Pigment-independent cAMP-mediated epidermal thickening protects against cutaneous UV injury by keratinocyte proliferation.

Abstract

The epidermis increases pigmentation and epidermal thickness in response to ultraviolet exposure to protect against UV-associated carcinogenesis; however, the contribution of epidermal thickness has been debated. In a humanized skin mouse model that maintains interfollicular epidermal melanocytes, we found that forskolin, a small molecule that directly activates adenylyl cyclase and promotes cAMP generation, up-regulated epidermal eumelanin accumulation in fair-skinned melanocortin-1-receptor (Mc1r)-defective animals. Forskolin-induced pigmentation was associated with a reproducible expansion of epidermal thickness irrespective of melanization or the presence of epidermal melanocytes. Rather, forskolin-enhanced epidermal thickening was mediated through increased keratinocyte proliferation, indirectly through secreted factor(s) from cutaneous fibroblasts. We identified keratinocyte growth factor (Kgf) as a forskolin-induced fibroblast-derived cytokine that promoted keratinocyte proliferation, as forskolin induced Kgf expression both in the skin and in primary fibroblasts. Lastly, we found that even in the absence of pigmentation, forskolin-induced epidermal thickening significantly diminished the amount of UV-A and UV-B that passed through whole skin and reduced the amount of UV-B-associated epidermal sunburn cells. These findings suggest the possibility of pharmacologic-induced epidermal thickening as a novel UV-protective therapeutic intervention, particularly for individuals with defects in pigmentation and adaptive melanization.

• Authors: Timothy L Scott, Perry A Christian, Melissa V Kesler, Kevin M Donohue, Brent Shelton, Kazumasa Wakamatsu, Shosuke Ito, John D'Orazio
• Journal: Experimental dermatology (Exp Dermatol) Vol. 21 Issue 10 Pg. 771-7 (Oct 2012) ISSN: 1600-0625 [Electronic] Denmark
• PMID: 23078399 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 John Wiley & Sons A/S.

Chemical References

• KRT14 protein, human
• Keratin-14
• Pigments, Biological
• Colforsin
• Cyclic AMP

Topics

• Animals
• Apoptosis (drug effects, radiation effects)
• Cell Proliferation (drug effects, radiation effects)
• Colforsin (pharmacology)
• Cyclic AMP (metabolism)
• Disease Models, Animal
• Epidermis (drug effects, injuries, metabolism, pathology, radiation effects)
• Humans
• Keratin-14 (genetics)
• Keratinocytes (drug effects, metabolism, pathology, radiation effects)
• Melanocytes (drug effects, metabolism, pathology, radiation effects)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Pigments, Biological (metabolism)
• Skin (drug effects, injuries, metabolism, pathology, radiation effects)
• Skin Pigmentation (drug effects, radiation effects)
• Ultraviolet Rays (adverse effects)