Blocking Smad7 restores TGF-β1 signaling in chronic inflammatory bowel disease
Giovanni Monteleone, … , Howard W. Steer, Thomas T. MacDonald
Giovanni Monteleone, … , Howard W. Steer, Thomas T. MacDonald
Published August 15, 2001
Citation Information: J Clin Invest. 2001;108(4):601-609. https://doi.org/10.1172/JCI12821.
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Article

Blocking Smad7 restores TGF-β1 signaling in chronic inflammatory bowel disease

Abstract

TGF-β1 functions as a negative regulator of T cell immune responses, signaling to target cells using the Smad family of proteins. We show here that Smad7, an inhibitor of TGF-β1 signaling, is overexpressed in inflammatory bowel disease (IBD) mucosa and purified mucosal T cells. Both whole tissue and isolated cells exhibit defective signaling through this pathway, as measured by phospho-Smad3 immunoreactivity. Specific antisense oligonucleotides for Smad7 reduce Smad7 protein expression in cells isolated from patients with IBD, permitting the cells to respond to exogenous TGF-β1. TGF-β1 cannot inhibit proinflammatory cytokine production in isolated lamina propria mononuclear cells from patients with Crohn disease (CD), but inhibition of Smad7 restores TGF-β1 signaling and enables TGF-β1 to inhibit cytokine production. In inflamed mucosal tissue explants from patients with CD, inhibition of Smad7 also restores p-Smad3 and decreases proinflammatory cytokine production, an effect that is partially blocked by anti–TGF-β1. These results show that Smad7 blockade of TGF-β1 signaling helps maintain the chronic production of proinflammatory cytokines that drives the inflammatory process in IBD and that inhibition of Smad7 enables endogenous TGF-β to downregulate this response.

Authors

Giovanni Monteleone, Andrea Kumberova, Nicholas M. Croft, Catriona McKenzie, Howard W. Steer, Thomas T. MacDonald

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Figure 1

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Smad 7 in IBD. (a) Representative expression of Smad7 (upper blot) and β...
Smad 7 in IBD. (a) Representative expression of Smad7 (upper blot) and β-actin (lower blot) protein in colonic mucosal samples taken from three normal controls, three patients with active CD, and three with UC. The example is representative of five separate experiments analyzing in total mucosal samples from eight patients with CD, eight with UC, and eight normal controls. Quantitative data are shown in the middle panel as measured by densitometry scanning of Western blots. Values are expressed in arbitrary units (a.u.). Each point represents the value (a.u.) of Smad7 in mucosal samples taken from a single subject. Horizontal bars indicate the median value. Shown in the bottom panel is expression of Smad7 protein in both CD3-depleted LPMCs and positively selected CD3+ T lymphocytes (T-LPL) from intestinal mucosal samples taken from three patients with CD, three patients with UC, and three normal controls. The example is representative of three separate experiments analyzing Smad7 in both CD3-depleted LPMCs and CD3+ T-LPLs from five patients with CD, four with UC, and six normal controls. (b) Expression of Smad7 (upper blot) and β-actin (lower blot) protein in CD: effect of disease activity. Colonic mucosal biopsy specimens were taken from two normal controls and from inflamed (I) and uninflamed (U) areas of three patients with CD. Arrows indicate Smad7 and β-actin detected by specific polyclonal antibodies. The example is representative of two separate experiments using in total samples from four controls and five CD patients.