Cyclic AMP, glucocorticoid, and retinoid modulation of in vitro keratinocyte growth.
The hypothesis that an imbalanced cyclic AMP and cyclic GMP ratio was central to the cutaneous expression of psoriasis prompted the design of a series of in vitro experiments. The aim of these studies was to describe the functional effects of increased intracellular cyclic AMP and of drugs therapeutic in psoriasis on epidermal keratinocyte growth. Epidermal basal cells trypsinized from neonatal mouse and adult and neonatal human skin were grown on plastic or on gelled collagen surfaces. These were used to study the effect of cyclic AMP analogues and cholera toxin (an irreversible stimulator of cyclic AMP synthesis) on keratinocyte growth. Greatly increased intracellular cyclic AMP levels, that is, 60-fold to 70-fold, stimulated neonatal mouse keratinocyte proliferation and differentiation; these same doses were cytotoxic to both neonatal and adult human cells. However, modest increases in intracellular cyclic AMP did stimulate adult human keratinocyte proliferation. The glucocorticoid triamcinolone acetonide inhibited neonatal mouse keratinocyte proliferation for approximately 1 week; the cells then became refractory to the triamcinolone acetonide effect. Triamcinolone acetonide did not apparently act through cyclic AMP-mediated events. In fact, this glucocorticoid inhibited cyclic AMP-stimulated epidermal keratinocyte proliferation. Likewise, vitamin A analogues, including the psoriasis therapy drug Ro 10-9359 inhibited neonatal mouse keratinocyte proliferation and specific differentiation events; the retinoids therapeutic in psoriasis apparently did not act via cyclic AMP-mediated events and inhibited cyclic AMP-stimulated functions. Our results indicated that cyclic AMP is a mitogenic signal for epidermal keratinocytes. This cyclic nucleotide may be important in regulating epidermal hyperproliferation. A central role for cyclic AMP in the cutaneous expression of psoriasis, however, is yet to be proven.
D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D000242:Cyclic AMP / Q000494:pharmacology*; D000078404:Epidermal Cells; D005050:Etretinate / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D012176:Retinoids; D014212:Tretinoin / Q000494:pharmacology; D014222:Triamcinolone Acetonide / Q000494:pharmacology; D014801:Vitamin A / Q000494:pharmacology*
D001565:Benzoates; D005938:Glucocorticoids; D012176:Retinoids; D014801:Vitamin A; D014212:Tretinoin; D005050:Etretinate; C034814:ethyl-p-((E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propenyl)benzoic acid; D000242:Cyclic AMP; D014222:Triamcinolone Acetonide; D006854:Hydrocortisone