Programmed cell death of stressed keratinocytes and its inhibition by vitamin D: the role of death and survival signaling pathways.
The epidermis is confronted with multiple environmental and pathophysiological stresses. This study shows that TNFalpha, oxidative stress, hyperosmotic and heat shock induced both caspase-dependent and independent cell death in human HaCaT keratinocytes. The hormonal form of vitamin D, 1,25(OH)2D3, which is an autocrine hormone in the epidermis, protected the cells from all the examined stresses and pathways leading to cell death. We aimed to define the signaling pathways that determine the life-death balance of stressed keratinocytes and participate in their protection by 1,25(OH)2D3. As assessed by employing specific inhibitors, the survival pathways mediated by the EGF receptor, ERK, PI-3K or Src kinase, or basal transcriptional activity are important for unstressed cell survival. However, only the EGF receptor, PI-3K and the Src kinase pathways mediate the survival of stressed cells in a stimulus-specific manner. Inhibition of the p38 and/or the JNK death pathways reduced caspase activation induced by oxidative stress, hyperosmotic shock and TNFalpha. The protective effect of 1,25(OH)2D3 was not mediated by the examined survival pathways. 1,25(OH)2D3 inhibited the stress-induced activation of p38 and JNK. Since mimicking this effect by pharmacological inhibition resulted in the attenuation of caspase activation, we infer that these pathways are involved in keratinocyte protection by 1,25(OH)2D3.
Basil and Gerald Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel.
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Diker-Cohen
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Koren
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Ravid
D017209:Apoptosis / Q000187:drug effects; D002117:Calcitriol / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009997:Osmotic Pressure; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology
D004791:Enzyme Inhibitors; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases; D002117:Calcitriol