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

Timothy L. Scott, Perry A. Christian, Melissa V. Kesler, Kevin M. Donohue, Brent Shelton, Kazumasa Wakamatsu, Ito Shosuke, John D'Orazio

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


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.

Original languageEnglish
Pages (from-to)771-777
Number of pages7
JournalExperimental Dermatology
Issue number10
StatePublished - 2012


  • Epidermal thickness
  • Melanin
  • Photoprotection
  • Topical cAMP

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology


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