Activation signal transduction by β1 integrin in T cells from patients with systemic lupus erythematosus
Activation signal transduction by β1 integrin in T cells from patients with systemic lupus erythematosus
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DOI：
10.1002/art.22581
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发表时间：
2007-05-01
影响因子：
--
通讯作者：
Tanaka, Yoshiya
中科院分区：
文献类型：
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作者：
Nakayamada, Shingo;Saito, Kazuyoshi;Tanaka, Yoshiya
客观的。 Beta 1 整合素是细胞-细胞和细胞-细胞外基质相互作用的代表性粘附分子，它向 T 细胞提供共刺激信号。然而，β1 整合素与系统性红斑狼疮 (SLE) 中 T 细胞激活的相关性仍不清楚。我们进行这项研究是为了对 SLE 患者的 β1 整合素介导的 T 细胞信号传导进行定量和功能分析。方法。通过流式细胞术分析评估细胞表面分子的表达。 β1 整合素的接合是通过使用特定的单克隆抗体进行交联来进行的。为了评估 β1 整合素介导的信号传导中的酪氨酸激酶，通过核转染用野生型 (WT) 粘着斑激酶 (FAK)、FAK 的显性失活截短或 WT PTEN 表达质粒转染细胞。结果。活动性SLE患者，特别是那些患有世界卫生组织IV级肾炎并发症的患者，外周血T细胞中β1整合素的表达显着上调，而与正常人相比，活动性SLE患者的CD28显着降低。 Beta I 整合素表达与血清低补体血症密切相关。 β1 整合素与活动性 SLE 患者的 T 细胞结合，但与正常个体的 T 细胞不结合，诱导细胞增殖以及 T 细胞上的 CD40L 表达。 β1 整合素刺激诱导的 CD40L 表达和 T 细胞增殖的上调可通过转染 FAK 或 WT PTEN 的显性失活截短体而完全抑制。结论。这些结果表明β1整合素与SLE T细胞的结合可以诱导FAK介导的信号传导以及随后的CD40L表达和增殖。因此，β1 整合素信号级联可能有助于增强自身反应性 T 细胞的激活。
Objective. Beta 1 integrin is a representative adhesion molecule for cell-cell and cell-extracellular matrix interactions, and it provides costimulatory signals to T cells. However, the relevance of beta 1 integrin to T cell activation in systemic lupus erythematosus (SLE) remains unclear. We undertook this study to perform a quantitative and functional analysis of beta 1 integrinmediated signaling to T cells in patients with SLE. Methods. Expression of cell surface molecules was assessed by flow cytometric analysis. Engagement of beta 1 integrins was performed by crosslinking using a specific monoclonal antibody. To assess tyrosine kinases in beta 1 integrin-mediated signaling, the cells were transfected with a wild-type (WT) focal adhesion kinase (FAK), a dominant-negative truncation of the FAK, or a WT PTEN expression plasmid via nucleofection. Results. Beta 1 integrin expression was significantly up-regulated on peripheral blood T cells from patients with active SLE, particularly those with the complication of World Health Organization class IV nephritis, whereas CD28 was significantly decreased in patients with active SLE compared with normal individuals. Beta I integrin expression closely correlated with serum hypocomplementemia. Engagement of beta 1 integrin on T cells from patients with active SLE, but not on those from normal individuals, induced cell proliferation as well as CD40L expression on T cells. Up-regulation of CD40L expression and T cell proliferation, induced by beta 1 integrin stimulation, were completely inhibited by transfection of the dominant-negative truncations of FAK or WT PTEN. Conclusion. These results suggest that engagement of beta 1 integrins on SLE T cells could induce FAK-mediated signaling and subsequent CD40L expression and proliferation. Thus, the beta 1 integrin signaling cascade might serve to enhance autoreactive T cell activation.