Pigment-independent cAMP-mediated epidermal thickening protects against cutaneous UV injury by keratinocyte proliferation.
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.
Department of Pediatrics and the Graduate Center for Toxicology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40536-0096, USA.
Timothy L
TL
Scott
Perry A
PA
Christian
Melissa V
MV
Kesler
Kevin M
KM
Donohue
Brent
B
Shelton
Kazumasa
K
Wakamatsu
Shosuke
S
Ito
John
J
D'Orazio
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D004195:Disease Models, Animal; D004817:Epidermis / Q000187:drug effects / Q000293:injuries / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D006801:Humans; D053547:Keratin-14 / Q000235:genetics; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010860:Pigments, Biological / Q000378:metabolism*; D012867:Skin / Q000187:drug effects / Q000293:injuries* / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D012880:Skin Pigmentation / Q000187:drug effects / Q000528:radiation effects; D014466:Ultraviolet Rays / Q000009:adverse effects*
C507540:KRT14 protein, human; D053547:Keratin-14; D010860:Pigments, Biological; D005576:Colforsin; D000242:Cyclic AMP