CD40 is expressed in normal human keratinocytes, especially in the basal cell layer. We have recently reported that CD40 ligation strongly inhibits keratinocyte proliferation and induces their differentiation. In this study, the CD40 pathway that prevents keratinocyte growth was investigated. We first reported that interferon-gamma treatment potentiated the CD40-mediated inhibition of keratinocyte proliferation. CD40-CD40 ligand interactions, in the presence or absence of interferon-gamma, neither enhanced spontaneous keratinocyte apoptosis, nor did it enhance apoptosis induced by various agents. More importantly, we showed that CD40 signaling altered the keratinocyte cell cycle, as demonstrated by a decreasing number of cells in the G1 and S phases and an accumulation in G2/M phase of the cell cycle. Furthermore, western blot analysis of cell cycle regulatory proteins, showed a decrease in cyclin A and E expression in CD40-activated keratinocytes. Collectively, these results indicate that CD40 ligation inhibits keratinocyte renewal by a mechanism independent of cell apoptosis and that modulation of the keratinocyte cell cycle is an additional outcome of CD40 signaling.

译文

CD40在正常人角质形成细胞中表达,特别是在基底细胞层中表达。我们最近报道CD40连接强烈抑制角质形成细胞增殖并诱导其分化。在这项研究中,研究了防止角质形成细胞生长的CD40途径。我们首先报道了干扰素-γ 治疗增强了角质形成细胞增殖的CD40-mediated抑制作用。在存在或不存在干扰素-γ 的情况下,CD40-CD40配体相互作用既不会增强自发性角质形成细胞的凋亡,也不会增强由各种药物诱导的凋亡。更重要的是,我们显示CD40信号传导改变了角质形成细胞的细胞周期,这通过在G1和S期的细胞数量减少以及在细胞周期的G2/M期的积累来证明。此外,细胞周期调节蛋白的western印迹分析显示CD40-activated角质形成细胞中细胞周期蛋白a和E表达降低。总的来说,这些结果表明CD40连接通过独立于细胞凋亡的机制抑制角质形成细胞的更新,而角质形成细胞周期的调节是CD40信号传导的另一结果。

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