Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.35 (matrix metalloproteinase 9)
 2,207 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Monocytes/macrophages are associated with chronic inflammatory lesions, such as periodontal disease and rheumatoid arthritis, in which there is extensive connective tissue destruction. Stimulation of human monocytes results in the production of matrix metalloproteinases (MMPs) via a prostaglandin E2 (PGE2)-cAMP-dependent pathway. Modulation of many monocyte functions by interleukin 10 (IL-10) suggested that this cytokine may influence the signal transduction pathway leading to the production of MMPs by monocytes. Pre-incubation of monocytes with IL-10 for 1 h prior to stimulation with ConA resulted in significant inhibition of prostaglandin H synthase-2 (PGHS-2, the inducible form of prostaglandin synthase). In contrast, PGHS-1, the constitutive PGHS, was not affected by IL-10. Suppression of PGHS-2 mRNA and protein levels was detected at 1 ng/ml of IL-10 with maximal inhibition at 20 ng/ml. Nuclear run-on transcription assays performed on monocytes exposed to ConA or the combination of ConA and IL-10 indicated that IL-10 treatment suppressed PGHS-2 expression at the level of transcription. Attenuation of PGHS-2 by IL-10 was accompanied by decreased prostaglandin production, including PGE2. The decrease in prostaglandin production was primarily related to the effect of IL-10 on PGHS-2, since the release of arachidonic acid was unaffected by this cytokine. The inhibition of PGE2 production by IL-10 resulted in the suppression of mRNA and protein for interstitial collagenase and 92-kDa type IV collagenase/gelatinase (gelatinase B). This conclusion is supported by the ability of exogenously added PGE2 or dibutyryl cAMP to restore the production of MMPs in IL-10-treated monocytes. Additionally, PGHS-2 was also restored by PGE2 or dibutyryl cAMP, indicating that PGHS-2 is regulated through a PGE2-cAMP amplification pathway. These data add further support to the anti-inflammatory properties of IL-10.
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PMID:Interleukin 10 suppression of monocyte prostaglandin H synthase-2. Mechanism of inhibition of prostaglandin-dependent matrix metalloproteinase production. 806 57

SPARC (secreted protein, acidic and rich in cysteine), also called osteonectin or BM-40, is a collagen-binding glycoprotein secreted by a variety of cells and is associated with functional responses involving tissue remodeling, cell movement and proliferation. Because SPARC and monocytes/macrophages are prevalent at sites of inflammation and remodeling in which there is connective tissue turnover, we examined the effect of SPARC on monocyte matrix metalloproteinase (MMP) production. Treatment of human peripheral blood monocytes with SPARC stimulated the production of gelatinase B (MMP-9) and interstitial collagenase (MMP-1). Experiments with synthetic peptides indicated that peptide 3.2, belonging to the alpha helical domain III of SPARC, is the major peptide mediating the MMP production by monocytes. SPARC and peptide 3.2 were also shown to induce prostaglandin synthase (PGHS)-2 as determined by Western and Northern blot analyses. The increase in PGHS-2 stimulated by SPARC or peptide 3.2 correlated with substantially elevated levels of prostaglandin E2 (PGE2) and other arachidonic acid metabolites as measured by radioimmunoassay and high performance liquid chromatography (HPLC), respectively. Moreover, the synthesis of MMP was dependent on the generation of PGE2 by PGHS-2, since indomethacin inhibited the production of these enzymes and their synthesis was restored by addition of exogenous PGE2 or dibutyryl cAMP (Bt2cAMP). These results demonstrate that SPARC might play a significant role in the modulation of connective tissue turnover due to its stimulation of PGHS-2 and the subsequent release of PGE2, a pathway that leads to the production of MMP by monocytes.
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PMID:Regulation of human monocyte matrix metalloproteinases by SPARC. 936 45