Calcineurin/Nuclear Factor of Activated T Cells and MAPK Signaling Induce TNF-α 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 ␣ 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.

Sirtuin 3 regulates mouse pancreatic beta cell function and is suppressed in pancreatic islets isolated from human type 2 diabetic patients

“…Through exposure to pro-inflammatory cytokines and other stimuli, beta cells can synthesise IL1β and TNFα [7,9]. This occurs in part through ROS-mediated activation of MAPKs (ERK, JNK and p38), which in turn activate NFκB with subsequent induction of IL1β.…”

“…Type 2 diabetes is a progressive inflammatory state, characterised by abnormally elevated islet levels of proinflammatory cytokines, such as IL1β and TNFα, which have been demonstrated to suppress beta cell function and mass [5][6][7][8][9].…”

Effect of Tacrolimus on Myocardial Infarction Is Associated with Inflammation, ROS, MAP Kinase and Akt Pathways in Mini-Pigs

“…Although an inflammatory reaction and oxidative stress have been found to be strongly associated with myocardial damage, the exact signaling pathways involved in the perpetuation of myocardial damage, LV dysfunction, and cardiac remodeling remain unclear. Previous studies have shown that the MAPK pathway is frequently up-regulated by environmental and oxidative stresses as well as inflammatory and cytokine stimulations, thereby leading to cell apoptosis and inflammatory cytokine production [12][13][14][15][16][17] . On the other hand, the Akt signaling pathway has been shown to be an essential contributor to vascular smooth muscle cell migration and proliferation in response to mechanical stress 18) .…”

“…Additionally, the MAPK pathway is activated in response to environmental and oxidative stresses, cellular proliferation and apoptosis, as well as inflammation and cytokine stimulation [12][13][14][15][16][17] . Another kinase signaling pathway, the PI-3 kinase/Akt signal pathway, has been shown to participate in the modulation of vascular smooth muscle cell migration and proliferation in response to mechanical stress 18) ; however, whether MAPK and PI-3 kinase/Akt signaling pathways are associated with the inflammatory response, generation of oxidative stress, increased infarct size and cardiac remodeling after AMI is currently unclear.…”

Islet adaptation to obesity and insulin resistance in WNIN/GR-Ob rats

“…Il-1b have been previously shown to induce TNF expression in endocrine cells (a and b cells) via calcineurin/nuclear factor of activated T cells (NFAT) and MAPK Signaling. 38 Furthermore, our earlier reports on adipose tissue 39 and mesenchymal stem cells (bone marrow) 40 have substantiated inflammation to play a central role in obesity with IR in WNIN mutant rat. We also found increased CD11b positive cells (macrophage marker) localized in islets as compared to lean littermates and controls.…”