Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.7 (plasmin)
 9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of bacteria in the initiation of periodontitis is well-documented and the end result, destruction of the alveolar bone and periodontal connective tissue, is readily observed; but the events occurring between these two points in time remain obscure and are the focus of this paper. Bacteria induce tissue destruction indirectly by activating host defense cells, which in turn produce and release mediators that stimulate the effectors of connective tissue breakdown. Components of microbial plaque have the capacity to induce the initial infiltrate of inflammatory cells including lymphocytes, macrophages, and PMNs. Microbial components, especially lipopolysaccharide (LPS), have the capacity to activate macrophages to synthesize and secrete a wide array of molecules including the cytokines interleukin-1 (IL-1) and tumor-necrosis factor-alpha (TNF-alpha), prostaglandins, especially PGE2, and hydrolytic enzymes. Likewise, bacterial substances activate T lymphocytes and they produce IL-1 and lymphotoxin (LT), a molecule having properties very similar to TNF-alpha. These cytokines manifest potent proinflammatory and catabolic activities, and play key roles in periodontal tissue breakdown. They induce fibroblasts and macrophages to produce neutral metalloproteinases such as procollagenase and prostromelysin, the serine proteinase urokinase-type plasminogen activator (u-PA), tissue inhibitor of metalloproteinase (TIMP), and prostaglandins, u-PA converts plasminogen into plasmin, which can activate neutral metalloproteinase proenzymes, and these enzymes degrade the extracellular matrix components. TIMP inactivates the active enzymes and thereby blocks further tissue degradation. Several amplification and suppression mechanisms are involved in the process. While LPS activates macrophages to produce IL-1, IL-1 is autostimulatory and can therefore amplify and perpetuate its own production. Interferon-gamma (INF-gamma) suppresses autostimulation, but it enhances LPS-induced IL-1 production. PGE2 exerts a control over the whole process by suppressing production of both IL-1 and TNF-alpha. Furthermore, the activated cells produce an IL-1 receptor antagonist that binds to the IL-1 receptor but does not induce the biologic consequences of IL-1 binding. Other cytokines such as transforming growth factor-beta (TGF-beta) suppress production of metalloproteinases and u-PA. Thus the progression and extent of tissue degradation is likely to be determined in major part by relative concentrations and half-life of IL-1, TNF-alpha, and related cytokines, competing molecules such as the IL-1 receptor antagonist, and suppressive molecules such as TGF-beta and PGE2. These molecules control levels of latent and active metalloproteinase and u-PA, and the availability and concentration of TIMP determines the extent and duration of degradative activity.
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PMID:The role of inflammatory mediators in the pathogenesis of periodontal disease. 167 30

Endothelial cells play an important role in the regulation of fibrinolysis by the production of several key regulatory proteins. The cytokines tumor necrosis factor (TNF), lymphotoxin, and interleukin-1 (IL-1), but not interleukin-6, increase the production of plasminogen activator inhibitor-1 (PAI-1) by endothelial cells, whereas they have no stimulatory effect on the production of tissue-type plasminogen activator (t-PA). Primary cultures of human endothelial cells release very little urokinase-type plasminogen activator (u-PA). We report here that TNF and lymphotoxin induce, in a concentration-dependent way, the production of both cellular and secreted u-PA antigen in primary and subcultured human endothelial cells. The TNF-induced increase was accompanied by a more than 10-fold increase in u-PA mRNA. Upon stimulation of early passage umbilical vein endothelial cells by TNF, u-PA was predominantly secreted at the basolateral side, whereas PAI activity and t-PA were found in more equal amounts at the apical and basolateral sides of the cell monolayers. TNF-stimulated u-PA secretion by subcultured human aorta endothelial cells showed only a marginal polarity. The u-PA antigen was present in a plasmin-activatable form (single chain u-PA) and in a nonactivatable form (probably u-PA: PAI-1 complex). During the induction of u-PA by TNF, the ratio between plasmin-activatable u-PA and total u-PA decreased markedly. This may indicate that TNF also increases the degree of u-PA activation. The parallel induction of the synthesis and secretion of both u-PA and PAI-1 by endothelial cells adds a new aspect to the alterations of the fibrinolytic system caused by inflammatory mediators. This aspect may be significant for the regulation of cell-associated and interstitial plasminogen activator activity.
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PMID:Tumor necrosis factor induces the production of urokinase-type plasminogen activator by human endothelial cells. 214 60

The vascular endothelium plays a central role in the regulation of extrinsic fibrinolysis and thus maintains vascular patency through clot dissolution. Plasminogen activation provides an important source of localized proteolytic activity not only during fibrinolysis but also during a variety of other physiological and pathological processes. Numerous studies have indicated that human endothelial cells can directly synthesize and secrete plasminogen activators (PA) and inhibitors of these activators. PAs specifically hydrolyse a single arginine-valine bond in plasminogen, an abundant and widely distributed plasma zymogen, to form the broad spectrum serine protease, plasmin. Tissue type-PA (t-PA) and urokinase type PA (u-PA) forms of PA have been described in endothelial cells, although t-PA production and secretion is elevated most frequently. The tPA form of PA functions predominantly in endothelial cell mediated fibrinolysis, while uPA is involved in tissue remodeling. During inflammatory reactions activated mononuclear phagocytes produce a variety of cytokines which may influence the phenotype of the endothelium through a process termed "endothelial cell activation". Tumor necrosis factor alpha (TNF alpha), a mononuclear cytokine, is a distinct polypeptide of Mr 17,000 and has been implicated as a mediator of gram negative induced sepsis as well as angiogenesis. TNF alpha is known to interact with specific endothelial cell receptors and to alter endothelial coagulant and anticoagulant properties implying that cytokines may be potent modulators of hemostasis. Recent observations have indicated that TNF alpha and lymphotoxin (TNF beta) can promote the expression, synthesis and secretion of urokinase plasminogen activator (uPA) in human endothelial cells. The upregulation of uPA results in an alteration in the fibrinolytic capacity of endothelial cells and allows cells the selective ability to degrade and invade underlying subendothelial extracellular matrix (ECM). Endothelial cells treated with TNF alpha also display, in an in vitro angiogenic assay, the ability to invade Matrigel and reorganize into tube-like structures, unlike control cultures. The effects of TNF alpha on the PA proteolytic system of endothelial cells, the biological significance of this event and potential in vivo consequences will be discussed. In addition, the influence of cytokine regulatory control systems will be described, since it is becoming increasingly clear that cytokines do not act in isolation. The vascular endothelium serves as a widely distributed anatomical interface between the blood and tissue with diverse capabilities, performing distinctive biologic functions at different sites and within specific organs.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Cytokine regulation of endothelial cell extracellular proteolysis. 835 23