Pancreatic β-Cell-Derived IP-10/CXCL10 Isletokine Mediates Early Loss of Graft Function in Islet Cell Transplantation
Pancreatic β-Cell-Derived IP-10/CXCL10 Isletokine Mediates Early Loss of Graft Function in Islet Cell Transplantation
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DOI：
10.2337/db17-0578
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发表时间：
2017-11-01
期刊：
影响因子：
7.7
通讯作者：
Lawrence, Michael C.
中科院分区：
文献类型：
--
作者：
Yoshimatsu, Gumpei;Kunnathodi, Faisal;Lawrence, Michael C.
胰岛在炎症和代谢应激反应中产生和分泌细胞因子和趋化因子。这些胰岛因子在健康和疾病中的生理作用在很大程度上是未知的。我们观察到，在接受胰岛移植的患者中，胰岛在输注数小时内释放多种炎症介质。促炎细胞因子干扰素- γ诱导蛋白10 （IP-10/CXCL10）的释放量最高，且高水平与胰岛移植预后不良相关。转基因小鼠研究证实，供体胰岛特异性表达IP-10有助于胰岛移植物的胰岛炎症和β细胞功能丧失。用抗IP-10中和性单克隆抗体处理供体和受体小鼠，可阻断胰岛源性IP-10的作用。体外研究表明，在氧化或炎症应激下，胰腺β细胞中的钙调磷酸酶依赖性NFAT信号通路介导了IP-10基因的诱导。NFAT和p300组蛋白乙酰转移酶与IP-10基因的持续关联需要p38和c-Jun n-末端激酶丝裂原活化蛋白激酶（MAPK）活性，其差异调节IP-10的表达和随后的蛋白释放。总的来说，这些发现阐明了在胰岛细胞中诱导胰岛因子表达的NFAT-MAPK信号传导模式，并揭示了IP-10是预防胰岛细胞移植后β细胞诱导的移植物功能炎症丧失的主要治疗靶点。
Pancreatic islets produce and secrete cytokines and chemokines in response to inflammatory and metabolic stress. The physiological role of these isletokines in health and disease is largely unknown. We observed that islets release multiple inflammatory mediators in patients undergoing islet transplants within hours of infusion. The proinflammatory cytokine interferon-gamma-induced protein 10 (IP-10/CXCL10) was among the highest released, and high levels correlated with poor islet transplant outcomes. Transgenic mouse studies confirmed that donor islet-specific expression of IP-10 contributed to islet inflammation and loss of beta-cell function in islet grafts. The effects of islet-derived IP-10 could be blocked by treatment of donor islets and recipient mice with anti-IP-10 neutralizing monoclonal antibody. In vitro studies showed induction of the IP-10 gene was mediated by calcineurin-dependent NFAT signaling in pancreatic beta-cells in response to oxidative or inflammatory stress. Sustained association of NFAT and p300 histone acetyltransferase with the IP-10 gene required p38 and c-Jun N-terminal kinase mitogen-activated protein kinase (MAPK) activity, which differentially regulated IP-10 expression and subsequent protein release. Overall, these findings elucidate an NFAT-MAPK signaling paradigm for induction of isletokine expression in beta-cells and reveal IP-10 as a primary therapeutic target to prevent beta-cell-induced inflammatory loss of graft function after islet cell transplantation.