Impaired IFN-γ-dependent inflammatory responses in human keratinocytes overexpressing the suppressor of cytokine signaling 1
Impaired IFN-γ-dependent inflammatory responses in human keratinocytes overexpressing the suppressor of cytokine signaling 1
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DOI：
10.4049/jimmunol.169.1.434
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发表时间：
2002-07-01
影响因子：
4.4
通讯作者：
Albanesi, C
中科院分区：
文献类型：
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作者：
Federici, M;Giustizieri, ML;Albanesi, C
角质形成细胞通过表达多种促炎分子而与炎性皮肤病的发病机制相关，其中T细胞衍生的IFN-γ是最有效的角质形成细胞活化剂。细胞因子信号传导抑制因子（SOCS）1和SOCS 3是IFN-γ信号传导的负调节因子，并且在许多细胞类型中由IFN-γ本身或由其他细胞因子诱导。在这项工作中，我们表明，SOCS 1，SOCS 2，SOCS 3，和胡萝卜素诱导的SH 2-含有蛋白质的mRNA上调IFN-γ在正常人角质形成细胞，而只有SOCS 1或SOCS 1和胡萝卜素诱导的SH 2-含有蛋白质的诱导TNF-α或IL-4，分别。SOCS 1、SOCS 2和SOCS 3蛋白在健康皮肤中检测不到，在银屑病和过敏性接触性皮炎的表皮中高度表达，但在特应性皮炎皮肤中仅弱表达。在用SOCS 1或SOCS 3瞬时转染的角质形成细胞中，IFN-γ诱导的IFN-γ应答报告基因的反式激活被显著抑制。角质形成细胞稳定克隆中SOCS 1和SOCS 3的过表达抑制IFN-γ诱导的IFN-γ R α磷酸化和STAT 1和STAT 3的活化。此外，SOCS 1和SOCS 3在较小程度上减少ICAM-1和HLA-DR的膜表达，以及IFN-γ诱导的蛋白-10、IFN-γ诱导的单核因子和IFN-γ促进的角质形成细胞克隆的单核细胞趋化蛋白-1的释放。与SOCS 2和SOCS 3克隆相比，SOCS 1表达的角质形成细胞表现出组成性更高的IL-8水平，但不是IFN-γ诱导的，并且对IFN-γ介导的生长抑制具有抗性。靶向角质形成细胞SOCS 1可能代表IFN-γ依赖性皮肤病的新治疗方法。
Keratinocytes contribute relevantly to the pathogenesis of inflammatory skin diseases by expressing a variety of proinflammatory molecules, with T cell-derived IFN-gamma being the most potent keratinocyte activator. Suppressor of cytokine signaling (SOCS)1 and SOCS3 are negative regulators of IFN-gamma signaling and are induced in many cell types by IFN-gamma itself or by other cytokines. We show in this work that SOCS1, SOCS2, SOCS3, and cytokine-inducible SH2-containing protein mRNA were up-regulated by IFN-gamma in normal human keratinocytes, whereas only SOCS1 or SOCS1 and cytokine-inducible SH2-containing protein were induced by TNF-alpha or IL-4, respectively. SOCS1, SOCS2, and SOCS3 proteins were undetectable in healthy skin and highly expressed in the epidermis of psoriasis and allergic contact dermatitis, but were only weakly expressed in atopic dermatitis skin. In keratinocytes transiently transfected with SOCS1 or SOCS3 the IFN-gamma-induced transactivation of an IFN-gamma-responsive reporter gene was markedly inhibited. SOCS1 and SOCS3 overexpression in keratinocyte stable clones inhibited IFN-gamma-induced phosphorylation of IFN-gammaRalpha and activation of STAT1 and STAT3. Furthermore, SOCS1 and, to a lesser extent, SOCS3 reduced membrane expression of ICAM-1 and HLA-DR, and release of IFN-gamma-inducible protein-10, monokine induced by IFN-gamma, and monocyte chemoattractant protein-1 by keratinocyte clones promoted by IFN-gamma. SOCS1-expressing keratinocytes showed constitutively higher, but not IFN-gamma-inducible, IL-8 levels compared with SOCS2 and SOCS3 clones, and were resistant to IFN-gamma-mediated growth inhibition. Targeting keratinocyte SOCS1 may represent a novel therapeutic approach to IFN-gamma-dependent skin diseases.