Regulation of epidermal expression of keratin K17 in inflammatory skin diseases
Regulation of epidermal expression of keratin K17 in inflammatory skin diseases
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DOI：
10.1111/1523-1747.ep12582820
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发表时间：
1996-10-01
影响因子：
6.5
通讯作者：
Blumenberg, M
中科院分区：
文献类型：
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作者：
Komine, M;Freedberg, IM;Blumenberg, M
角蛋白K17（肌上皮角蛋白）在银屑病中表达，但在健康皮肤中不存在。银屑病与γ干扰素（IFN γ）的产生有关，IFN γ通过激活转录因子STAT 1诱导角蛋白K17的表达。我们的假设表明，K17的诱导是特异性的炎症反应与高水平的IFN γ和STAT 1的激活。该假说的一个推论是，STAT 1激活细胞因子应该诱导角蛋白K17的表达，而那些通过其他机制起作用的细胞因子不应该。此外，由于STAT激活途径依赖于蛋白磷酸化事件，磷酸化抑制剂应减弱角蛋白K17的诱导，而蛋白磷酸酶抑制剂应增强它。为了验证这一假设，我们使用免疫荧光分析了炎性疾病的病变样本，在各种细胞因子存在下，用K17基因启动子DNA转染角质形成细胞，并使用特异性抗体跟踪角质形成细胞中STAT 1的核转位。证实了这一假设，我们发现K17在银屑病和迟发型超敏反应引起的皮炎中被诱导，这与高水平的IFN γ有关，但在特应性皮炎样品中没有，这不是。两种细胞因子，白细胞介素-6和白血病抑制因子，可以诱导STAT 1的磷酸化，也可以诱导K17的表达，而白细胞介素-3，白细胞介素-4，白细胞介素-10，和粒细胞巨噬细胞集落刺激因子对K17的表达没有影响。正如预期的那样，星形孢菌素和染料木黄酮抑制，而冈田酸增强，诱导K17的IFN γ。我们的数据表明，在炎症性皮肤病，淋巴细胞，通过它们产生的细胞因子，不同地调节不仅彼此，而且角蛋白基因在表皮，它们的靶组织之一的表达。
Keratin K17, the myoepithelial keratin, is expressed in psoriasis but is not present in healthy skin. Psoriasis is associated with production of gamma interferon (IFN gamma), which induces the expression of keratin K17 by activating transcription factor STAT1. Our hypothesis states that the induction of K17 is specific for the inflammatory reactions associated with high levels of IFN gamma and activation of STAT1. One of the corollaries of the hypothesis is that the STAT1-activating cytokines should induce the expression of keratin K17, whereas those cytokines that work through other mechanisms should not. Furthermore, because the STAT activation pathway is dependent upon protein phosphorylation events, phosphorylation inhibitors should attenuate the induction of keratin K17, whereas protein phosphatase inhibitors should augment it. To test this hypothesis, we analyzed lesional samples of inflammatory diseases using immunofluorescence, transfected keratinocytes with K17 gene promoter DNAs in the presence of various cytokines, and followed nuclear translocation of STAT1 in keratinocytes using specific antibodies. Confirming the hypothesis, we found that K17 is induced in psoriasis and dermatitis caused by delayed type hypersensitivity, which are associated with high levels of IFN gamma, but not in samples of atopic dermatitis, which is not. Two cytokines, interleukin-6 and leukemia inhibitory factor, which can induce phosphorylation of STAT1, can also induce K17 expression, whereas interleukin-3, interleukin-4, interleukin-10, and granulocyte macrophage colony stimulating factor have no effect on K17 expression. As expected, staurosporine and genistein inhibited, whereas okadaic acid augmented, the induction of K17 by IFN gamma. Our data indicate that in inflammatory skin diseases, lymphocytes, through the cytokines they produce, differently regulate not only each other, but also keratin gene expression in epidermis, one of their target tissues.