Grether-Beck S, Bonizzi G, Schmitt-Brenden H, Felsner I, Timmer A, Sies H, Johnson J P, Piette J, Krutmann J
Clinical and Experimental Photodermatology, Department of Dermatology, Heinrich-Heine-University, Moorenstrabetae 5, D-40225 Düsseldorf, Germany.
EMBO J. 2000 Nov 1;19(21):5793-800. doi: 10.1093/emboj/19.21.5793.
Ceramide is a key component of intracellular stress responses. Evidence is provided for a novel mechanism of ceramide formation that mediates solar ultraviolet (UV) A radiation-induced expression of the intercellular adhesion molecule (ICAM)-1. Similarly to UVA radiation, ceramide stimulation of human keratinocytes induced ICAM-1 mRNA expression and activated the ICAM-1 promoter through transcription factor AP-2. Ceramide-activated AP-2 and ceramide-induced ICAM-1 reporter gene activation were abrogated through deletion of the AP-2 binding site. UVA radiation increased the level of ceramide in keratinocytes and inhibition of sphingomyelin synthesis prevented UVA radiation-induced ICAM-1 expression. Hitherto, two pathways have been identified for ceramide accumulation: hydrolysis from sphingomyelin through neutral and acid sphingomyelinases, and de novo synthesis by ceramide synthase. UVA radiation did not activate any of these enzymes. Ceramide generation in UVA-irradiated cells, however, was inhibited by singlet oxygen quenchers and mimicked in unirradiated cells by a singlet oxygen-generating system. In addition, UVA radiation and singlet oxygen both generated ceramide in protein-free, sphingomyelin-containing liposomes. This study indicates that singlet oxygen triggers a third, non-enzymatic mechanism of ceramide formation.
神经酰胺是细胞内应激反应的关键组成部分。本文提供了一种新的神经酰胺形成机制的证据，该机制介导太阳紫外线A（UVA）辐射诱导的细胞间黏附分子（ICAM）-1的表达。与UVA辐射类似，神经酰胺刺激人角质形成细胞可诱导ICAM-1 mRNA表达，并通过转录因子AP-2激活ICAM-1启动子。通过缺失AP-2结合位点，可消除神经酰胺激活的AP-2和神经酰胺诱导的ICAM-1报告基因激活。UVA辐射可增加角质形成细胞中神经酰胺的水平，抑制鞘磷脂合成可阻止UVA辐射诱导的ICAM-1表达。迄今为止，已确定了两条神经酰胺积累途径：通过中性和酸性鞘磷脂酶从鞘磷脂水解，以及由神经酰胺合酶从头合成。UVA辐射未激活这些酶中的任何一种。然而，UVA照射细胞中神经酰胺的生成受到单线态氧猝灭剂的抑制，而在未照射细胞中，单线态氧生成系统可模拟这种生成。此外，UVA辐射和单线态氧均可在无蛋白、含鞘磷脂的脂质体中生成神经酰胺。这项研究表明，单线态氧触发了神经酰胺形成的第三种非酶机制。
