Galectin-3 Exerts Cytokine-Like Regulatory Actions through the JAK-STAT Pathway
Galectin-3 Exerts Cytokine-Like Regulatory Actions through the JAK-STAT Pathway
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DOI：
10.4049/jimmunol.1000154
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发表时间：
2010-12-01
影响因子：
4.4
通讯作者：
Park, Eun Jung
中科院分区：
文献类型：
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作者：
Jeon, Sae-Bom;Yoon, Hee Jung;Park, Eun Jung
Galectin-3是一种β-半乳糖苷结合凝集素，在多种病理生理条件下具有多方面的功能。然而，Galectin-3的特性及其分子作用机制在很大程度上仍不清楚。在这项研究中，我们证明了Galectin-3在大鼠和小鼠脑内驻留免疫细胞中发挥细胞因子样调节作用。在干扰素-γ刺激的炎症条件下，胶质细胞Galectin-3的表达及其分泌到细胞外室的能力显著增强。在暴露于Galectin-3后，神经胶质细胞产生高水平的促炎介质，并表现出激活的特性。值得注意的是，在Galectin-3暴露后的几分钟内，JAK2和STAT1、STAT3和STAT5显示出相当大的酪氨酸磷酸化增强；此后，STAT信号的下游事件也显著增强。用JAK2的药物抑制剂处理细胞可减少Galectin-3刺激的炎症介质的增加。使用干扰素-伽马受体1缺陷的小鼠，我们进一步发现干扰素-伽马R1可能是依赖Galectin-3激活JAK-STAT级联所必需的。然而，Galectin-3显著诱导干扰素-γ缺陷小鼠神经胶质细胞中STATS的磷酸化，这表明干扰素-γ不介导STATS的激活。总之，我们的发现表明Galectin-3在大脑的病理条件下作为内源性危险信号分子，为Galectin-3相关病理事件的分子基础提供了潜在的解释。《免疫学杂志》，2010,185：7037-7046。
Galectin-3, a beta-galactoside-binding lectin, has been proposed to have multifaceted functions in various pathophysiological conditions. However, the characteristics of galectin-3 and its molecular mechanisms of action are still largely unknown. In this study, we show that galectin-3 exerts cytokine-like regulatory actions in rat and mouse brain-resident immune cells. Both the expression of galectin-3 and its secretion into the extracellular compartment were significantly enhanced in glia under IFN-gamma-stimulated, inflamed conditions. After exposure to galectin-3, glial cells produced high levels of proinflammatory mediators and exhibited activated properties. Notably, within minutes after exposure to galectin-3, JAK2 and STAT1, STAT3, and STAT5 showed considerable enhancement of tyrosine phosphorylation; thereafter, downstream events of STAT signaling were also significantly enhanced. Treatment of the cells with pharmacological inhibitors of JAK2 reduced the galectin-3-stimulated increases of inflammatory mediators. Using IFN-gamma receptor 1-deficient mice, we further found that IFN-gamma R 1 might be required for galectin-3-dependent activation of the JAK-STAT cascade. However, galectin-3 significantly induced phosphorylation of STATs in glial cells from IFN-gamma-deficient mice, suggesting that IFN-gamma does not mediate activation of STATs. Collectively, our findings suggest that galectin-3 acts as an endogenous danger signaling molecule under pathological conditions in the brain, providing a potential explanation for the molecular basis of galectin-3-associated pathological events. The Journal of Immunology, 2010, 185: 7037-7046.