Calcineurin/nuclear factor of activated T cells and MAPK signaling induce TNF-{alpha} gene expression in pancreatic islet endocrine cells.
J Biol Chem
; 286(2): 1025-36, 2011 Jan 14.
Article
em En
| MEDLINE
| ID: mdl-21059644
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 ß cells express tumor necrosis factor-α (TNF-α) and other cytokines capable of promoting islet inflammation when exposed to interleukin-1ß (IL-1ß). Cytokine expression by ß 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 ß-cell-specific transcriptional activator MafA could repress NFAT-mediated TNF-α gene expression whenever C/EBP-ß 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 ß cells. Both p38 and JNK were required for induction of TNF-α mRNA and protein expression. Collectively, the data show that glucose and IL-1ß can activate signaling pathways, which control induction and repression of cytokines in pancreatic endocrine cells. Thus, by these mechanisms, pancreatic ß cells themselves may contribute to islet inflammation and their own immunological destruction in the pathogenesis of diabetes.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fator de Necrose Tumoral alfa
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Calcineurina
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Sistema de Sinalização das MAP Quinases
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Células Secretoras de Glucagon
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Células Secretoras de Insulina
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Fatores de Transcrição NFATC
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Estados Unidos