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

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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 PGE2 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 PGE2 showed a similar time course, with a lag period of 6 hours, which suggests that PGE2 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 κB (NF–κB) activation impaired the release of MMPs in response to PGE2 challenge, indicating the involvement of multiple steps in the process. The ability of fetal hepatocytes to release MMPs in response to growth factors and inflammatory stimuli constitutes a model for the study of the extracellular matrix remodeling that accompanies most liver diseases.

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