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J Lipid Res. 2000 Jun;41(6):873-81.

Prostaglandin E(2) regulation of cyclooxygenase expression in keratinocytes is mediated via cyclic nucleotide-linked prostaglandin receptors.

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  • 1The University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, P.O. Box 389, Smithville, TX 78957, USA.


Inflammatory responses are thought to be mediated in part by the prostaglandins derived from arachidonic acid (AA) by the action of prostaglandin H synthase, also referred to as cyclooxygenase (COX). The mitogen-inducible isoform, COX-2, is over-expressed in numerous chronic inflammatory disease conditions and in neoplasms from both human and experimental animal models. COX-1 expression, on the other hand, has been referred to as constitutive or non-inducible. In this study, we present evidence demonstrating autoregulation of prostaglandin (PG) production by the PGs themselves and their precursor, AA. We observed that AA and PGs induced COX-2, as well as COX-1, expression in cultured murine keratinocytes approximately 3 h after treatment. In primary keratinocytes transiently transfected with a full-length COX-2 promoter linked to a luciferase reporter gene, we observed enhanced transcription by AA, PGE(2), and the other prostaglandins. Forskolin, a known activator of adenylate cyclase, and dibutryl-cAMP, a cAMP analog, induced COX-1 and 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 expression may be through one of the cAMP-linked PGE(2) receptors. 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 this autoregulation probably occurs via prostaglandin receptors linked to a cAMP signal transduction pathway.

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