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Metabolic Endotoxemia-Activated Macrophages Promote Pancreatic ß Cell Death via IFNß-Xaf1 Pathway.

Tsuruta, Mitsudai; Iwashita, Misaki; Shinjo, Takanori; Matsunaga, Hiroaki; Yamashita, Akiko; Nishimura, Fusanori.
Horm Metab Res; 50(2): 160-167, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29132171
Metabolic endotoxemia has been implicated in the pathogenesis of type 2 diabetes. In addition to adipose tissue inflammation, inflammatory cell infiltration is also observed in islets, although its effect on islets is largely unknown. We hypothesized that macrophage infiltration into islets leads to impairment of α or ß cell function, which ultimately act to exacerbate the pathophysiology of diabetes. Gene expression in a murine α cell line, αTC1, and ß cell line, ßTC6, was investigated by DNA microarray after co-culturing the cells with a murine macrophage cell line, RAW 264.7, in the presence or absence of bacterial endotoxin. Among the genes showing highly upregulated expression, genes specifically upregulated only in ß cells were evaluated to determine the roles of the gene products on the cellular function of ß cells. In both α and ß cells, expression of type I interferon-responsive genes was highly upregulated upon endotoxin stimulation. Among these genes, expression of the X-linked inhibitor of apoptosis (Xiap)-associated factor 1 (Xaf1) gene, which is associated with the induction of apoptosis, was specifically enhanced in ß cells by endotoxin stimulation. This upregulation appeared to be mediated by macrophage-derived interferon ß (IFNß), as endotoxin-stimulated macrophages produced higher amounts of IFNß, and exogenous addition of IFNß into ßTC6 cultures resulted in increased Xaf1 protein production and cleaved caspase 3, which accelerated ß-cell apoptosis. Macrophages activated by metabolic endotoxemia infiltrated into islets and produced IFNß, which induced ß-cell apoptosis by increasing the expression of Xaf1.
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