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Genetic deficiency or pharmacological inhibition of cyclooxygenase‐1 or ‐2 induces mouse keratinocyte differentiation in vitro and in vivo
Author(s) -
Akunda Jacqueline K.,
Lao HueiChen,
Lee Chris A.,
Sessoms Alisha R.,
Slade Rachel M.,
Langenbach Robert
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-1192fje
Subject(s) - keratinocyte , in vivo , cyclooxygenase , gene isoform , cell culture , in vitro , apoptosis , wild type , cancer research , microbiology and biotechnology , biology , chemistry , enzyme , biochemistry , mutant , gene , genetics
Previously we demonstrated that genetic deficiency of the cyclooxygenases (COX‐1 or COX‐2) altered keratinocyte differentiation in mouse skin [Tiano et. al. (2002) Cancer Res. 62 , 3395–3401]. In this study, we show that topical application of SC‐560 (a COX‐1 selective inhibitor) or celecoxib (COX‐2 selective) to TPA‐treated wild‐type skin caused fivefold increases in the number of basal keratinocytes expressing the early differentiation marker keratin 1 (K1). In contrast to skin, COX‐2 not COX‐1 was the major isoform expressed in cultured primary keratinocytes. COX‐1 was predominantly expressed in detached, differentiated cells, whereas COX‐2 was found in the attached, proliferating cells. High Ca ++ medium induced K1 and COX‐1 in wild‐type keratinocytes but did not change COX‐2 expression. As observed in skin, COX‐1 −/− and COX‐2 −/− primary keratinocytes expressed fivefold more K1 than wild‐type cells. K1 levels in cultured wild‐type keratinocytes were also increased by treatment with celecoxib and indomethacin. However, unlike its in vivo effect, SC‐560, possibly due to low COX‐1 expression in cultured mouse keratinocytes, did not increase K1 levels. Furthermore, no increases in apoptotic cell numbers were observed in COX‐deficient keratinocytes or COX‐inhibitor treated wild‐type cells. Thus, a major effect of COX inhibitors and COX‐deficiency is the induction of keratinocyte differentiation.