8S-lipoxygenase products activate peroxisome proliferator-activated receptor alpha and induce differentiation in murine keratinocytes.
8S-lipoxygenase products activate peroxisome proliferator-activated receptor alpha and induce differentiation in murine keratinocytes.
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发表时间：
2000-08
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通讯作者：
S. Muga;P. Thuillier;A. Pavone;J. Rundhaug;W. Boeglin;Mitsuo Jisaka;A. Brash;Susan M. Fischer
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作者：
S. Muga;P. Thuillier;A. Pavone;J. Rundhaug;W. Boeglin;Mitsuo Jisaka;A. Brash;Susan M. Fischer
为了确定花生四烯酸的8S-脂氧合酶(8-LOX)产物--8S-羟基二十碳四烯酸(8S-HETE)的功能和作用机制，利用氯化试剂启动子，建立了8-LOX靶向角质形成细胞的转基因小鼠。组织学分析表明，转基因小鼠的皮肤、舌头和胃高度分化，皮肤的免疫印迹和免疫组织化学显示与野生型小鼠相比，角蛋白-1的表达水平更高。然而，转基因表皮的标记指数是野生型表皮的两倍。此外，8S-HETE处理野生型原代角质形成细胞可诱导角蛋白-1的表达。过氧化物酶体增殖物激活受体α(PPARpha)是角蛋白-1诱导的关键成分，通过瞬时转染PPARpha、PPARGamma和显性阴性PPAR的表达载体，以及使用已知的PPAR激动剂。从这些研究中可以得出结论，8S-HETE在角质形成细胞分化过程中起着重要的作用，至少其部分作用是由PPARα介导的。
To determine the function and mechanism of action of the 8S-lipoxygenase (8-LOX) product of arachidonic acid, 8S-hydroxyeicosatetraenoic acid (8S-HETE), which is normally synthesized only after irritation of the epidermis, transgenic mice with 8-LOX targeted to keratinocytes through the use of a loricrin promoter were generated. Histological analyses showed that the skin, tongue, and stomach of transgenic mice are highly differentiated, and immunoblotting and immunohistochemistries of skin showed higher levels of keratin-1 expression compared with wild-type mice. The labeling index, however, of the transgenic epidermis was twice that of the wild-type epidermis. Furthermore, 8S-HETE treatment of wild-type primary keratinocytes induced keratin-1 expression. Peroxisome proliferator activated receptor alpha (PPARalpha) was identified as a crucial component of keratin-1 induction through transient transfection with expression vectors for PPARalpha, PPARgamma, and a dominant-negative PPAR, as well as through the use of known PPAR agonists. From these studies, it is concluded that 8S-HETE plays an important role in keratinocyte differentiation and that at least some of its effects are mediated by PPARalpha.