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Gene Review

TIMP1  -  TIMP metallopeptidase inhibitor 1

Homo sapiens

Synonyms: CLGI, Collagenase inhibitor, EPA, EPO, Erythroid-potentiating activity, ...
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Disease relevance of TIMP1


Psychiatry related information on TIMP1

  • We measured the levels of matrix metalloproteinases (MMPs)-2 and -9 and the tissue inhibitor of MMPs (e.g. TIMP-1 and TIMP-2) in CSF samples from patients with Parkinson's Disease (PD), Huntington's Disease (HD), AD and ALS as compared to age-matched control patients [5].
  • These results suggest that abnormalities in MMP and TIMP profiles may be helpful in the biochemical characterisation of CJD [6].
  • We did not find evidence that depressive symptoms were reliably associated with modulation of either MMP or TIMP expression [7].
  • The gene encoding TIMP-1 (TIMP 1) maps to the short arm of the X chromosome, in a region previously suggested as conferring genetic susceptibility for Alzheimer's disease (AD) [8].
  • The Holyoake Codependency Index (HCI; G. E. Dear & C. M. Roberts, 2000) is a 13-item self-report measure of codependent traits that has previously shown adequate to high reliability, initial evidence of construct validity, and an internal structure that is consistent across samples [9].

High impact information on TIMP1

  • Here we report the crystal structure of an MMP-TIMP complex formed between the catalytic domain of human stromelysin-1 (MMP-3) and human TIMP-1 [10].
  • Mechanism of inhibition of the human matrix metalloproteinase stromelysin-1 by TIMP-1 [10].
  • Purified EPA specifically stimulates human and murine cells of the erythroid lineage, unlike murine interleukin-3 (IL-3) which stimulates precursor cells from all haematopoietic lineages [11].
  • This purified glycoprotein of relative molecular mass (Mr) 28,000 also stimulates colony formation by more mature erythroid precursors (CFU-E) and is therefore referred to as erythroid-potentiating activity (EPA) [11].
  • Compared with vector control cells, cell surface alpha(6)-integrin expression decreased by approximately 80% (difference = 78.7%; 95% confidence interval [CI] = 77.8% to 79.6), MMP-9 activity decreased by approximately 50%, and TIMP activity increased by approximately 50% in EGFR-antisense cells [12].

Chemical compound and disease context of TIMP1

  • Biophysical and functional characterization of full-length, recombinant human tissue inhibitor of metalloproteinases-2 (TIMP-2) produced in Escherichia coli. Comparison of wild type and amino-terminal alanine appended variant with implications for the mechanism of TIMP functions [13].
  • BACKGROUND: Angiotensin II and tissue type inhibitor metalloproteinase-1 (TIMP-1) have been implicated in renal tubulointerstitial fibrosis, but the exact mediating signaling pathway is still unknown [14].
  • Osteoblast-derived Matrix metalloproteinse-1 (MMP-1), MMP-2, and tissue inhibitor of metalloproteinase-1 (TIMP-1) recently were implicated as playing important roles in initiating bone resorption [15].
  • The results suggest that tranilast inhibits the formation of keloid scarring through the suppression of factors such as MMPs and TIMP, which are essential for tissue remodelling, from inflammatory cells [16].
  • The effects of dibutyryl cyclic AMP (DBcAMP) on tissue inhibitor metalloproteinase (TIMP) expression were studied in the human hepatoma cell line PLC/PRF/5 with relation to the invasive activity of the cells [17].

Biological context of TIMP1


Anatomical context of TIMP1


Associations of TIMP1 with chemical compounds

  • Conversely, TIMP1 production was reduced by hyperhomocysteinaemia in both conditions, especially in high glucose [23].
  • When added together, dexamethasone antagonizes the interleukin-1 alpha-induced increase of stromelysin, gelatinase B, and TIMP1 in a dose-dependent manner [24].
  • Unlike the changes in PAI-1, neither TIMP1, nor MMP-2 expression was affected by withdrawal to steroid-free or to RU 486-medium [25].
  • Deficient migration by specific lines of aged fibroblasts was not related to the capacity to attach, express alpha2 integrin, or secrete MMPs and TIMP1, but was characterized by disorganized cytoskeletal actin and reduced alpha2beta1 function [26].
  • In addition, the secretion of tissue inhibitor of metalloproteinases (TIMP-1 and TIMP-2) and plasminogen activator inhibitor-1 was significantly decreased by FSH and LH (100 or 1,000 ng/mL) [27].
  • Liquid chromatography-mass spectrometry and tandem mass spectrometry analyses demonstrated that methionine and N-terminal cysteine residues were rapidly oxidized by MPO-derived HOCl but only oxidation of the N-terminal cysteine of TIMP-1 correlated well with loss of inhibitory activity [28].

Physical interactions of TIMP1


Regulatory relationships of TIMP1

  • Apoptosis-induced pro-MMP-2 activation was inhibited by the tissue inhibitors of metalloproteinases (TIMP)-2 but not by TIMP-1, implying involvement of an MT-MMP-mediated process [34].
  • Addition of active MMP-1 or blocking antibodies to TIMP-1 did not affect the migration of hmECs in 3D collagen [35].
  • The K562 cells expressed more TIMP-1 than the HL-60 cells and neither cell line expressed TIMP-3 [36].
  • RT-PCR result showed that the expression of metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were reduced by rhDecorin in LX-2 cells stimulated by TGF-beta1 [37].
  • IL-10 inhibits metalloproteinase and stimulates TIMP-1 production in human mononuclear phagocytes [38].

Other interactions of TIMP1

  • This unusual architecture of the interface between MMP-3 and TIMP-1 suggests new possibilities for designing TIMP variants and synthetic MMP inhibitors with potential therapeutic applications [10].
  • LV myocardial abundance of TIMP-1 and TIMP-2 increased by >500% with DCM [39].
  • PATIENTS AND METHODS: Expression of MMP-1, -2, -3, -9, -11, -13, and -14 and TIMP-1, -2, -3, and -4 was evaluated by immunohistochemistry (IHC) [40].
  • By contrast, TIMP-1, an efficient inhibitor of soluble MMP-2 activity, failed to affect gel contraction [41].
  • Recombinant (r) TGF-beta 1 and rTGF-beta 2, but not rTGF-beta 3, induced expression of TIMP-1 in normal intestinal myofibroblasts [42].

Analytical, diagnostic and therapeutic context of TIMP1

  • We further evaluated the relationship between TIMP1 expression and STAT3 activation in 43 ALCL tumors (19 ALK(+) and 24 ALK(-)) using immunohistochemistry and a tissue microarray [1].
  • Recent data suggest that TIMP1 expression may be regulated by signal transducer and activator of transcription (STAT)-3 [1].
  • Incubation of progelatinase B-TIMP1 complex with active matrilysin resulted in 78 and 68 kDa active forms, as measured by SDS-PAGE and enzyme activity assays [43].
  • Simultaneous measurement of MMP9 and TIMP1 mRNA in human non small cell lung cancers by multiplex real time RT-PCR [44].
  • The presence and distribution of mRNAs encoding a matrix metalloproteinase (MMP) stromelysin 3 and two tissue inhibitors of MMP, TIMP1 and TIMP-2 have been studied by in situ hybridization of 18 human epidermoid head and neck carcinomas and four normal tissues [45].


  1. Signal transducer and activator of transcription-3 activation contributes to high tissue inhibitor of metalloproteinase-1 expression in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. Lai, R., Rassidakis, G.Z., Medeiros, L.J., Ramdas, L., Goy, A.H., Cutler, C., Fujio, Y., Kunisada, K., Amin, H.M., Gilles, F. Am. J. Pathol. (2004) [Pubmed]
  2. Expression profiling of microdissected pancreatic adenocarcinomas. Crnogorac-Jurcevic, T., Efthimiou, E., Nielsen, T., Loader, J., Terris, B., Stamp, G., Baron, A., Scarpa, A., Lemoine, N.R. Oncogene (2002) [Pubmed]
  3. TIMP1 and adverse prognosis in non-small cell lung cancer. Fong, K.M., Kida, Y., Zimmerman, P.V., Smith, P.J. Clin. Cancer Res. (1996) [Pubmed]
  4. Expression of MMP2, MMP9, MT1-MMP, TIMP1, and TIMP2 mRNA in valvular lesions of the heart. Soini, Y., Satta, J., Määttä, M., Autio-Harmainen, H. J. Pathol. (2001) [Pubmed]
  5. Tissue inhibitors of matrix metalloproteinases are elevated in cerebrospinal fluid of neurodegenerative diseases. Lorenzl, S., Albers, D.S., LeWitt, P.A., Chirichigno, J.W., Hilgenberg, S.L., Cudkowicz, M.E., Beal, M.F. J. Neurol. Sci. (2003) [Pubmed]
  6. Matrix metalloproteinase profile in patients with Creuztfeldt-Jakob disease. Kettlun, A., Collados, L., García, L., Cartier, L.A., Wolf, M.E., Mosnaim, A.D., Valenzuela, M.A. International journal of clinical practice. (2003) [Pubmed]
  7. Stress-related modulation of matrix metalloproteinase expression. Yang, E.V., Bane, C.M., MacCallum, R.C., Kiecolt-Glaser, J.K., Malarkey, W.B., Glaser, R. J. Neuroimmunol. (2002) [Pubmed]
  8. Genetic polymorphisms and cerebrospinal fluid levels of tissue inhibitor of metalloproteinases 1 in sporadic Alzheimer's disease. Wollmer, M.A., Papassotiropoulos, A., Streffer, J.R., Grimaldi, L.M., Kapaki, E., Salani, G., Paraskevas, G.P., Maddalena, A., de Quervain, D., Bieber, C., Umbricht, D., Lemke, U., Bosshardt, S., Degonda, N., Henke, K., Hegi, T., Jung, H.H., Pasch, T., Hock, C., Nitsch, R.M. Psychiatr. Genet. (2002) [Pubmed]
  9. Validation of the holyoake codependency index. Dear, G.E., Roberts, C.M. The Journal of psychology. (2005) [Pubmed]
  10. Mechanism of inhibition of the human matrix metalloproteinase stromelysin-1 by TIMP-1. Gomis-Rüth, F.X., Maskos, K., Betz, M., Bergner, A., Huber, R., Suzuki, K., Yoshida, N., Nagase, H., Brew, K., Bourenkov, G.P., Bartunik, H., Bode, W. Nature (1997) [Pubmed]
  11. Molecular characterization and expression of the gene encoding human erythroid-potentiating activity. Gasson, J.C., Golde, D.W., Kaufman, S.E., Westbrook, C.A., Hewick, R.M., Kaufman, R.J., Wong, G.G., Temple, P.A., Leary, A.C., Brown, E.L. Nature (1985) [Pubmed]
  12. Epidermal growth factor receptor signaling and the invasive phenotype of ovarian carcinoma cells. Alper O, n.u.l.l., Bergmann-Leitner, E.S., Bennett, T.A., Hacker, N.F., Stromberg, K., Stetler-Stevenson, W.G. J. Natl. Cancer Inst. (2001) [Pubmed]
  13. Biophysical and functional characterization of full-length, recombinant human tissue inhibitor of metalloproteinases-2 (TIMP-2) produced in Escherichia coli. Comparison of wild type and amino-terminal alanine appended variant with implications for the mechanism of TIMP functions. Wingfield, P.T., Sax, J.K., Stahl, S.J., Kaufman, J., Palmer, I., Chung, V., Corcoran, M.L., Kleiner, D.E., Stetler-Stevenson, W.G. J. Biol. Chem. (1999) [Pubmed]
  14. STAT proteins mediate angiotensin II-induced production of TIMP-1 in human proximal tubular epithelial cells. Chen, X., Wang, J., Zhou, F., Wang, X., Feng, Z. Kidney Int. (2003) [Pubmed]
  15. Effects of 17beta-estradiol on the expression of matrix metalloproteinase-1, -2 and tissue inhibitor of metalloproteinase-1 in human osteoblast-like cell cultures. Liao, E.Y., Luo, X.H. Endocrine (2001) [Pubmed]
  16. Effect of tranilast on matrix metalloproteinase production from neutrophils in-vitro. Shimizu, T., Kanai, K., Kyo, Y., Asano, K., Hisamitsu, T., Suzaki, H. J. Pharm. Pharmacol. (2006) [Pubmed]
  17. Dibutyryl cyclic AMP-induced enhancement of tissue inhibitor of metalloproteinases-3 expression and its possible relation to the invasive activity of the human hepatoma cell line PLC/PRF/5. Okamoto, Y., Nakano, H. Anticancer Res. (1999) [Pubmed]
  18. Polymorphic X-chromosome inactivation of the human TIMP1 gene. Anderson, C.L., Brown, C.J. Am. J. Hum. Genet. (1999) [Pubmed]
  19. Variability of X chromosome inactivation: effect on levels of TIMP1 RNA and role of DNA methylation. Anderson, C.L., Brown, C.J. Hum. Genet. (2002) [Pubmed]
  20. Active and tissue inhibitor of matrix metalloproteinase-free gelatinase B accumulates within human microvascular endothelial vesicles. Nguyen, M., Arkell, J., Jackson, C.J. J. Biol. Chem. (1998) [Pubmed]
  21. Imbalance of expression of matrix metalloproteinases (MMPs) and tissue inhibitors of the matrix metalloproteinases (TIMPs) in human pancreatic carcinoma. Bramhall, S.R., Neoptolemos, J.P., Stamp, G.W., Lemoine, N.R. J. Pathol. (1997) [Pubmed]
  22. Rheumatoid synovial endothelial cells secrete decreased levels of tissue inhibitor of MMP (TIMP1). Jackson, C.J., Arkell, J., Nguyen, M. Ann. Rheum. Dis. (1998) [Pubmed]
  23. High glucose and homocysteine synergistically affect the metalloproteinases-tissue inhibitors of metalloproteinases pattern, but not TGFB expression, in human fibroblasts. Solini, A., Santini, E., Nannipieri, M., Ferrannini, E. Diabetologia (2006) [Pubmed]
  24. Regulation of the levels of human trabecular matrix metalloproteinases and inhibitor by interleukin-1 and dexamethasone. Samples, J.R., Alexander, J.P., Acott, T.S. Invest. Ophthalmol. Vis. Sci. (1993) [Pubmed]
  25. Implications of decidualization-associated protease expression in implantation and menstruation. Schatz, F., Krikun, G., Runic, R., Wang, E.Y., Hausknecht, V., Lockwood, C.J. Semin. Reprod. Endocrinol. (1999) [Pubmed]
  26. Impaired migration, integrin function, and actin cytoskeletal organization in dermal fibroblasts from a subset of aged human donors. Reed, M.J., Ferara, N.S., Vernon, R.B. Mech. Ageing Dev. (2001) [Pubmed]
  27. Gonadotropins activate proteolysis and increase invasion through protein kinase A and phosphatidylinositol 3-kinase pathways in human epithelial ovarian cancer cells. Choi, J.H., Choi, K.C., Auersperg, N., Leung, P.C. Cancer Res. (2006) [Pubmed]
  28. Myeloperoxidase inactivates TIMP-1 by oxidizing its N-terminal cysteine residue: an oxidative mechanism for regulating proteolysis during inflammation. Wang, Y., Rosen, H., Madtes, D.K., Shao, B., Martin, T.R., Heinecke, J.W., Fu, X. J. Biol. Chem. (2007) [Pubmed]
  29. Kinetic analysis of the binding of human matrix metalloproteinase-2 and -9 to tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. Olson, M.W., Gervasi, D.C., Mobashery, S., Fridman, R. J. Biol. Chem. (1997) [Pubmed]
  30. Matrix metalloproteinases and tissue inhibitors of metalloproteinases in synovial fluids of patients with temporomandibular joint osteoarthritis. Kanyama, M., Kuboki, T., Kojima, S., Fujisawa, T., Hattori, T., Takigawa, M., Yamashita, A. Journal of orofacial pain. (2000) [Pubmed]
  31. Mechanisms for pro matrix metalloproteinase activation. Murphy, G., Stanton, H., Cowell, S., Butler, G., Knäuper, V., Atkinson, S., Gavrilovic, J. APMIS (1999) [Pubmed]
  32. Preferential inhibition of 72- and 92-kDa gelatinases by tissue inhibitor of metalloproteinases-2. Howard, E.W., Bullen, E.C., Banda, M.J. J. Biol. Chem. (1991) [Pubmed]
  33. Transcription factor early growth response 1 activity up-regulates expression of tissue inhibitor of metalloproteinases 1 in human synovial fibroblasts. Aicher, W.K., Alexander, D., Haas, C., Kuchen, S., Pagenstecher, A., Gay, S., Peter, H.H., Eibel, H. Arthritis Rheum. (2003) [Pubmed]
  34. Apoptosis of human hepatic myofibroblasts promotes activation of matrix metalloproteinase-2. Preaux, A.M., D'ortho, M.P., Bralet, M.P., Laperche, Y., Mavier, P. Hepatology (2002) [Pubmed]
  35. MT1-MMP, but not secreted MMPs, influences the migration of human microvascular endothelial cells in 3-dimensional collagen gels. Koike, T., Vernon, R.B., Hamner, M.A., Sadoun, E., Reed, M.J. J. Cell. Biochem. (2002) [Pubmed]
  36. The role of matrilysin (MMP-7) in leukaemia cell invasion. Lynch, C.C., McDonnell, S. Clin. Exp. Metastasis (2000) [Pubmed]
  37. Effects of rhDecorin on TGF-beta1 induced human hepatic stellate cells LX-2 activation. Shi, Y.F., Zhang, Q., Cheung, P.Y., Shi, L., Fong, C.C., Zhang, Y., Tzang, C.H., Chan, B.P., Fong, W.F., Chun, J., Kung, H.F., Yang, M. Biochim. Biophys. Acta (2006) [Pubmed]
  38. IL-10 inhibits metalloproteinase and stimulates TIMP-1 production in human mononuclear phagocytes. Lacraz, S., Nicod, L.P., Chicheportiche, R., Welgus, H.G., Dayer, J.M. J. Clin. Invest. (1995) [Pubmed]
  39. Increased matrix metalloproteinase activity and selective upregulation in LV myocardium from patients with end-stage dilated cardiomyopathy. Thomas, C.V., Coker, M.L., Zellner, J.L., Handy, J.R., Crumbley, A.J., Spinale, F.G. Circulation (1998) [Pubmed]
  40. Expression and prognostic significance of metalloproteinases and their tissue inhibitors in patients with small-cell lung cancer. Michael, M., Babic, B., Khokha, R., Tsao, M., Ho, J., Pintilie, M., Leco, K., Chamberlain, D., Shepherd, F.A. J. Clin. Oncol. (1999) [Pubmed]
  41. Remodeling of collagen matrix by human tumor cells requires activation and cell surface association of matrix metalloproteinase-2. Deryugina, E.I., Bourdon, M.A., Reisfeld, R.A., Strongin, A. Cancer Res. (1998) [Pubmed]
  42. Expression and regulation of tissue inhibitor of metalloproteinase-1 and matrix metalloproteinases by intestinal myofibroblasts in inflammatory bowel disease. McKaig, B.C., McWilliams, D., Watson, S.A., Mahida, Y.R. Am. J. Pathol. (2003) [Pubmed]
  43. Activation of gelatinase-tissue-inhibitors-of-metalloproteinase complexes by matrilysin. von Bredow, D.C., Cress, A.E., Howard, E.W., Bowden, G.T., Nagle, R.B. Biochem. J. (1998) [Pubmed]
  44. Simultaneous measurement of MMP9 and TIMP1 mRNA in human non small cell lung cancers by multiplex real time RT-PCR. Simi, L., Andreani, M., Davini, F., Janni, A., Pazzagli, M., Serio, M., Orlando, C. Lung Cancer (2004) [Pubmed]
  45. Localization by in situ hybridization of mRNAs encoding stromelysin 3 and tissue inhibitors of metallo-proteinases TIMP-1 and TIMP-2 in human head and neck carcinomas. Polette, M., Clavel, C., Birembaut, P., De Clerck, Y.A. Pathol. Res. Pract. (1993) [Pubmed]
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