Prostaglandins, cyclic nucleotides and the effect of phorbol ester tumor promoters on mouse skin in vivo.
Topical application of prostaglandin E1 or E2 onto the mouse skin results in a 2- to 3-fold increase of the cyclic AMP level in epidermis within 5 min. (15S)-15-methyl-PGE1 is more active in this respect, whereas PGD2 and PGF2 alpha are ineffective. The level of cyclic GMP is not altered by E- or F-prostaglandins. A single PGE2 application desensitizes the cyclic AMP response of mouse epidermis to further treatments in a dose dependent and agonist-specific manner. Delayed and longlasting refractoriness of PGE2-induced cyclic AMP accumulation is also caused by hyperplasiogenic skin irritants such as the phorbol ester tumor promoter TPA or the nonpromoting agents RPA and A23187. The non-irritant skin mitogen 4-O-methyl-TPA does not evoke desensitization. TPA-induced PGE2 refractoriness cannot be prevented by inhibitors of protein synthesis, anti-inflammatory steroids, indomethacin or phentolamine. The development of tachyphylaxis does not seem to be related to endogenous formation of PGE or cyclic AMP. A 2-fold increase of epidermal cyclic AMP observed within 1-2 h of TPA application can be inhibited by indomethacin treatment and correlates with delayed accumulation of PGE2 in TPA-treated epidermis, whilst immediate PGE accumulation (5-10 min after TPA application) which has been shown to be critical for development of TPA-induced epidermal hyperplasia is not accompanied by any change of the intraepidermal cyclic AMP level. It is concluded that mouse epidermis contains two types of PGE-regulated effector systems, one of which is coupled to adenylate cyclase, one of which is not. Only the latter system is involved in the induction of hyperplasia. At least as far as the mitogenic effect is concerned, cyclic AMP does not seem to be involved in TPA action.
D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D005260:Female; D007545:Isoproterenol / Q000633:toxicity; D007700:Kinetics; D051379:Mice; D008815:Mice, Inbred Strains; D010703:Phorbol Esters / Q000633:toxicity*; D010704:Phorbols / Q000633:toxicity*; D011453:Prostaglandins / Q000494:pharmacology*; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
D010703:Phorbol Esters; D010704:Phorbols; D011453:Prostaglandins; D000242:Cyclic AMP; D007545:Isoproterenol; D013755:Tetradecanoylphorbol Acetate