Abstract
Gluten-sensitive enteropathy is characterized by small intestinal damage. The pathogenic mechanisms involved are not precisely understood. There is recent interest in the possibility that matrix metalloproteinases might play a pathogenic role. Using immunohistochemistry technique, we examined the protein expression of matrix metalloproteinases-1, -3, and -9 and the tissue inhibitor metalloproteinase-1 in duodenal biopsies from 30 patients with celiac disease and dermatitis herpetiformis. We demonstrated that the percentage of cells expressing these enzymes and their inhibitor in all patients was significantly greater than in the normal controls (P < 0.0001). This was evident even in patients with a minimal lesion but was most marked in patients with severe damage, mirroring the degree of inflammation in the small intestinal tissue. The increased expression of these enzymes and their inhibitor in the duodenal mucosa of patients with gluten-sensitive enteropathy suggests a role for these enzymes in the tissue remodeling which is a feature of these disorders.
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References
Maki M, Collin P (1979) Coeliac disease. Lancet 349:1755–1759
Savilahti E, Reunala T, Maki M (1992) Increase of lymphocytes bearing the gamma/delta T cell receptor in the jejunum of patients with dermatitis herpetiformis. Gut 33:206–211
Sollid LM (2000) Molecular basis of celiac disease. Annu Rev Immunol 18:53–81
Kilmartin C, Lynch S, Abuzakouk M, et al. (2003) Avenin fails to induce a Th1 response in coeliac tissue following in vitro culture. Gut 52:47–52
Forsberg G, Hernell O, Melgar S, Israelsson A, Hammarstrom S, Hammarstrom ML (2002) Paradoxical coexpression of proinflammatory and down-regulatory cytokines in intestinal T cells in childhood celiac disease. Gastroenterology 123:667–678
Daum S, Bauer U, Foss HD, et al. (1999) Increased expression of mRNA for matrix metalloproteinases-1 and -3 and tissue inhibitor of metalloproteinases-1 in intestinal biopsy specimens from patients with coeliac disease. Gut 44:17–25
Salmela MT, Pender SL, Reunala T, MacDonald TT, Saarialho-Kere U (2001) Parallel expression of macrophage metalloelastase (MMP-12) in duodenal and skin lesions of patients with dermatitis herpetiformis. Gut 48:496–502
Ciccocioppo R, Sabatino AD, Bauer M, et al. (2005) Matrix metalloproteinase pattern in celiac duodenal mucosa. Lab Invest 85:397–407
Khasigov PZ, Podobed OV, Ktzoeva SA, et al. (2001) Matrix metalloproteinases of normal human tissues. Biochemistry (Mosc) 66:130–140
Nagase H, Woessner JFJr (1999) Matrix metalloproteinases. J Biol Chem 274:21491–21494
Goetzl EJ, Banda MJ, Leppert D (1996) Matrix metalloproteinases in immunity. J Immunol 156:1–4
Salmela MT, Pender SL, Karjalainen-Lindsberg ML, Puolakkainen P, Macdonald TT, Saarialho-Kere U (2004) Collagenase-1 (MMP-1), matrilysin-1 (MMP-7), and stromelysin-2 (MMP-10) are expressed by migrating enterocytes during intestinal wound healing. Scand J Gastroenterol 39:1095–1104
Kirkegaard T, Hansen A, Bruun E, Brynskov J (2004) Expression and localisation of matrix metalloproteinases and their natural inhibitors in fistulae of patients with Crohn’s disease. Gut 53:701–709
de Coignac AB, Elson G, Delneste Y, et al. (2000) Cloning of MMP-26, a novel matrilysin-like proteinase. Eur J Biochem 267:3323–3329
Grant GM, Giambernardi TA, Grant AM, et al. (1999) Overview of expression of matrix metalloproteinases (MMP-17, MMP-18, and MMP-20) in cultured human cells. Matrix Biol 18:145–148
Welgus HG, Fliszar CJ, Seltzer JL, et al. (1990) Differential susceptibility of type X collagen to cleavage by two mammalian interstitial collagenases and 72-kDa type IV collagenase. J Biol Chem 265:13521–13527
Welgus HG, Jeffrey JJ, Eisen AZ (1981) The collagen substrate specificity of human skin fibroblast collagenase. J Biol Chem 256:9511–9515
Salmela MT, MacDonald TT, Black D, et al. (2002) Upregulation of matrix metalloproteinases in a model of T cell mediated tissue injury in the gut: analysis by gene array and in situ hybridisation. Gut 51:540–547
von Lampe B, Barthel B, Coupland SE, et al. (2000) Differential expression of matrix metalloproteinases and their tissue inhibitors in colon mucosa of patients with inflammatory bowel disease. Gut 47:63–73
Brew K, Dinakarpandian D, Nagase H (2000) Tissue inhibitors of metalloproteinases: evolution, structure and function. Biochim Biophys Acta 1477:267–283
Gomez DE, Alonso DF, Yoshiji H, et al. (1997) Tissue inhibitors of metalloproteinases: structure, regulation and biological functions. Eur J Cell Biol 74:111–122
Pender SL, Tickle SP, Docherty AJ, Howie D, Wathen NC, MacDonald TT (1997) A major role for matrix metalloproteinases in T cell injury in the gut. J Immunol 158:1582–1590
Bailey CJ, Hembry RM, Alexander A, et al. (1994) Distribution of the matrix metalloproteinases stromelysin, gelatinases A and B, and collagenase in Crohn’s disease and normal intestine. J Clin Pathol 47:113–116
Kontakou M, Przemioslo RT, Sturgess RP, et al. (1995) Cytokine mRNA expression in the mucosa of treated coeliac patients after wheat peptide challenge. Gut 37:52–57
Pender SL, MacDonald TT (1998) Regulation of matrix metalloproteinase production in human fetal intestinal mesenchymal cells by cytokines and the bacterial superantigen Staphylococcus aureus enterotoxin B. Ann NY Acad Sci 859:188–191
Heuschkel RB, MacDonald TT, Monteleone G, et al. (2000) Imbalance of stromelysin-1 and TIMP-1 in the mucosal lesions of children with inflammatory bowel disease. Gut 47:57–62
Yoshihara Y, Nakamura H, Obata K, et al. (2000) Matrix metalloproteinases and tissue inhibitors of metalloproteinases in synovial fluids from patients with rheumatoid arthritis or osteoarthritis. Ann Rheum Dis 59:455–461
Klimiuk PA, Sierakowski S, Latosiewicz R, Cylwik B, Skowronski J, Chwiecko J (2000) Serum matrix metalloproteinases and tissue inhibitors of metalloproteinases in different histological variants of rheumatoid synovitis. Rheumatology (Oxford) 41:78–87
Zhang S, Li L, Lin JY, Lin H (2003) Imbalance between expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in invasiveness and metastasis of human gastric carcinoma. World J Gastroenterol 9:899–904
Murray GI, Duncan ME, Arbuckle E, et al. (1998) Matrix metalloproteinases and their inhibitors in gastric cancer. Gut 43:791–797
Stallmach A, Chan CC, Ecker KW, et al. (2000) Comparable expression of matrix metalloproteinases 1 and 2 in pouchitis and ulcerative colitis. Gut 47:415–422
Louis E, Ribbens C, Godon A, et al. (2000) Increased production of matrix metalloproteinase-3 and tissue inhibitor of metalloproteinase-1 by inflamed mucosa in inflammatory bowel disease. Clin Exp Immunol 120:241–246
Wiercinska-Drapalo A, Jaroszewicz J, Flisiak R, Prokopowicz D (2003) Plasma matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 as biomarkers of ulcerative colitis activity. World J Gastroenterol 9:2843–2845
Bamba S, Andoh A, Yasui H, Araki Y, Bamba T, Fujiyama Y (2003) Matrix metalloproteinase-3 secretion from human colonic subepithelial myofibroblasts: role of interleukin-17. J Gastroenterol 38:548–554
Acknowledgments
The authors would like to thank Dr. J. Kearney for advice on statistical analysis and Dr. J. Jackson and Ms. Caroline Liddy for general support. We would also like to acknowledge the Department of Histopathology, St. James’s Hospital, Dublin, Ireland.
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Mohamed, B.M., Feighery, C., Kelly, J. et al. Increased Protein Expression of Matrix Metalloproteinases -1, -3, and -9 and TIMP-1 in Patients with Gluten-Sensitive Enteropathy. Dig Dis Sci 51, 1862–1868 (2006). https://doi.org/10.1007/s10620-005-9038-4
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DOI: https://doi.org/10.1007/s10620-005-9038-4