Rendl Michael, Ban Jozef, Mrass Paul, Mayer Christoph, Lengauer Barbara, Eckhart Leopold, Declerq Wim, Tschachler Erwin
Division of Immunology, Allergy, and Infectious Diseases, Department of Dermatology, University of Vienna Medical School, Austria.
J Invest Dermatol. 2002 Nov;119(5):1150-5. doi: 10.1046/j.1523-1747.2002.19532.x.
Caspase-14 is the only member of the caspase family that shows a restricted tissue expression. It is mainly confined to epidermal keratinocytes and in contrast to other caspases, is not activated during apoptosis induced by ultraviolet irradiation or cytotoxic substances. As it is cleaved under conditions leading to terminal differentiation of keratinocytes we suggested that caspase-14 plays a part in the physiologic cell death of keratinocytes leading to skin barrier formation. Here we show that retinoic acid, at concentrations inhibiting terminal differentiation of keratinocytes, strongly suppressed caspase-14 mRNA and protein expression by keratinocytes in monolayer culture and in a three-dimensional in vitro model of differentiating human epidermis (skin equivalent). By contrast, the expression of the caspases 3 and 8, which are both activated during conventional apoptosis, was increased and unchanged, respectively, after retinoic acid treatment. In addition to inhibition of differentiation in skin equivalents, retinoic acid treatment led to keratinocyte apoptosis and activation of caspase-3, both of which were undetectable in differentiated control skin equivalents. As this occurred in the absence of detectable caspase-14, our data demonstrate that caspase-14 is dispensable for keratinocyte apoptosis. The fact that in contrast to caspase-3 and caspase-8, caspase-14, similarly to other keratinocyte differentiation-associated proteins, is downregulated by retinoids, strongly suggests that this caspase, but not caspase-3 and -8, plays a part in terminal keratinocyte differentiation and skin barrier formation.
半胱天冬酶 -14是半胱天冬酶家族中唯一显示出组织表达受限的成员。它主要局限于表皮角质形成细胞，与其他半胱天冬酶不同，在紫外线照射或细胞毒性物质诱导的细胞凋亡过程中不会被激活。由于它在导致角质形成细胞终末分化的条件下被切割，我们推测半胱天冬酶 -14在角质形成细胞的生理性细胞死亡中起作用，从而导致皮肤屏障的形成。在此我们表明，视黄酸在抑制角质形成细胞终末分化的浓度下，强烈抑制单层培养的角质形成细胞以及在人表皮分化的三维体外模型（皮肤替代物）中角质形成细胞的半胱天冬酶 -14 mRNA和蛋白质表达。相比之下，在传统细胞凋亡过程中均被激活的半胱天冬酶3和8的表达，在视黄酸处理后分别增加和未改变。除了抑制皮肤替代物中的分化外，视黄酸处理还导致角质形成细胞凋亡和半胱天冬酶 -3的激活，而在分化的对照皮肤替代物中均未检测到这些情况。由于这发生在未检测到半胱天冬酶 -14的情况下，我们的数据表明半胱天冬酶 -14对于角质形成细胞凋亡是可有可无的。与半胱天冬酶 -3和 -8不同，半胱天冬酶 -14与其他角质形成细胞分化相关蛋白类似，会被类视黄醇下调，这一事实强烈表明该半胱天冬酶而非半胱天冬酶 -3和 -8在角质形成细胞终末分化和皮肤屏障形成中起作用。
