Calcineurin/nuclear factor of activated T cells and MAPK signaling induce TNF-{alpha} gene expression in pancreatic islet endocrine cells.
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.
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. Michael.Lawrence@UTSouthwestern.edu
Michael C
MC
Lawrence
Bashoo
B
Naziruddin
Marlon F
MF
Levy
Andrew
A
Jackson
Kathleen
K
McGlynn
D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000276:immunology / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000276:immunology / Q000378:metabolism; D019703:Calcineurin / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D050416:Glucagon-Secreting Cells / Q000276:immunology* / Q000378:metabolism; D005937:Glucaric Acid / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism; D037181:Lectins, C-Type / Q000276:immunology / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D050778:NFATC Transcription Factors / Q000276:immunology* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism
D050976:Basic-Leucine Zipper Transcription Factors; D022782:CCAAT-Enhancer-Binding Protein-beta; D053583:Interleukin-1beta; C094696:Klrg1 protein, rat; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D050778:NFATC Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019703:Calcineurin; D005937:Glucaric Acid