Expression of cyclooxygenase-2 promotes the release of matrix metalloproteinase-2 and-9 in fetal rat hepatocytes

Treatment of primary cultures of fetal hepatocytes with proinflammatory cyt okines, lipopolysaccharide (LPS), and hepatocyte growth factor promoted the expression of cyclooxygenase-2 (COX-2) and the synthesis of high amounts o f prostaglandins (PGs). Under these conditions, the active forms of the mat rix metalloproteinases-2 and -9 (MMPs) were released to the extracellular m edium. This process was inhibited when the synthesis of PGs was suppressed pharmacologically with COX-2 inhibitors. Addition to the cell cultures of P GE(2) promoted the release of MMPs through a mechanism that involved the ex pression 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 c ourse, with a lag period of 6 hours, which suggests that PGE(2) does not ac t directly on the mechanism of MMP processing and release. Inhibitors of pr otein kinase A, p38 MAP kinase, phosphatidylinositol-3-kinase, and nuclear factor kappaB (NF-kappaB) activation impaired the release of MMPs in respon se to PGE(2) challenge, indicating the involvement of multiple steps in the process. The ability of fetal hepatocytes to release MMPs in response to g rowth factors and inflammatory stimuli constitutes a model for the study of the extracellular matrix remodeling that accompanies most liver diseases.