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-κB in a variety of different cell types. The mechanisms/factors that negatively regulate NF-κB in the human gut and the pathways leading to the sustained NF-κB activation in gut inflammation remain to be identified. Pretreatment of normal human intestinal lamina propria mononuclear cells (LPMC) with transforming growth factor-β1 (TGF-β1) resulted in a marked suppression of TNF-α-induced NF-κB p65 accumulation in the nucleus, NF-κB binding DNA activity, and NF-κB-dependent gene activation. TGF-β1 also increased IκBα transcripts and protein in normal LPMC. In marked contrast, treatment of LPMC from patients with inflammatory bowel disease with TGF-β1 did not reduce TNF-induced NF-κB activation due to the overexpression of Smad7. Indeed inhibiting Smad7 by specific antisense oligonucleotides increased IκBα expression and reduced NF-κB p65 accumulation in the nucleus. This effect was due to endogenous TGF-β1. TGF-β1 directly stimulated IκBα promoter transcriptional activity in gut fibroblasts in vitro, and overexpression of Smad7 blocked this effect. These data show that TGF-β1 is a negative regulator of NF-κB activation in the gut and that Smad7 maintains high NF-κB activity in gut inflammation by blocking TGF-β1 signaling