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

Chemokines are important mediators of cell migration during inflammation and normal leukocyte trafficking. Inflammatory chemokines are induced in multiple cell types at sites of infection. Here, we describe a novel bovine CC chemokine, designated regakine-1, that is constitutively present at high concentrations in plasma. Cloning of its gene revealed an expected two intron/three exon organization, with a rather long first intron. In addition to a 21-residue signal peptide, the coding sequence corresponded to a 71-residue secreted protein. However, the natural regakine-1 protein missed the COOH-terminal lysine residue. Regakine-1 has only weak sequence similarity (<50% identical residues) with other animal or human chemokines. Northern blot analysis demonstrated regakine-1 RNA expression in spleen and lung. At physiological concentrations (30-100 ng/mL), natural 7.5 kDa regakine-1 stimulated gelatinase B release from neutrophils and chemoattracted immature myeloid HL-60 cells, as well as mature granulocytes. Regakine-1 was more potent on human myeloid cells than the human plasma CC chemokine hemofiltrate CC chemokine-1 (HCC-1). Moreover, regakine-1 synergized with the bacterial peptide N-formylmethionylleucylphenylalanine (fMLP), yielding a 10-fold increase in neutrophil chemotactic response above their additive effect. Regakine-1 did not compete with interleukin-8 (IL-8) for binding to neutrophils, nor did it affect fMLP-induced calcium signaling, suggesting that regakine-1 recognizes a different receptor. In view of its high constitutive plasma concentration, regakine-1 is believed to recruit myeloid cells into the circulation, whereas its synergy with other neutrophil chemoattractants suggests that it also enhances the inflammatory response to infection.
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PMID:Gene cloning of a new plasma CC chemokine, activating and attracting myeloid cells in synergy with other chemoattractants. 1157 Aug 72

Monocyte chemoattractant protein (MCP)-3 is inactivated upon cleavage by the matrix metalloproteinase (MMP) gelatinase A (MMP-2). We investigated the susceptibility to proteolytic processing of the 4 human MCPs by 8 recombinant MMPs to determine whether MCP-3 is an isolated example or represents a general susceptibility of chemokines to proteolytic inactivation by these important inflammatory proteases. In addition to MMP-2, MCP-3 is efficiently cleaved by membrane type 1 (MT1)-MMP, the cellular activator of MMP-2, and by collagenase-1 and collagenase-3 (MMP-1, MMP-13) and stromelysin-1 (MMP-3). Specificity was shown by absence of cleavage by matrilysin (MMP-7) and the leukocytic MMPs neutrophil collagenase (MMP-8) and gelatinase B (MMP-9). The closely related chemokines MCP-1, MCP-2, and MCP-4 were not cleaved by MMP-2 or MT1-MMP, but were cleaved by MMP-1 and MMP-3 with varying efficiency. MCPs were typically cleaved between residues 4 and 5, but MCP-4 was further processed at Val7-Pro8. Synthetic MCP analogs corresponding to the MMP-cleaved forms bound CC chemokine receptor (CCR)-2 and CCR-3, but lacked chemoattractant activity in pre-B cells transfected with CCR-2 and CCR-3 or in THP-1 monocytic cells, a transformed leukemic cell line. Moreover, the truncated products of MCP-2 and MCP-4, like MCP-3, were potent antagonists of their cognate CC chemokine receptors in transwell cell migration assays in vitro. When they were injected 24 hours after the initiation of carrageenan-induced inflammation in rat paws, their in vivo antagonist activities were revealed by a greater than 66% reduction in inflammatory edema progression after 12 hours. We propose that MMPs have an important role in modulating inflammatory and immune responses by processing chemokines in wound healing and in disease.
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PMID:Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo. 1214 83