Expression of Cyclooxygenase–2 Promotes the Release of Matrix Metalloproteinase–2 and –9 in Fetal Rat Hepatocytes

Abstract

Treatment of primary cultures of fetal hepatocytes with proinflammatory cytokines, lipopolysaccharide (LPS), and hepatocyte growth factor promoted the expression of cyclooxygenase-2 (COX-2) and the synthesis of high amounts of prostaglandins (PGs). Under these conditions, the active forms of the matrix metalloproteinases-2 and -9 (MMPs) were released to the extracellular medium. This process was inhibited when the synthesis of PGs was suppressed pharmacologically with COX-2 inhibitors. Addition to the cell cultures of PGE 2 promoted the release of MMPs through a mechanism that involved the expression of COX-2 and the synthesis of additional PGs. Kinetic analysis of the secretion of MMPs in response to LPS and PGE 2 showed a similar time course, with a lag period of 6 hours, which suggests that PGE 2 does not act directly on the mechanism of MMP processing and release. Inhibitors of protein kinase A, p38 MAP kinase, phosphatidylinositol-3-kinase, and nuclear factor B Prostaglandin H synthase, also known as cyclooxygenase (COX), catalyzes the synthesis of prostaglandin H 2 from arachidonate and constitutes a key regulatory step in the biosynthesis of prostanoids. 1-3 Two distinct isoforms of COX are known: COX-1 and COX-2. The two isoenzymes are encoded by different genes, and the control of their expression, regulation of enzyme activity, and physiologic functions are very different. 1,4 COX-1 seems to be involved in the house keeping function of prostaglandins (PGs) 4 and is expressed constitutively. In contrast, COX-2 is inducible, is expressed as an immediate early gene, and is involved in the onset of inflammation and mitogenic responses. 1,3,5,6 COX-2 expression is positively regulated by lipopolysaccharide (LPS), interleukin 1␤, tumor necrosis factor ␣, and reactive oxygen intermediates in different cells. 7,8 In addition to these stimuli, it has been described that hepatocyte growth factor (HGF) and epidermal growth factor (EGF) triggered the expression of COX-2 in rat gastric epithelial cells, in human amnion-derived WISH cells, and in human gingival fibroblasts, and this effect was mediated through the activation of the ERK2 signaling pathway. [9][10][11] Our previous results showed that adult hepatocytes failed to express COX-2 regardless of the proinflammatory factors used. However, fetal hepatocytes, which exhibit a liver phenotype distinct from the adult counterpart, were able to express COX-2 upon challenge with LPS and proinflammatory cytokines. 8 Regarding the mechanism responsible for the suppression of COX-2 inducibility in adult hepatocytes, our data suggest the existence of a close relationship between COX-2 induction and the decrease of C/EBP␣ levels that bind to the nuclear factor-interleukin 6 site of the COX-2 promoter. 12 In addition to inflammation and cell growth regulation, COX-2 expression has been associated with carcinogenesis and tumor development. 3,6 Several population-based studies have detected a 40% to 50% decrease in relative risk for colorectal cancer in persons who regularl...

Cellular Prostaglandin E2 Production by Membrane-bound Prostaglandin E Synthase-2 via Both Cyclooxygenases-1 and -2

“…It is therefore likely that the induced expression of mPGES-1 and attendant augmented production of PGE 2 in myocardiocytes after infarction may contribute to protection of myocardiocytes from injury and reduction of cardiac cell death, whereas PGE 2 produced via the constitutive mPGES-2 may play a role in the maintenance of cardiac homeostasis. Likewise, COX-derived PGs, particularly PGE 2 , play a role in liver regeneration and protection of hepatic tissues from damage (52)(53)(54)(55)(56). Hepatocyte proliferation after partial hepatectomy is significantly reduced when COX-1-deficient mice are treated with a COX-2 inhibitor (55), suggesting the involvement of both COX isoforms in liver regeneration.…”

Cooperative effects of matrix metalloproteinase and cyclooxygenase-2 inhibition on intestinal adenoma reduction

“…This raises the possibility that these compounds alter converging pathways that affect tumour cell apoptosis. COX-2 has been shown to increase the levels of MMP-2, -9, and -14, while NSAIDS and COX-2 inhibitors have been reported to alter the levels of MMP-1, -2, -3, -9 (Ito et al, 1995;Takahashi et al, 1997Takahashi et al, , 1999Attiga et al, 2000;McLaren et al, 2000;Callejas et al, 2001;Jiang et al, 2001). Recent reports have shown that NSAIDs inhibit MMP expression and activation through both COX-2-dependent and independent mechanisms such as through modulation of gene transcription via the ERK/Sp1 signalling pathway or through induction of the membraneanchored MMP inhibitor RECK (Pan et al, 2001;Liu et al, 2002;Pan and Hung, 2002).…”

Expression of COX-2 mRNA in Peripheral Blood Monocytes from Patients with Acute Myocardial Infarction and Its Significance

“…It is now recognized that the antiinflammatory and analgesic actions of nonsteroidal antiinflammatory drugs are largely attributable to inhibition of COX-2 isoenzyme. COX-2 and prostaglandin E 2 are known to induce production of the inflammatory cytokine IL-6 (11 ) and promote the release and activation of MMPs (12 ). Recent studies have shown that expression of COX-2 has also been specifically linked to cardiovascular disease.…”

“…COX-2-mediated eicosanoid production by activated macrophages may promote atherosclerosis through several mechanisms, including activation of chemotaxis, increased vascular permeability, propagation of the inflammatory cytokine cascade, stimulation of macrophage and smooth muscle cell migration, and stimulation of chemotaxis of human monocytes by LDL (9,11,12,15,20,21 ). It has been reported that COX-2 is also correlated with endothelial dysfunction and oxidative stress, which promote the progress of atherosclerotic inflammation.…”