GLUCOSYLCERAMIDES STIMULATE MURINE EPIDERMAL HYPERPROLIFERATION
GLUCOSYLCERAMIDES STIMULATE MURINE EPIDERMAL HYPERPROLIFERATION
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DOI：
10.1172/jci117997
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发表时间：
1995-06-01
影响因子：
15.9
通讯作者：
HOLLERAN, WM
中科院分区：
文献类型：
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作者：
MARSH, NL;ELIAS, PM;HOLLERAN, WM
葡糖神经酰胺（GlcCer）通过β-葡糖脑苷脂酶水解产生神经酰胺，这是表皮渗透屏障的关键组分。神经酰胺还参与调节多种细胞类型中的细胞增殖和分化。尽管大多数研究都集中在神经酰胺及其鞘氨醇碱代谢物作为生长抑制剂，但GlcCer显然起相反的作用（即，作为有丝分裂原）。为了确定GlcCer含量的增加是否刺激表皮有丝分裂，我们研究了无毛小鼠表皮对内源性和/或外源性GlcCer改变的反应。局部应用Conduritol B环氧化物（一种β-葡萄糖脑苷脂酶的特异性不可逆抑制剂）可使表皮GlcCer水平增加两倍，这种改变主要局限于基底增殖细胞层（增加四倍）;并刺激表皮增殖（[H-3]胸苷掺入提高2.3倍; P小于或等于0.001），放射自显影再次局限于基底层，并导致表皮增生，皮内给予GlcCer（2.0 mg）也刺激表皮DNA合成，而同时用Conduritol B环氧化物加GlcCer处理导致DNA合成的累加增加。表皮增殖的这些增加不能归因于改变的表皮渗透屏障功能，这些结果强烈地表明GlcCer直接刺激表皮有丝分裂发生。
Hydrolysis of glucosylceramides (GlcCer) by beta-glucocerebrosidase generates ceramides, critical components of the epidermal permeability barrier. Ceramides also are involved in the regulation of cellular proliferation and differentiation in a variety of cell types. Whereas most studies have focused on ceramides and their sphingoid base metabolites as growth inhibitors, GlcCer apparently acts oppositely (i,e,, as a mitogen). To determine whether enhancement of GlcCer content stimulates epidermal mitogenesis, we examined the response of hairless mouse epidermis to alterations in endogenous and/or exogenous GlcCer. Topical applications of conduritol B epoxide, a specific irreversible inhibitor of beta-glucocerebrosidase, increased epidermal GlcCer levels twofold, an alteration localized largely to the basal, proliferative cell layer (fourfold increase); and stimulated epidermal proliferation (2.3-fold elevation in [H-3]thymidine incorporation; P less than or equal to 0.001), localized autoradiographically again to the basal layer, and resulting in epidermal hyperplasia, Intracutaneous administration of GlcCer (2.0 mg) also stimulated epidermal DNA synthesis, while simultaneous treatment with conduritol B epoxide plus GlcCer resulted in an additive increase in DNA synthesis, These increases in epidermal proliferation could not be attributed either to altered epidermal permeability barrier function, or to nonspecific irritant effects, as determined by four separate criteria, These results strongly suggest that GlcCer directly stimulates epidermal mitogenesis.