IL-10 inhibits endothelium-dependent T cell costimulation by up-regulation of ILT3/4 in human vascular endothelial cells
IL-10 inhibits endothelium-dependent T cell costimulation by up-regulation of ILT3/4 in human vascular endothelial cells
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DOI：
10.1002/eji.200636498
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发表时间：
2007-01-01
影响因子：
5.4
通讯作者：
Dengler, Thomas J.
中科院分区：
文献类型：
--
作者：
Gleissner, Christian A.;Zastrow, Arne;Dengler, Thomas J.
IL-10对内皮依赖性T细胞活化的影响尚未有详细的研究。我们证实了IL-10受体在人脐静脉内皮细胞(HUVEC)中的表达和通过STAT-3的有效信号传递。在CD4T细胞与人脐静脉内皮细胞共培养中，IL-10对内皮细胞的增殖有明显的抑制作用，且呈剂量依赖关系，在开始共培养前去除IL-10后也会出现这种抑制。增殖的T细胞Th1/Th2极化、内皮一氧化氮(NO)和IL-12的产生没有变化。然而，IL-10刺激导致细胞因子分泌的负调控因子SOCS-3上调，并诱导EC表面抑制分子免疫球蛋白样转录本3和4(ILT3/ILT4)，可能涉及糖皮质激素诱导的亮氨酸拉链(GILZ)。在EC/T细胞共培养中加入针对ILT3/ILT4的封闭抗体，可使T细胞的增殖几乎完全恢复。相反，加入可溶性ILT3或在共培养中过度表达ILT3可显著降低T细胞的增殖。未见Foxp3(+)调节性T细胞的诱导。综上所述，IL-10通过上调IL-3/IL-4的表达而显著抑制人内皮细胞的T细胞共刺激潜能，明显不参与Treg的产生。这确定了IL-10在EC中的新作用，并成为局部免疫调节的潜在治疗靶点。
Effects of IL-10 on endothelium-dependent T cell activation have not been investigated in detail. We confirm expression of the IL-10 receptor and effective signaling via STAT-3 in human umbilical vein endothelial cells (HUVEC). In CD4 T cell cocultures with HUVEC, pretreatment of endothelial cells with IL-10 resulted in significant dose-dependent inhibition of CD4 T cell proliferation, which also occurred when IL-10 was removed after pretreatment before starting cocultures. Th1/Th2 polarization of proliferated T cells, endothelial nitric oxide (NO), or IL-12 production were unchanged. However, IL-10 stimulation resulted in up-regulation of SOCS-3, a negative regulator of cytokine secretion, and induction of the inhibitory surface molecules immunoglobulin-like transcript 3 and 4 (ILT3/ILT4) in EC, potentially involving glucocorticoid-induced leucine zipper (GILZ). Addition of blocking antibodies against ILT3/ILT4 to EC/T cell cocultures resulted in nearly complete reestablishment of T cell proliferation. In contrast, addition of soluble ILT3 or overexpression of ILT3 in cocultures significantly reduced T cell proliferation. No induction of foxp3(+) regulatory T cells was seen. In conclusion, the T cell costimulatory potential of human EC is markedly suppressed by IL-10 due to up-regulation of ILT3/ILT4, obviously not involving generation of Treg. This identifies a novel action of IL-10 in EC and a potential therapeutical target for local immunomodulation.