CD40–CD40 Ligand Interaction Activates Proinflammatory Pathways in Pancreatic Islets

Abstract

Pancreatic islet transplantation is becoming an alternative to insulin therapy in patients suffering from brittle type 1 diabetes. A major obstacle to the procedure is the early graft loss caused by nonspecific inflammation at the site of implantation. We recently discovered that CD40, a member of tumor necrosis factor (TNF) receptor family, is expressed in pancreatic β-cells. CD40 expression in nonhematopoietic cells is generally associated with inflammation. Therefore, we investigated the potential proinflammatory role of CD40 in human and nonhuman primate islets. Islet β-cells responded to CD40L interaction by secreting interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1, and macrophage inflammatory protein (MIP)-1β, the latter a chemokine first reported to be produced by islets. Induction of IL-8 and MIP-1β was confirmed at the transcriptional level by quantitative RT-PCR. MIP-1β expression in β-cells was verified by double-immunofluorescence staining. CD40-CD40L interaction activates extracellular signal–regulated kinase 1/2 and nuclear factor-κB pathways in insulinoma NIT-1 cells, and inhibitors of either pathway suppress cytokine/chemokine production in islets. Moreover, ligation of CD40 receptor upregulates intercellular adhesion molecule-1, associated with inflammation, at both transcriptional and translational levels. Our results in vitro indicate that the CD40 receptor expressed by β-cells could be activated in vivo, inducing proinflammatory responses contributing to early islet graft loss after transplantation.