Disease relevance of TIMP4

• Double immunofluorescence labeling and confocal laser scanning microscopy revealed that MMP-26 was colocalized with MMP-9, TIMP-2, and TIMP-4 in DCIS cells [1].
• Full-length human TIMP-4 was expressed in E. coli, folded from inclusion bodies, and the active component was purified by MMP-1 affinity chromatography [2].
• We therefore examined whether TIMP4 is involved in human inflammatory cardiovascular disorders, specifically atherosclerosis, giant cell arteritis and chronic rejection of heart allografts [3].
• Differential expression and localization of TIMP-1 and TIMP-4 in human gliomas [4].
• To investigate the locations and functions of TIMP-4 in human breast cancer, a highly specific polyclonal anti-TIMP-4 peptide antibody (pAb-T4-S61) was developed [5].

High impact information on TIMP4

• However, TIMP-4 protein was significantly reduced in ICM myocardium [6].
• TIMP-2 and TIMP-4 also inhibited the activation of pro-MMP-9 by MMP-26 in vitro [1].
• However, here we report that systemic administration of human TIMP-4 by electroporation-mediated i.m. injection of naked TIMP-4 DNA stimulates tumorigenesis of human breast cancer cells in nude mice [7].
• Total conversion of tissue inhibitor of metalloproteinase (TIMP) for specific metalloproteinase targeting: fine-tuning TIMP-4 for optimal inhibition of tumor necrosis factor-{alpha}-converting enzyme [8].
• Transplantation of only three residues, Pro-Phe-Gly, onto the AB-loop of N-TIMP-4 resulted in a 10-fold enhancement in binding affinity; the K(i) values of the resultant mutant were almost comparable with that of TIMP-3 [8].

Biological context of TIMP4

• We therefore speculate that the human TIMP4 gene will be located in intron V of the human synapsin-II gene on chromosome 3p25, and we present preliminary evidence that a human synapsin-IV gene is located near the TIMP2 gene on chromosome 17q23-q25 [9].
• In conclusion, the data demonstrate upregulation of TIMP4 in human cardiovascular disorders exhibiting inflammation, suggesting its future use as a novel systemic marker for vascular inflammation [3].
• Animal studies have suggested a role for TIMP4 in several inflammatory diseases and cardiovascular pathologies [3].
• We evaluated the promoter regions, exon-intron junctions, and the exons of the TIMP2 and TIMP4 genes by direct sequencing, and compared single nucleotide polymorphisms frequencies among the study groups [10].
• We investigated single nucleotide polymorphisms of the TIMP2 and TIMP4 genes in FMMD patients to determine genetic predispositions [10].

Anatomical context of TIMP4

• TIMP4 was most clearly visible in cardiovascular tissue areas populated by abundant inflammatory cells, mainly macrophages and CD3+ T cells [3].
• We demonstrate with immunohistochemical analysis of healthy human tissue that TIMP4 is present in medial smooth muscle cells and adventitial capillaries of arteries as well as in cardiomyocytes [3].
• Using western blotting and immunocytochemistry, human blood derived lymphocytes, monocytes/macrophages and mast cells were shown to produce TIMP4 [3].
• Occasional staining for TIMP-4 protein was detected in stromal cells of chronic ulcers near blood vessels [11].
• TIMP-4 was expressed in IPF lungs by epithelial and plasma cells [12].

Associations of TIMP4 with chemical compounds

• TIMP-3 and TIMP-4 levels were significantly higher in steroid hormone receptor-positive samples, although the levels of TIMP-4 were much lower than those of the other TIMPs [13].
• RESULT(S): Endometrium from women with a normal menstrual cycle and users of levonorgestrel implants expresses MMP-26, TIMP-3, and TIMP-4 [14].
• The mutation of cysteine at position 1 of TIMP-4 failed to block the development of AIA [15].
• 7. The release of TIMP-4 was reduced by prostacyclin and S-nitroso-glutathione (GSNO), an NO donor [16].
• TIMP-4 protein was only occasionally found in the stroma but was consistently present in granules of the apical part of luminal and glandular epithelial cells [17].

Physical interactions of TIMP4

• However, TIMP-4 binds to MT1-MMP inhibiting its autocatalytic processing [18].

Co-localisations of TIMP4

• 5. TIMP-4 co-localized with MMP-2 in resting platelets and was released upon platelet aggregation induced by collagen and thrombin [16].

Regulatory relationships of TIMP4

• However, transfer of both the AB loop and C-terminal domain of TIMP-2 to TIMP-4 generates a mutant that can activate pro-MMP-2 and so demonstrates that both these regions of TIMP-2 are important for the activation process [19].

Other interactions of TIMP4

• Here we report that tissue inhibitor of metalloproteinases (TIMP)-2 and TIMP-4 are potent inhibitors of MMP-26, with apparent K(i) values of 1.6 and 0.62 nM, respectively [1].
• The inhibitory properties of TIMP-4 for matrix metalloproteinases (MMPs) were compared to those of TIMP-1 and TIMP-2 [2].
• In contrast, while MMP-2 and TIMP-4 were localized to both stem and mature CNS cells, their levels of expression were substantially reduced in the latter [20].
• Stromal immunoreactivity ranged from 6% for TIMP-4 to 87% for MMP-13 [21].
• Although full-length TIMP-4 displayed negligible activity against TACE, N-TIMP-4 is a slow tight-binding inhibitor with low nanomolar binding affinity [8].

Analytical, diagnostic and therapeutic context of TIMP4

• The expression levels of MMP-26, MMP-9, TIMP-2, and TIMP-4 proteins in DCIS were significantly higher than those in IDC, atypical intraductal hyperplasia, and normal breast epithelia adjacent to DCIS and IDC by immunohistochemistry and integrated morphometry analysis [1].
• TIMP-4 expression was seen in RT-PCR, however, only a faint band was visible in all the tissues tested [22].
• RESULTS: In normal human liver, messenger RNAs (mRNAs) of TIMP-1, -2, and -3, but not of TIMP-4 and none of the 10 MMPs studied, were expressed in DNA microarray [23].
• METHODS: We administered human TIMP-4 by electroporation-mediated intramuscular injection of naked DNA using the rat adjuvant-induced arthritis (AIA) model [15].
• Arthritis-inhibiting effects of TIMP-4 may suggest a unique application of this gene therapy method for arthritis [15].

References