A failure of transforming growth factor-beta1 negative regulation maintains sustained NF-kappaB 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-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.
Dipartimento di Medicina Interna e Centro di Eccellenza per lo Studio delle Malattie Complesse e Multifattoriali, Università Tor Vergata, Rome 00133, Italy. Gi.Monteleone@Med.uniroma2.it
Giovanni
G
Monteleone
Jelena
J
Mann
Ivan
I
Monteleone
Piero
P
Vavassori
Ronald
R
Bremner
Massimo
M
Fantini
Giovanna
G
Del Vecchio Blanco
Roberto
R
Tersigni
Luciano
L
Alessandroni
Derek
D
Mann
Francesco
F
Pallone
Thomas T
TT
MacDonald
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D002478:Cells, Cultured; D003424:Crohn Disease / Q000209:etiology / Q000276:immunology / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D051906:Smad7 Protein; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D051996:Transcription Factor RelA; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D020319:Oligodeoxyribonucleotides, Antisense; D011994:Recombinant Proteins; C497806:SMAD7 protein, human; D051906:Smad7 Protein; C508960:TGFB1 protein, human; D015534:Trans-Activators; D051996:Transcription Factor RelA; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha