Vitamin D inhibits the activation of stress-activated protein kinases by physiological and environmental stresses in keratinocytes

A. Ravid*, E. Rubinstein, A. Gamady, C. Rotem, U. A. Liberman, R. Koren

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


In addition to its known effects on keratinocyte proliferation and differentiation, the hormonal form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), has been shown to protect keratinocytes from UV- and chemotherapy-induced damage. Epidermal keratinocytes contain both the machinery needed to produce 1,25(OH)2D3 and vitamin D receptors. The activation of the stress-activated protein kinases (SAPKs), such as c-Jun N-terminal kinase (JNK) and p38, is an early cellular response to stress signals and an important determinant of cell fate. This study examines whether modulation of these SAPKs is associated with the effects of 1,25(OH)2D3 on keratinocytes under stress. HaCaT keratinocytes were exposed to heat shock, hyperosmotic concentrations of sorbitol, the epidermal growth factor receptor tyrosine kinase inhibitor AG1487, the pro-inflammatory cytokine tumor necrosis factor α, and H2O2. These stresses activated both SAPKs. Pretreatment with 1,25(OH)2D3 inhibited the activation of JNK by all stresses and the activation of p38 by heat shock, AG1478 and tumor necrosis factor α. Under the same conditions, treatment with 1,25(OH)2D3 protected HaCaT keratinocytes from cytotoxicity induced by exposure to H2O2 and hyperosmotic shock. The effect of 1,25(OH)2D3 was dose-dependent, already apparent at nanomolar concentrations, and time-dependent, maximal after a 24-h pre-incubation. We suggest that inhibition of SAPK activation may account for some of the well-documented protective effects of 1,25(OH)2D3 on epidermal cells during exposure to UV or chemotherapy and may also be related to the anti-inflammatory actions of the hormone in skin.

Original languageEnglish
Pages (from-to)525-532
Number of pages8
JournalJournal of Endocrinology
Issue number3
StatePublished - 2002
Externally publishedYes


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