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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

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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 6

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(a) Inhibition of Smad7 protein by a specific Smad7 antisense oligonucle...
(a) Inhibition of Smad7 protein by a specific Smad7 antisense oligonucleotide in CD mucosal tissue results in increased p-Smad3 and decreased tissue TNF-α and IFN-γ. The example is representative of four separate experiments, in each of which inflamed mucosal tissue from one CD patient was used. Identical results were seen in each patient. (b) Addition of a neutralizing TGF-β1 antibody decreases but does not abrogate the Smad7 antisense effect on both p-Smad3 and cytokine expression. The example is representative of three separate experiments, in each of which, inflamed mucosal tissue from one CD patient was used. Identical results were seen in each patient.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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