growth factor-beta1 negative regulation maintains sustained NF-kappaB activation in gut inflammation. THE JOURNAL OF BIOLOGICAL CHEMISTRY, 279(6), 3925-3932 [10.1074/jbc.M303654200].
Monteleone, G; Mann, J; Monteleone, I; Vavassori, P; Bremner, R; Fantini, Mc; DEL VECCHIO BLANCO, G; Tersigni, R; Alessandroni, L; Mann, D; Pallone, F...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/40775
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