Skip to main content
NCBI home page
Gut logoLink to Gut
. 2000 Jul;47(1):57–62. doi: 10.1136/gut.47.1.57

Imbalance of stromelysin-1 and TIMP-1 in the mucosal lesions of children with inflammatory bowel disease

R Heuschkel 1, T MacDonald 1, G Monteleone 1, M Bajaj-Elliott 1, J Smith 1, S Pender 1
PMCID: PMC1727949  PMID: 10861265

Abstract

BACKGROUND—Degradation of the extracellular matrix and ulceration of the mucosa are major features of inflammatory bowel disease (IBD). One of the most important enzymes in degrading the matrix and produced in excess by cytokine activated stromal cells, is stromelysin-1. The activity of stromelysin-1 is controlled by tissue inhibitor of metalloproteinase (TIMP-1), its natural inhibitor. In model systems excess stromelysin-1 produces mucosal degradation.
METHODS—Quantitative competitive RT-PCR was used to analyse stromelysin-1 and TIMP-1 transcripts; western blotting was used to measure the amount of stromelysin-1 and TIMP-1 protein in biopsy samples from children with IBD.
RESULTS—In biopsies from patients with active Crohn's disease (n=24), ulcerative colitis (n=23), and controls (n=16), TIMP-1 transcripts and protein were abundant and unchanged. Stromelysin-1 transcripts and protein were markedly elevated in mucosal biopsies obtained from inflamed sites of patients with active IBD but were not elevated in adjacent endoscopically normal mucosa (n=10). Elevated levels of stromelysin-1 transcripts in active Crohn's disease (n=5) returned to normal levels following treatment with enteral nutrition.
CONCLUSIONS—Stromelysin-1 is markedly overexpressed at inflamed sites in patients with IBD whereas TIMP-1 remains unaltered. Excess stromelysin-1 is likely to be responsible for loss of mucosal integrity in IBD.


Keywords: inflammatory bowel disease; enteral nutrition; intestine; matrix metalloproteinase; tissue inhibitor of metalloproteinase

Full Text

The Full Text of this article is available as a PDF (162.9 KB).

Figure 1  .

Figure 1  

Open in a new tab

Stromelysin-1 (A), TIMP-1 (B) mRNA, and their ratio (C) in active Crohn's disease and ulcerative colitis (UC), and in normal controls, as measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR).

Figure 2  .

Figure 2  

Open in a new tab

Quantitative analysis of stromelysin-1 protein (A), TIMP-1 protein (B), and their ratio (C) in active Crohn's disease and ulcerative colitis (UC), and in normal controls, as measured by densitometric scanning of western blots.

Figure 3  .

Figure 3  

Open in a new tab

Western blot showing increased expression of stromelysin-1 in children with active Crohn's disease and ulcerative colitis (UC) compared with normal controls (60 and 58 kDa latent bands, with 56, 54, and 44 kDa active enzyme bands).

Figure 4  .

Figure 4  

Open in a new tab

Stromelysin-1 mRNA in endoscopically normal and abnormal large bowel mucosa in children with IBD (Crohn's disease (•), ulcerative colitis (◯).

Figure 5  .

Figure 5  

Open in a new tab

Stromelysin-1 mRNA before and after enteral nutrition in children with Crohn's disease.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bailey C. J., Hembry R. M., Alexander A., Irving M. H., Grant M. E., Shuttleworth C. A. Distribution of the matrix metalloproteinases stromelysin, gelatinases A and B, and collagenase in Crohn's disease and normal intestine. J Clin Pathol. 1994 Feb;47(2):113–116. doi: 10.1136/jcp.47.2.113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Baugh M. D., Perry M. J., Hollander A. P., Davies D. R., Cross S. S., Lobo A. J., Taylor C. J., Evans G. S. Matrix metalloproteinase levels are elevated in inflammatory bowel disease. Gastroenterology. 1999 Oct;117(4):814–822. doi: 10.1016/s0016-5085(99)70339-2. [DOI] [PubMed] [Google Scholar]
  3. Beattie R. M., Nicholls S. W., Domizio P., Williams C. B., Walker-Smith J. A. Endoscopic assessment of the colonic response to corticosteroids in children with ulcerative colitis. J Pediatr Gastroenterol Nutr. 1996 May;22(4):373–379. doi: 10.1097/00005176-199605000-00006. [DOI] [PubMed] [Google Scholar]
  4. Breese E. J., Michie C. A., Nicholls S. W., Williams C. B., Domizio P., Walker-Smith J. A., MacDonald T. T. The effect of treatment on lymphokine-secreting cells in the intestinal mucosa of children with Crohn's disease. Aliment Pharmacol Ther. 1995 Oct;9(5):547–552. doi: 10.1111/j.1365-2036.1995.tb00419.x. [DOI] [PubMed] [Google Scholar]
  5. Brennan F. M., Browne K. A., Green P. A., Jaspar J. M., Maini R. N., Feldmann M. Reduction of serum matrix metalloproteinase 1 and matrix metalloproteinase 3 in rheumatoid arthritis patients following anti-tumour necrosis factor-alpha (cA2) therapy. Br J Rheumatol. 1997 Jun;36(6):643–650. doi: 10.1093/rheumatology/36.6.643. [DOI] [PubMed] [Google Scholar]
  6. Delaissé J. M., Eeckhout Y., Sear C., Galloway A., McCullagh K., Vaes G. A new synthetic inhibitor of mammalian tissue collagenase inhibits bone resorption in culture. Biochem Biophys Res Commun. 1985 Dec 17;133(2):483–490. doi: 10.1016/0006-291x(85)90932-5. [DOI] [PubMed] [Google Scholar]
  7. Di Girolamo N., Lloyd A., McCluskey P., Filipic M., Wakefield D. Increased expression of matrix metalloproteinases in vivo in scleritis tissue and in vitro in cultured human scleral fibroblasts. Am J Pathol. 1997 Feb;150(2):653–666. [PMC free article] [PubMed] [Google Scholar]
  8. Di Girolamo N., Verma M. J., McCluskey P. J., Lloyd A., Wakefield D. Increased matrix metalloproteinases in the aqueous humor of patients and experimental animals with uveitis. Curr Eye Res. 1996 Oct;15(10):1060–1068. doi: 10.3109/02713689609017656. [DOI] [PubMed] [Google Scholar]
  9. Eeckhout Y., Vaes G. Further studies on the activation of procollagenase, the latent precursor of bone collagenase. Effects of lysosomal cathepsin B, plasmin and kallikrein, and spontaneous activation. Biochem J. 1977 Jul 15;166(1):21–31. doi: 10.1042/bj1660021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gomez D. E., Alonso D. F., Yoshiji H., Thorgeirsson U. P. Tissue inhibitors of metalloproteinases: structure, regulation and biological functions. Eur J Cell Biol. 1997 Oct;74(2):111–122. [PubMed] [Google Scholar]
  11. Grant G. A., Goldberg G. I., Wilhelm S. M., He C., Eisen A. Z. Activation of extracellular matrix metalloproteases by proteases and organomercurials. Matrix Suppl. 1992;1:217–223. [PubMed] [Google Scholar]
  12. Günther U., Matthes H., Herbst H., Stallmach A., Riecken E. O., Schuppan D. Phenotype of cells expressing matrix metalloproteinase-3 in ulcerative colitis. Ann N Y Acad Sci. 1998 Nov 17;859:237–240. doi: 10.1111/j.1749-6632.1998.tb11137.x. [DOI] [PubMed] [Google Scholar]
  13. Hyams J. S., Ferry G. D., Mandel F. S., Gryboski J. D., Kibort P. M., Kirschner B. S., Griffiths A. M., Katz A. J., Grand R. J., Boyle J. T. Development and validation of a pediatric Crohn's disease activity index. J Pediatr Gastroenterol Nutr. 1991 May;12(4):439–447. [PubMed] [Google Scholar]
  14. Isaacs K. L., Sartor R. B., Haskill S. Cytokine messenger RNA profiles in inflammatory bowel disease mucosa detected by polymerase chain reaction amplification. Gastroenterology. 1992 Nov;103(5):1587–1595. doi: 10.1016/0016-5085(92)91182-4. [DOI] [PubMed] [Google Scholar]
  15. Leco K. J., Apte S. S., Taniguchi G. T., Hawkes S. P., Khokha R., Schultz G. A., Edwards D. R. Murine tissue inhibitor of metalloproteinases-4 (Timp-4): cDNA isolation and expression in adult mouse tissues. FEBS Lett. 1997 Jan 20;401(2-3):213–217. doi: 10.1016/s0014-5793(96)01474-3. [DOI] [PubMed] [Google Scholar]
  16. Mahida Y. R., Wu K., Jewell D. P. Enhanced production of interleukin 1-beta by mononuclear cells isolated from mucosa with active ulcerative colitis of Crohn's disease. Gut. 1989 Jun;30(6):835–838. doi: 10.1136/gut.30.6.835. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Mignatti P., Rifkin D. B. Plasminogen activators and matrix metalloproteinases in angiogenesis. Enzyme Protein. 1996;49(1-3):117–137. doi: 10.1159/000468621. [DOI] [PubMed] [Google Scholar]
  18. Monteleone G., MacDonald T. T., Wathen N. C., Pallone F., Pender S. L. Enhancing Lamina propria Th1 cell responses with interleukin 12 produces severe tissue injury. Gastroenterology. 1999 Nov;117(5):1069–1077. doi: 10.1016/s0016-5085(99)70391-4. [DOI] [PubMed] [Google Scholar]
  19. Murch S. H., Braegger C. P., Walker-Smith J. A., MacDonald T. T. Location of tumour necrosis factor alpha by immunohistochemistry in chronic inflammatory bowel disease. Gut. 1993 Dec;34(12):1705–1709. doi: 10.1136/gut.34.12.1705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Muzzillo D. A., Imoto M., Fukuda Y., Koyama Y., Saga S., Nagai Y., Hayakawa T. Clinical evaluation of serum tissue inhibitor of metalloproteinases-1 levels in patients with liver diseases. J Gastroenterol Hepatol. 1993 Sep-Oct;8(5):437–441. doi: 10.1111/j.1440-1746.1993.tb01544.x. [DOI] [PubMed] [Google Scholar]
  21. Pender S. L., Breese E. J., Günther U., Howie D., Wathen N. C., Schuppan D., MacDonald T. T. Suppression of T cell-mediated injury in human gut by interleukin 10: role of matrix metalloproteinases. Gastroenterology. 1998 Sep;115(3):573–583. doi: 10.1016/s0016-5085(98)70136-2. [DOI] [PubMed] [Google Scholar]
  22. Pender S. L., Fell J. M., Chamow S. M., Ashkenazi A., MacDonald T. T. A p55 TNF receptor immunoadhesin prevents T cell-mediated intestinal injury by inhibiting matrix metalloproteinase production. J Immunol. 1998 Apr 15;160(8):4098–4103. [PubMed] [Google Scholar]
  23. Pender S. L., Lionetti P., Murch S. H., Wathan N., MacDonald T. T. Proteolytic degradation of intestinal mucosal extracellular matrix after lamina propria T cell activation. Gut. 1996 Aug;39(2):284–290. doi: 10.1136/gut.39.2.284. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Pender S. L., Tickle S. P., Docherty A. J., Howie D., Wathen N. C., MacDonald T. T. A major role for matrix metalloproteinases in T cell injury in the gut. J Immunol. 1997 Feb 15;158(4):1582–1590. [PubMed] [Google Scholar]
  25. Richards C. D., Shoyab M., Brown T. J., Gauldie J. Selective regulation of metalloproteinase inhibitor (TIMP-1) by oncostatin M in fibroblasts in culture. J Immunol. 1993 Jun 15;150(12):5596–5603. [PubMed] [Google Scholar]
  26. Roeb E., Graeve L., Müllberg J., Matern S., Rose-John S. TIMP-1 protein expression is stimulated by IL-1 beta and IL-6 in primary rat hepatocytes. FEBS Lett. 1994 Jul 25;349(1):45–49. doi: 10.1016/0014-5793(94)00636-9. [DOI] [PubMed] [Google Scholar]
  27. Roeb E., Purucker E., Breuer B., Nguyen H., Heinrich P. C., Rose-John S., Matern S. TIMP expression in toxic and cholestatic liver injury in rat. J Hepatol. 1997 Sep;27(3):535–544. doi: 10.1016/s0168-8278(97)80359-5. [DOI] [PubMed] [Google Scholar]
  28. Saarialho-Kere U. K., Vaalamo M., Puolakkainen P., Airola K., Parks W. C., Karjalainen-Lindsberg M. L. Enhanced expression of matrilysin, collagenase, and stromelysin-1 in gastrointestinal ulcers. Am J Pathol. 1996 Feb;148(2):519–526. [PMC free article] [PubMed] [Google Scholar]
  29. Salamonsen L. A. Matrix metalloproteinases and endometrial remodelling. Cell Biol Int. 1994 Dec;18(12):1139–1144. doi: 10.1006/cbir.1994.1040. [DOI] [PubMed] [Google Scholar]
  30. Stetler-Stevenson W. G., Krutzsch H. C., Liotta L. A. Tissue inhibitor of metalloproteinase (TIMP-2). A new member of the metalloproteinase inhibitor family. J Biol Chem. 1989 Oct 15;264(29):17374–17378. [PubMed] [Google Scholar]
  31. Targan S. R., Hanauer S. B., van Deventer S. J., Mayer L., Present D. H., Braakman T., DeWoody K. L., Schaible T. F., Rutgeerts P. J. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group. N Engl J Med. 1997 Oct 9;337(15):1029–1035. doi: 10.1056/NEJM199710093371502. [DOI] [PubMed] [Google Scholar]
  32. Tarnuzzer R. W., Macauley S. P., Farmerie W. G., Caballero S., Ghassemifar M. R., Anderson J. T., Robinson C. P., Grant M. B., Humphreys-Beher M. G., Franzen L. Competitive RNA templates for detection and quantitation of growth factors, cytokines, extracellular matrix components and matrix metalloproteinases by RT-PCR. Biotechniques. 1996 Apr;20(4):670–674. doi: 10.2144/19962004670. [DOI] [PubMed] [Google Scholar]
  33. Uría J. A., Ferrando A. A., Velasco G., Freije J. M., López-Otín C. Structure and expression in breast tumors of human TIMP-3, a new member of the metalloproteinase inhibitor family. Cancer Res. 1994 Apr 15;54(8):2091–2094. [PubMed] [Google Scholar]
  34. Vaalamo M., Karjalainen-Lindsberg M. L., Puolakkainen P., Kere J., Saarialho-Kere U. Distinct expression profiles of stromelysin-2 (MMP-10), collagenase-3 (MMP-13), macrophage metalloelastase (MMP-12), and tissue inhibitor of metalloproteinases-3 (TIMP-3) in intestinal ulcerations. Am J Pathol. 1998 Apr;152(4):1005–1014. [PMC free article] [PubMed] [Google Scholar]
  35. Vaalamo M., Weckroth M., Puolakkainen P., Kere J., Saarinen P., Lauharanta J., Saarialho-Kere U. K. Patterns of matrix metalloproteinase and TIMP-1 expression in chronic and normally healing human cutaneous wounds. Br J Dermatol. 1996 Jul;135(1):52–59. [PubMed] [Google Scholar]
  36. Witte M. B., Thornton F. J., Kiyama T., Efron D. T., Schulz G. S., Moldawer L. L., Barbul A. Metalloproteinase inhibitors and wound healing: a novel enhancer of wound strength. Surgery. 1998 Aug;124(2):464–470. [PubMed] [Google Scholar]
  37. Woessner J. F., Jr Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J. 1991 May;5(8):2145–2154. [PubMed] [Google Scholar]
  38. Yoshihara Y., Obata K., Fujimoto N., Yamashita K., Hayakawa T., Shimmei M. Increased levels of stromelysin-1 and tissue inhibitor of metalloproteinases-1 in sera from patients with rheumatoid arthritis. Arthritis Rheum. 1995 Jul;38(7):969–975. doi: 10.1002/art.1780380713. [DOI] [PubMed] [Google Scholar]

Articles from Gut are provided here courtesy of BMJ Publishing Group

RESOURCES