Agonist-specific regulation of monocyte chemoattractant protein-1 expression by cyclooxygenase metabolites in hepatic stellate cells

Activated hepatic stellate cells (HSC) regulate the liver "wound-healing" r esponse through expression of chemokines, including monocyte chemoattractan t protein-1 (MCP-1), which participate in the formation of the inflammatory infiltrate during liver injury. Cyclooxygenase (COX) catalyzes the convers ion of arachidonic acid into prostaglandins, which may contribute to the in flammatory response. In this study, we investigated the effects of COX inhi bitors on the expression of MCP-1 in cultured HSC. Pretreatment of HSC with nonspecific COX inhibitors such as indomethacin or ibuprofen markedly redu ced the expression of MCP-1 caused by exposure to tumor necrosis factor cy (TNF-alpha) or interleukin-1 alpha (IL-1 alpha). NS-398, a specific COX-2 i nhibitor, also resulted in a dose-dependent inhibition of MCP-1 gene and pr otein expression. These effects were dependent on reduced MCP-1 transcripti on, as established using a reporter plasmid, In contrast, the up-regulation of MCP-1 expression caused by interferon gamma (IFN-gamma) was not sensiti ve to COX inhibitors. Quiescent HSC did not show detectable expression of C OX-2, which became evident after activation in culture, and while TNF-alpha and IL-1 alpha markedly increased the expression of COX-2, IFN-gamma did n ot have any effects. Pretreatment of HSC with the stable cyclic adenosine m onophosphate (cAMP) analog, 8-bromo cAMP, reverted the effects of the COX-2 inhibitor, but not of a nuclear factor-kappaB (NF-kappaB) inhibitor, demon strating that prostaglandins modulate MCP-1 expression via production of cA MP. On the other hand, the action of NF-kappaB inhibitors was negligible in IFN-gamma -stimulated cells. These findings indicate that cross-talk betwe en cytokines and a prostaglandin-cAMP pathway differentially regulates the proinflammatory potential of HSC, contributing to the modulation of liver t issue inflammation.