Calcineurin/nuclear factor of activated T cells and MAPK signaling induce TNF-{alpha} gene expression in pancreatic islet endocrine cells

Abstract

Cytokines contribute to pancreatic islet inflammation, leading to impaired glucose homeostasis and diabetic diseases. A plethora of data shows that proinflammatory cytokines are produced in pancreatic islets by infiltrating mononuclear immune cells. Here, we show that pancreatic islet α cells and β cells express tumor necrosis factor-α (TNF-α) and other cytokines capable of promoting islet inflammation when exposed to interleukin-1β (IL-1β). Cytokine expression by β cells was dependent on calcineurin (CN)/nuclear factor of activated T cells (NFAT) and MAPK signaling. NFAT associated with the TNF-α promoter in response to stimuli and synergistically activated promoter activity with ATF2 and c-Jun. In contrast, the β-cell-specific transcriptional activator MafA could repress NFAT-mediated TNF-α gene expression whenever C/EBP-β was bound to the promoter. NFAT differentially regulated the TNF-α gene depending upon the expression and MAPK-dependent activation of interacting basic leucine zipper partners in β cells. Both p38 and JNK were required for induction of TNF-α mRNA and protein expression. Collectively, the data show that glucose and IL-1β can activate signaling pathways, which control induction and repression of cytokines in pancreatic endocrine cells. Thus, by these mechanisms, pancreatic β cells themselves may contribute to islet inflammation and their own immunological destruction in the pathogenesis of diabetes.