Elias Peter M, Ahn Sung K, Denda Mitsuhiro, Brown Barbara E, Crumrine Debra, Kimutai Llewellyn K, Kömüves Laszlo, Lee Seung H, Feingold Kenneth R
Dermatology and Medical Services, Veterans Administration Medical Center, University of California School of Medicine, San Francisco 94121, USA.
J Invest Dermatol. 2002 Nov;119(5):1128-36. doi: 10.1046/j.1523-1747.2002.19512.x.
Mammalian epidermis normally displays a distinctive calcium gradient, with low levels in the basal/spinous layers and high levels in the stratum granulosum. Although changes in stratum granulosum calcium regulate the lamellar body secretory response to permeability barrier alterations, whether modulations in calcium also regulate the expression of differentiation-specific proteins in vivo remains unknown. As acute barrier perturbations reduce calcium levels in stratum granulosum, we studied the regulation of murine epidermal differentiation after loss of calcium accompanying acute barrier disruption and by exposure of such acutely perturbed skin sites to either low (0.03 M) or high (1.8 M) calcium. Three hours after acute barrier disruption, coincident with reduced calcium and ultrastructural evidence of accelerated lamellar body secretion, both northern analyses and in situ hybridization revealed decreased mRNA levels for loricrin, profilaggrin, and involucrin in the outer epidermis, but protein levels did not change significantly. Moreover, exposure of acutely disrupted skin sites to low calcium solutions sustained the reduction in mRNA levels, whereas exposure to high calcium solutions restored normal mRNA levels (blocked by the L-type calcium channel inhibitor, nifedipine). Finally, with prolonged exposure to a low (<10% relative humidity) or high (>80% relative humidity) humidity, calcium levels increased and declined, respectively. Accordingly, mRNA and protein levels of the differentiation-specific markers increased and decreased at low and high relative humidity, respectively. These results provide direct evidence that acute and sustained fluctuations in epidermal calcium regulate expression of differentiation-specific proteins in vivo, and demonstrate that modulations in epidermal calcium coordinately regulate events late in epidermal differentiation that together form the barrier.
哺乳动物的表皮通常呈现出独特的钙梯度，在基底层/棘层中含量低，而在颗粒层中含量高。尽管颗粒层中钙的变化调节了板层小体对通透性屏障改变的分泌反应，但钙的调节是否也在体内调节分化特异性蛋白的表达仍不清楚。由于急性屏障破坏会降低颗粒层中的钙水平，我们研究了伴随急性屏障破坏而钙流失后，以及将此类急性受损皮肤部位暴露于低钙（0.03M）或高钙（1.8M）环境下时，小鼠表皮分化的调节情况。急性屏障破坏三小时后，伴随着钙水平降低以及板层小体分泌加速的超微结构证据，Northern分析和原位杂交均显示外层表皮中loricrin、聚丝蛋白原和兜甲蛋白的mRNA水平下降，但蛋白水平没有显著变化。此外，将急性受损皮肤部位暴露于低钙溶液中会使mRNA水平持续降低，而暴露于高钙溶液中则可恢复正常的mRNA水平（被L型钙通道抑制剂硝苯地平阻断）。最后，长时间暴露于低（<10%相对湿度）或高（>80%相对湿度）湿度环境下，钙水平分别升高和降低。相应地，分化特异性标志物的mRNA和蛋白水平在低相对湿度和高相对湿度下分别升高和降低。这些结果提供了直接证据，表明表皮钙的急性和持续波动在体内调节分化特异性蛋白的表达，并证明表皮钙的调节协同调节表皮分化后期共同形成屏障的事件。
