Inflammation targets CDK11 in autoimmune diabetes as a protective mechanism against beta cell apoptosis.

Abstract

Abstract Autoimmune diabetes (T1D) is caused by the immune-mediated destruction of insulin-producing beta cells in the pancreas leading to hyperglycemia. Apoptosis is the main mechanism responsible for beta cell demise, including Fas-receptor engagement and Perforin release as essential death executers. However, the chronic inflammatory milieu pervading pancreatic islets prior to diabetes onset, alters beta cells function and primes beta cells for apoptosis long before the debut of the disease. To identify those genes that are targeted by inflammation and are causally related to beta cell fitness and viability we have used the microarray technology. We have identified several candidate genes being downregulated by inflammation, one of this genes is Cdk11, a cyclin-dependent kinase which is involved in transcription (CDK11p130), mitosis and apoptosis (CDK11p58). L-type cyclins are the partners for Cdk11p130, and Cyclin D3 is the partner of CDK11p58. The Cdk11 gene, when is transcribed, generates a single mRNA form, that can be translated either into CDK11p130 or CDK11p58 by a differential IRES (Internal Ribosome Entry Site) usage, being CDK11p58 only expressed during mitosis, while CDK11p130is expressed during all cell cycle phases. We have addressed the role of CDK11 in autoimmune diabetes using the T1D-prone NOD mouse model hemideficient in CDK11, since the CDK11 null mutation is embryonically lethal. First of all, we have confirmed the effect of inflammation on Cdk11 mRNA expression in islet cells by submitting NODSCID mice to adoptive transfer of increasing amounts of diabetogenic NOD splenocytes, and, observed that Cdk11 expression in islet endocrine cells is downregulated by inflammation in a dose-response dependent manner.