Int J Mol Med
INSERM U539, Faculté de Médecine, F-44035 Nantes, France.
Published: January 2009
Inflammatory bowel diseases (IBD) are characterized by tumor necrosis factor alpha (TNF-alpha)-mediated epithelial barrier disruption. TNF-alpha production and the bioavailability of its receptors on the cell surface are regulated by TACE (TNF-alpha converting enzyme), a pleiotropic metalloprotease also known as ADAM17, and its specific inhibitor TIMP3. We therefore examined ADAM17 and TIMP3 expression in human intestinal epithelial cells (IEC) using immunohistochemistry on tissue microarrays and real-time PCR on preparations of IEC isolated from human normal and IBD colon. The effects of TACE inhibition by TIMP3 or a pharmacological inhibitor were assessed in inflammatory conditions on a TIMP3-deficient colonic cell line HT29-Cl.16E. Both TACE and TIMP3 were found to be constitutively expressed by intestinal epithelial cells in the normal and inflammatory human intestinal barrier. In the TIMP3-deficient cell line, the addition of recombinant human TIMP3 or of Tapi-2, a pharmacological ADAM17 inhibitor, i) sensitized the cells to TNF-alpha-mediated hyperpermeability, ii) down-regulated tight junction-associated protein expression and iii) inhibited TNFRI shedding. In conclusion, our data showed that TACE and TIMP3 were co-expressed in the human intestinal barrier and that TACE inhibition, either physiologically or pharmacologically, amplified TNF-alpha-mediated hyperpermeability. TIMP3 could thus play a major role in inflammatory conditions by creating an autocrine effect leading to amplified epithelial barrier hyperpermeability.
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Adv Sci (Weinh)
December 2024
Department of Interventional Center, Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, P. R. China.
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Division of Biotechnology, School of Life Sciences, JSS Academy of Higher Education and Research, Ooty Campus, Ooty, India.
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View Article and Find Full Text PDFJ Exp Clin Cancer Res
November 2024
School of Public Health, Fudan University, 130 Dong-An Road, Shanghai, 200032, China.
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College of Pharmacy, QU Health, Qatar University, Doha 2713, Qatar.
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