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