Abstract
Type 1 diabetes is an autoimmune disease characterised by selective destruction of pancreatic beta cells by the immune system. The transcription factor nuclear factor-kappa B (NF-κB) regulates innate and adaptive immune responses. Using gene targeting and in vitro analysis of pancreatic islets and immune cells, NF-κB activation has been implicated in type 1 diabetes development. Here we use a non-obese diabetic (NOD) mouse model that expresses a luciferase reporter of transcriptionally active NF-κB to determine its activation in vivo during development of diabetes. Increased luciferase activity was readily detected upon treatment with Toll-like receptor ligands in vitro and in vivo, indicating activation of NF-κB. However, activated NF-κB was detectable at low levels above background in unmanipulated NOD mice, but did not vary with age, despite the progression of inflammatory infiltration in islets over time. NF-κB was highly activated in an accelerated model of type 1 diabetes that requires CD4+ T cells and inflammatory macrophages. These data shed light on the nature of the inflammatory response in the development of type 1 diabetes.
Highlights
Type 1 diabetes is caused by a breakdown of immune tolerance resulting in infiltration of the pancreatic islets by immune cells and the subsequent destruction of insulin-producing beta cells
We developed a transgenic non-obese diabetic (NOD) mouse model (NOD.NGL) that contains a luciferase reporter of activated NF-κB
Bone marrow-derived macrophages and dendritic cells (DC) from NOD.NGL mice were cultured with the Toll-like receptor (TLR) ligands LPS or PAM3Cys for four hours to activate NF-κB, after which a luciferase assay was performed
Summary
Type 1 diabetes is caused by a breakdown of immune tolerance resulting in infiltration of the pancreatic islets by immune cells and the subsequent destruction of insulin-producing beta cells This is a complex process involving coordination between many cell types. Conditional blockade of NF-κB in beta cells prevented diabetes in the multiple low-dose streptozotocin dependent (MLDS) model of diabetes suggesting a pro-apoptotic role[12]. Despite this evidence for a role of NF-κB in the development of diabetes, the extent of activated NF-κB in the natural progression of diabetes in NOD mice has not yet been characterised in vivo. Results show that while NF-κB transcriptional activity was observed in the islets of NOD mice, this was at low levels compared to that observed in a more acute, accelerated CD4+ T cell-dependent model of diabetes
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