Inflammation targets cell-cycle actors at the onset of autoimmune diabetes (T1D) in pancreatic endocrine cells from the NOD mouse model

Abstract

Abstract Prior to the massive beta cell demise that leads to autoimmune diabetes (Type 1 Diabetes or T1D), profound profiling changes are imprinted onto the beta cell by an aggressive pro-inflammatory environment that interferes negatively with cell functionality and viability. Ourgoal is to determine key signaling pathways altered in beta cells by the autoimmune assault that are responsible for T1D progression. To this end we have used the T1D-prone NOD (Non Obese Diabetic) mouse model. We have identified several candidate genes the expression of which is altered in the NOD isletendocrine cells prior to the diabetes onset. Interestingly, several of these genes are related to cell cycle progression and are downregulated due to the insulitic attack to the islet. One of these genes is cyclin D3, a D-type cyclin that complexes with either Cdk4 or Cdk6 topromote G1/S cycle progression. The cyclin D3 promoter has binding sequences to NF-kB. However, we have reported that cyclin D3 protects beta cells against cytokine-induced apoptosis and is required for proper beta cell function in a cell-cycle independent fashion. Cdk11 is also affected by inflammation in islet cells and is a cyclin-dependent kinase which is involved in transcription, mitosis and apoptosis. The natural partners of Cdk11 are L-type cyclins, but cyclin D3 has been reported to interact with Cdk11 too. We have addressed whether cdk11 downregulationis responsible for beta cell death.