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.

Long-Term Control of Diabetes in Immunosuppressed Nonhuman Primates (NHP) by the Transplantation of Adult Porcine Islets

“…The surgical procedure was performed identically throughout the study period and is described elsewhere (12,13). After transportation, islet isolation was performed using the modified Ricordi method that has been previously described (13).…”

Mechanisms Linking Inflammation to Insulin Resistance

“…Moreover, the excessive activation of JNK in peripheral insulin-sensitive tissues promotes IR [ 67 ]. It was demonstrated that inhibiting JNK reduced the release of IR-related proinflammatory cytokines such as TNF- α and MCP-1 [ 68 – 70 ]. Interestingly, JNK-1 deficiency in adipose tissue protects against hepatic steatosis and promotes glucose intolerance, insulin clearance, IR, and hepatic steatosis.…”

Inflammatory Response in Islet Transplantation

“…The use of JNK inhibitor SP600125 in combination with nicotinamide and simvastatin protected porcine islets from peritransplant inflammation and apoptosis. Intraductal administration of JNK inhibitor protected islets by inhibiting the production of proinflammatory cytokines IL-1 β , TNF- α , IFN- γ , IL-6, IL-8, and MCP-1 in vivo [145]. …”