Prostaglandin E(2) regulation of cyclooxygenase expression in keratinocytes is mediated via cyclic nucleotide-linked prostaglandin receptors.
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.
Maldve
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The University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, P.O. Box 389, Smithville, TX 78957, USA.
Kim
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Y
Muga
S J
SJ
Fischer
S M
SM
D016718:Arachidonic Acid / Q000502:physiology; D000242:Cyclic AMP / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000502:physiology*; D004790:Enzyme Induction; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics*; D015603:Keratinocytes / Q000201:enzymology*; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D011982:Receptors, Prostaglandin / Q000502:physiology*; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000502:physiology
D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D011982:Receptors, Prostaglandin; D016718:Arachidonic Acid; D000242:Cyclic AMP; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone