Epidermal COX-2 induction following ultraviolet irradiation: suggested mechanism for the role of COX-2 inhibition in photoprotection.
The cyclooxygenase isoforms, COX-1 and COX-2, are involved in the biosynthesis of prostaglandin E2, a major prostaglandin involved in epidermal homeostasis and repair. Cancer originating in the epidermis can develop when keratinocyte proliferation and apoptosis become dysregulated, resulting in sustained epidermal hyperplasia. COX-2 inhibitors, which demonstrate significant in vivo selectivity relative to COX-1, suppress both ultraviolet-induced epidermal tumor development and progression, suggesting that prostaglandin regulation of keratinocyte biology is involved in the pathogenesis of epidermal neoplasia. In this study, we characterized the expression of COX-1 and COX-2, as well as keratinocyte proliferation, differentiation, and apoptosis, following acute ultraviolet irradiation in the hairless SKH-1 mouse. Following acute ultraviolet exposure, COX-2 expression was predominantly induced in the basal keratinocyte layer coincident with an increase in keratinocyte proliferation and apoptosis. The role of COX-2 was further evaluated using a selective COX-2 inhibitor, SC-791, as well as the traditional nonsteroidal COX inhibitor, indomethacin. Following acute ultraviolet irradiation, inhibition of COX-2 with either inhibitor decreased epidermal keratinocyte proliferation. Likewise, keratinocyte apoptosis was increased with COX-2 inhibition, particularly in the proliferating basal keratinocyte layer. There was also a modest inhibition of keratinocyte differentiation. These data suggest that COX-2 expression is probably necessary for keratinocyte survival and proliferation occurring after acute ultraviolet irradiation. We hypothesize that selective COX-2 inhibition, as described herein, may lead to enhanced removal of ultraviolet-damaged keratinocytes, thereby decreasing malignant transformation in the epidermis.
Tripp
Catherine S
CS
Department of Arthritis and Inflammation Pharmacology, Pharmacia Corporation, St Louis, Missouri, USA.
Blomme
Eric A G
EA
Chinn
Kevin S
KS
Hardy
Medora M
MM
LaCelle
Peter
P
Pentland
Alice P
AP
D000208:Acute Disease; D000818:Animals; D002455:Cell Division / Q000502:physiology / Q000528:radiation effects; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D000078404:Epidermal Cells; D004817:Epidermis / Q000201:enzymology / Q000528:radiation effects; D005260:Female; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000201:enzymology* / Q000528:radiation effects*; D051379:Mice; D008812:Mice, Hairless; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D012871:Skin Diseases / Q000188:drug therapy / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism / Q000517:prevention & control*; D014466:Ultraviolet Rays / Q000009:adverse effects
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases