Xenotransplantation Research Center, Seoul National University Hospital, 103 Daehak-ro Jongno-gu, Seoul, Republic of Korea.
Cell Transplant. 2011;20(7):1139-51. doi: 10.3727/096368910X550170. Epub 2010 Dec 22.
Intraductal administration of a c-Jun NH(2)-terminal kinase (JNK) inhibitor enhances islet viability. However, its role in reducing the inflammatory response in islets is unknown. It is also unknown whether a JNK inhibitor could act in synergy with statins. We examined if the sequential combination of a JNK inhibitor and simvastatin would reduce islet inflammation and improve islet viability. We performed porcine islet isolation with or without intraductal administration of SP600125, a JNK inhibitor. This was followed by culture medium supplementation with either nicotinamide alone or nicotinamide plus simvastatin. We assessed the viability of islets by flow cytometry, islet loss during overnight culture, graft function in NOD/SCID mice, and expression of inflammation-related genes in islets. The sequential combination of a JNK inhibitor and simvastatin increased the β-cell viability index of porcine islets cultured overnight (p = 0.015) as well as islet viability as assessed by a DNA binding dye staining (p = 0.011). The combination of a JNK inhibitor and simvastatin significantly increased the islet survival rate (p = 0.027) when the histomorphometry of donor pancreas indicated a large islet proportion of greater than 50.55%. When we transplanted the same islet mass per recipient for each group, there was no difference in overall islet graft function. Intraductal administration of JNK inhibitor significantly suppressed mRNA expression levels of interleukin-1β (IL-1β), interferon-γ, tumor necrosis factor-α, IL-6, IL-8, and macrophage chemoattractant protein-1. It also decreased the concentration of IL-1β (p = 0.040) and IL-8 (p = 0.023) in the culture supernatant. In conclusion, the sequential combination of a JNK inhibitor and simvastatin protected porcine islets from peritransplant apoptosis. Inhibition of JNK reduced the inflammatory response and could be considered an alternative target for suppression of porcine islet inflammation.
腔内给予 c-Jun NH（2）-末端激酶（JNK）抑制剂可增强胰岛活力。然而，其在减轻胰岛炎症反应中的作用尚不清楚。也不清楚 JNK 抑制剂是否可以与他汀类药物协同作用。我们研究了 JNK 抑制剂与辛伐他汀序贯联合是否会减少胰岛炎症并改善胰岛活力。我们进行了猪胰岛分离，其中包括或不包括腔内给予 JNK 抑制剂 SP600125。随后，培养基中分别补充烟酰胺或烟酰胺加辛伐他汀。我们通过流式细胞术评估胰岛活力、过夜培养期间的胰岛丢失、NOD/SCID 小鼠中的移植物功能以及胰岛中炎症相关基因的表达。JNK 抑制剂与辛伐他汀序贯联合可增加猪胰岛培养过夜的β细胞活力指数（p=0.015），以及用 DNA 结合染料染色评估的胰岛活力（p=0.011）。当供体胰腺的组织形态计量学显示胰岛比例大于 50.55%时，JNK 抑制剂与辛伐他汀的联合显著增加了胰岛存活率（p=0.027）。当我们为每个组移植相同的胰岛质量时，整体胰岛移植物功能没有差异。腔内给予 JNK 抑制剂可显著抑制白细胞介素-1β（IL-1β）、干扰素-γ、肿瘤坏死因子-α、IL-6、IL-8 和巨噬细胞趋化蛋白-1 的 mRNA 表达水平。它还降低了培养上清液中 IL-1β（p=0.040）和 IL-8（p=0.023）的浓度。总之，JNK 抑制剂与辛伐他汀的序贯联合可防止猪胰岛发生移植前凋亡。JNK 抑制可减轻炎症反应，可被视为抑制猪胰岛炎症的替代靶标。
