Marchell N L, Uchida Y, Brown B E, Elias P M, Holleran W M
Department of Veterans Affairs Medical Center and Department of Dermatology, School of Medicine, University of California, San Francisco 94121, USA.
J Invest Dermatol. 1998 Apr;110(4):383-7. doi: 10.1046/j.1523-1747.1998.00145.x.
Glucosylceramides (GlcCer) and ceramides (Cer) appear to have opposite effects on epidermal growth and differentiation. Whereas Cer inhibit mitosis and induce terminal differentiation and apoptosis in cultured keratinocytes, GlcCer is mitogenic in young murine epidermis. Using a recently described murine model of chronologic senescence we explored whether GlcCer is mitogenic in aged epidermis. Epidermal GlcCer content increases following topical applications of either conduritol-B epoxide (CBE), an inhibitor of GlcCer hydrolysis, or exogenous GlcCer in a penetration-enhancing vehicle. During chronologic aging in the hairless mouse, baseline epidermal DNA synthesis rates remain normal until 18 mo, but decline significantly at 24 mo. Topical CBE stimulates a 1.5- to 1.9-fold increase in epidermal DNA synthesis in all age groups (i.e., 1-2, 18, and 24 mo). Although the CBE induced increase in [3H]thymidine incorporation in 24 mo old animals is significant (p < 0.01), it is not sufficient to reach the absolute levels reached in similarly treated, younger mouse epidermis. Moreover, topical GlcCer induced mitogenesis is both dose dependent and hexose specific in young (1-2 mo old) animals, and remains effective in aged (< or = 24 mo old) animals. Furthermore, the CBE induced increase in DNA synthesis in aged epidermis is sufficient to produce epidermal hyperplasia. Finally, although an increased GlcCer:Cer ratio can alter stratum corneum barrier function and membrane structure, neither stratum corneum function nor extracellular membrane structure change under these experimental conditions, and therefore the mitogenic effects of increased epidermal GlcCer cannot be attributed to effects on the stratum corneum. These results show that: (i) elevations in endogenous GlcCer are mitogenic for aged as well as young murine epidermis; (ii) topical GlcCer is also mitogenic when delivered in an enhancing vehicle; and (iii) despite the putative importance of epidermal DNA synthesis for barrier homeostasis, these mitogenic alterations do not alter stratum corneum function.
葡糖神经酰胺（GlcCer）和神经酰胺（Cer）对表皮生长和分化似乎具有相反的作用。Cer可抑制培养的角质形成细胞的有丝分裂并诱导终末分化和凋亡，而GlcCer在幼鼠表皮中具有促有丝分裂作用。我们使用最近描述的自然衰老小鼠模型，探究GlcCer在衰老表皮中是否具有促有丝分裂作用。局部应用GlcCer水解抑制剂环氧氯醇-B（CBE）或在渗透促进剂中加入外源性GlcCer后，表皮GlcCer含量会增加。在无毛小鼠自然衰老过程中，表皮DNA合成率在18个月龄前保持正常，但在24个月龄时显著下降。局部应用CBE可使所有年龄组（即1 - 2个月、18个月和24个月）的表皮DNA合成增加1.5至1.9倍。虽然CBE诱导24个月龄动物的[3H]胸腺嘧啶核苷掺入量显著增加（p < 0.01），但仍不足以达到同样处理的年轻小鼠表皮所达到的绝对水平。此外，局部应用GlcCer诱导的有丝分裂在幼龄（1 - 2个月龄）动物中具有剂量依赖性和己糖特异性，并且在老龄（≤24个月龄）动物中仍然有效。此外，CBE诱导的衰老表皮DNA合成增加足以导致表皮增生。最后，虽然GlcCer:Cer比值增加可改变角质层屏障功能和膜结构，但在这些实验条件下，角质层功能和细胞外膜结构均未改变，因此表皮GlcCer增加的促有丝分裂作用不能归因于对角质层的影响。这些结果表明：（i）内源性GlcCer升高对老龄和幼龄小鼠表皮均具有促有丝分裂作用；（ii）当在促进剂中递送时，局部应用GlcCer也具有促有丝分裂作用；（iii）尽管表皮DNA合成对屏障稳态具有假定的重要性，但这些促有丝分裂改变并未改变角质层功能。
