Metabolic Endotoxemia-Activated Macrophages Promote Pancreatic β Cell Death via IFNβ-Xaf1 Pathway

Mitsudai Tsuruta, Misaki Iwashita, Takanori Shinjo, Hiroaki Matsunaga, Akiko Yamashita, Fusanori Nishimura

Research output: Contribution to journalArticle

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Abstract

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 β cell function, which ultimately act to exacerbate the pathophysiology of diabetes. Gene expression in a murine α cell line, αTC1, and β cell line, βTC6, 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 β cells were evaluated to determine the roles of the gene products on the cellular function of β cells. In both α and β 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 β cells by endotoxin stimulation. This upregulation appeared to be mediated by macrophage-derived interferon β (IFNβ), as endotoxin-stimulated macrophages produced higher amounts of IFNβ, and exogenous addition of IFNβ into βTC6 cultures resulted in increased Xaf1 protein production and cleaved caspase 3, which accelerated β-cell apoptosis. Macrophages activated by metabolic endotoxemia infiltrated into islets and produced IFNβ, which induced β-cell apoptosis by increasing the expression of Xaf1.

Original languageEnglish
Pages (from-to)160-167
Number of pages8
JournalHormone and Metabolic Research
Volume50
Issue number2
DOIs
Publication statusPublished - Feb 1 2018

Fingerprint

Endotoxemia
Macrophages
Cell death
Interferons
Cell Death
Endotoxins
Genes
Gene expression
Apoptosis
Cells
Medical problems
Infiltration
Interferon Type I
Gene Expression
Microarrays
Caspase 3
Cell Line
Tissue
Cytotoxic T-Lymphocytes
Oligonucleotide Array Sequence Analysis

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

Metabolic Endotoxemia-Activated Macrophages Promote Pancreatic β Cell Death via IFNβ-Xaf1 Pathway. / Tsuruta, Mitsudai; Iwashita, Misaki; Shinjo, Takanori; Matsunaga, Hiroaki; Yamashita, Akiko; Nishimura, Fusanori.

In: Hormone and Metabolic Research, Vol. 50, No. 2, 01.02.2018, p. 160-167.

Research output: Contribution to journalArticle

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