title: The sequential combination of a JNK inhibitor and simvastatin protects porcine islets from peritransplant apoptosis and inflammation.
abstract: 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.
authors.affiliation: Xenotransplantation Research Center, Seoul National University Hospital, 103 Daehak-ro Jongno-gu, Seoul, Republic of Korea.
authors.forename: Sang-Man
authors.initials: SM
authors.lastname: Jin
authors.forename: Kang Seok
authors.initials: KS
authors.lastname: Kim
authors.forename: Song-Yi
authors.initials: SY
authors.lastname: Lee
authors.forename: Chang-Hoon
authors.initials: CH
authors.lastname: Gong
authors.forename: Su Kyoung
authors.initials: SK
authors.lastname: Park
authors.forename: Jun Seop
authors.initials: JS
authors.lastname: Shin
authors.forename: Chung-Gyu
authors.initials: CG
authors.lastname: Park
authors.forename: Sang-Joon
authors.initials: SJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology*; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival; D002478:Cells, Cultured; D018836:Inflammation Mediators / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology* / Q000473:pathology; D016381:Islets of Langerhans Transplantation; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D009536:Niacinamide / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology*; D013552:Swine
chemical_list: D000873:Anthracenes; D000924:Anticholesteremic Agents; D018836:Inflammation Mediators; C432165:pyrazolanthrone; D009536:Niacinamide; D019821:Simvastatin; D048031:JNK Mitogen-Activated Protein Kinases