Prostaglandin E-2 regulation of cyclooxygenase expression in keratinocytesis mediated via cyclic nucleotide-linked prostaglandin receptors

Inflammatory responses are thought to be mediated in part by the prostaglan dins derived from arachidonic acid (AA) by the action of prostaglandin H sy nthase, also referred to as cyclooxygenase (COX). The mitogen-inducible iso form, COX-2, is over-expressed in numerous chronic inflammatory disease con ditions and in neoplasms from both human and experimental animal models. CO X-1 expression, on the other hand, has been referred to as constitutive or non-inducible. In this study we present evidence demonstrating autoregulati on of prostaglandin (PG) production by the PGs themselves and their precurs or, AA. We observed that AA and PGs induced COX-2, as well as COX-1, expres sion in cultured murine keratinocytes approximately 3 h after treatment. In primary keratinocytes transiently transfected with a full-length COX-2 pro moter linked to a luciferase reporter gene, we observed enhanced transcript ion by AA, PGE(2), and the other prostaglandins. Forskolin, a known activat or of adenylate cyclase, and dibutryl-cAMP, a cAMP analog, induced COX-1 an d COX-2 mRNA, suggesting that cAMP is a second messenger for COX expression . SQ 22536, an adenylate cyclase inhibitor, inhibited COX-2 mRNA induction by PGE(2) in a dose-dependent manner suggesting that PGE(2)-induced express ion may be through one of the cAMP-linked PGE(2) receptors. jlr The results of this study demonstrate that both COX-1 and COX-2 are inducible. Further , both COX isoforms can be up-regulated by their products, the PGs, and thi s autoregulation probably occurs tia prostaglandin receptors linked to a cA MP signal transduction pathway.