Epstein-Barr virus-induced gene 3 (EBI3) can mediate IL-6 trans-signaling
Epstein-Barr virus-induced gene 3 (EBI3) can mediate IL-6 trans-signaling
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DOI：
10.1074/jbc.m116.762021
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发表时间：
2017-04-21
影响因子：
4.8
通讯作者：
Gauchat, Jean-Francois
中科院分区：
文献类型：
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作者：
Chehboun, Salma;Labrecque-Carbonneau, Jeremie;Gauchat, Jean-Francois
Epstein-Barr病毒诱导基因3 (EBI3)是复合细胞因子IL-27和IL-35的一个亚基。两者在感染性和自身免疫性疾病模型中都有有益的功能或作用。这表明施用EBI3可以通过结合游离p28和p35产生IL-27和IL-35而具有治疗作用。EBI3不依赖于il -27和il -35的功能可能影响其治疗用途。因此，我们评估了EBI3对细胞因子受体表达细胞的影响。我们观察到EBI3激活STAT3并诱导il -6依赖性B9小鼠浆细胞瘤细胞系的增殖。使用阻断单抗和表达gp130的Ba/F3转染物进行分析表明，EBI3活性与其介导IL-6反式信号传导的能力有关，尽管其效率低于可溶性IL-6R α。与这一解释相一致，免疫共沉淀和SPR实验表明EBI3与IL-6结合。IL-6反式信号的一个重要促炎功能是激活血管内皮细胞。我们观察到EBI3联合IL-6可诱导人静脉内皮细胞表达趋化因子。我们的研究结果表明，EBI3可以通过介导反式信号传导来促进促炎IL-6功能。这些意想不到的观察结果表明，使用EBI3作为自身免疫性疾病的治疗生物制剂可能需要同时给药可溶性gp130，以防止与IL-6反式信号传导相关的副作用。加上先前的研究表明p28 （IL-30）激活IL-6R，新的发现进一步表明IL-27和IL-6之间存在复杂的相互关系。
Epstein-Barr virus-induced gene 3 (EBI3) is a subunit of the composite cytokines IL-27 and IL-35. Both have beneficial functions or effects in models of infectious and autoimmune diseases. This suggests that administration of EBI3 could be therapeutically useful by binding free p28 and p35 to generate IL-27 and IL-35. IL-27-and IL-35-independent functions of EBI3 could compromise its therapeutic uses. We therefore assessed the effects of EBI3 on cytokine receptor-expressing cells. We observed that EBI3 activates STAT3 and induces the proliferation of the IL-6-dependent B9 mouse plasmacytoma cell line. Analyses using blocking mAbs and Ba/F3 transfectants expressing gp130 indicate that EBI3 activity was linked to its capacity to mediate IL-6 trans-signaling, albeit less efficiently than soluble IL-6R alpha. In line with this interpretation, co-immunoprecipitation and SPR experiments indicated that EBI3 binds IL-6. An important pro-inflammatory function of IL-6 trans-signaling is to activate blood vessel endothelial cells. Weobserved that EBI3 in combination with IL-6 could induce the expression of chemokines by human venal endothelial cells. Our results indicate that EBI3 can promote pro-inflammatory IL-6 functions by mediating trans-signaling. These unexpected observations suggest that use of EBI3 as a therapeutic biologic for autoimmune diseases will likely require co-administration of soluble gp130 to prevent the side effects associated with IL-6 trans-signaling. Together with previous studies that demonstrated activation of IL-6R by p28 (IL-30), new findings further suggest a complex interrelation between IL-27 and IL-6.