C-Jun amino terminal kinase 1 deficient mice are protected from streptozotocin-induced islet injury

In vitro studies have implicated the c-Jun amino terminal kinase (JNK) in cytokine-induced pancreatic injury leading to a loss of insulin production and hyperglycemia. We examined the role of JNK1 in the multiple low dose streptozotocin (MLD-STZ) model in which islet injury and hyperglycemia are dependent upon T cell immunity and pro-inflammatory cytokines. MLD-STZ in wild type mice induced islet leukocyte infiltration, cytokine production, P-cell apoptosis, and hyperglycemia. In contrast, Jnk1-/- mice were substantially protected from a loss of insulin producing cells and hyperglycemia in the NILD-STZ model despite a marked islet T cell and macrophage infiltrate. Based upon several lines of evidence, this protection was attributed to a reduction in TNF-alpha production by infiltrating Jnk1-/- macrophages leading to reduced P-cell apoptosis. In conclusion, JNK1 signaling plays an essential role in macrophage induced P-cell apoptosis and the development of hyperglycemia in MLD-STZ induced pancreatic injury. (c) 2007 Elsevier Inc. All rights reserved.