Original ResearchBasic and Translational—Alimentary TractTissue Inhibitor of Metalloproteinase-3 Regulates Inflammation in Human and Mouse Intestine
Section snippets
Mucosal Samples
Mucosal biopsy specimens were taken from involved areas of 30 patients with active CD (median age, 35 y, range, 25–55 y). In 6 of the 30 CD patients, paired biopsy samples were taken from endoscopically inflamed and uninflamed mucosa. Eleven CD patients were receiving corticosteroids, and the remaining patients were on mesalazine. Resected intestinal tissue was taken from 8 patients with severe disease poorly responsive to medical treatment and used to isolate lamina propria mononuclear cells
Down-regulation of TIMP-3 Expression in CD
TIMP-3 transcripts were reduced in CD as compared with UC and normal samples (Figure 1A). TIMP-3 RNA expression did not differ between UC and controls (Figure 1A). In CD, decreased TIMP-3 RNA expression was restricted to areas of active inflammation (Figure 1A), and the same biopsy specimens showed enhanced α-secretase activity (Figure 1B). Moreover, we analyzed TACE and ADAM-15 in the same intestinal samples used to evaluate TIMP-3. Data from these experiments show that TACE and ADAM-15
Discussion
This study set out to determine if TIMP-3 is a determinant of human and mouse gut inflammation. We first showed that TIMP-3 expression was decreased in CD mucosa, particularly in T cells, CD68+ cells, and also in epithelial cells. CD samples consistently showed enhanced α-secretase activity, suggesting that the improved α-secretase activity present in CD gut mucosa is the result of a reduced expression of TIMP-3. There was no difference in TIMP-3 expression and α-secretase activity between UC
Acknowledgments
The authors thank Rama Khokha for kindly providing the tissue inhibitor of metalloproteinases-3–deficient mice.
GM and TTM are both co-senior authors of the study.
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Conflicts of interest The authors disclose no conflicts.
Funding This work was supported by Fondazione Umberto Di Mario Onlus (Rome, Italy), Giuliani Spa (Milan, Italy), funding for the Opportunity for Drug Discovery consortium under Grant Agreement 202020 of the Seventh Research Framework Programme of the European Union; and by Telethon GGP08065, Fondazione Roma 2008, Juvenile Diabetes Research Foundation RRG 1-2007-665, FP7-Health-241913, The role of intestinal microflora in non-alcoholic fatty liver disease, and the Ministry of Health RF 2007.