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Clin Sci (Lond). 2016 Jul 1;130(14):1257-68. doi: 10.1042/CS20160192. Epub 2016 Apr 26.

Macrophage TCF-4 co-activates p65 to potentiate chronic inflammation and insulin resistance in mice.

Author information

1
Department of Orthopaedics, Chengdu Military General Hospital, 270 Rongdu Avenue, Jinniu District, Chengdu, Sichuan 610083, China.
2
Department of Biochemistry and Molecular Biology, Third Military Medical University, Chongqing 400038, China.
3
Department of Orthopaedics, Chengdu Military General Hospital, 270 Rongdu Avenue, Jinniu District, Chengdu, Sichuan 610083, China hongmingmiao@sina.com zhengweipaper@sina.com.
4
Department of Biochemistry and Molecular Biology, Third Military Medical University, Chongqing 400038, China hongmingmiao@sina.com zhengweipaper@sina.com.

Abstract

Transcription factor 4 (TCF-4) was recently identified as a candidate gene for the cause of type 2 diabetes, although the mechanisms have not been fully elucidated. In the present study, we demonstrated that the TCF-4 transgene in macrophages aggravated high-fat diet (HFD)-induced insulin resistance and chronic inflammation, characterized by the elevation of proinflammatory cytokines in the blood, liver and white adipose tissue, as well as a proinflammatory profile of immune cells in visceral fats in mice. Mechanistically, TCF-4 functioned as a co-activator of p65 to amplify the saturated free fatty acid (FFA)-stimulated promoter activity, mRNA transcription and secretion of proinflammatory cytokines in primary macrophages. Blockage of p65 with a specific interfering RNA or inhibitor could prevent TCF-4-enhanced expression of proinflammatory cytokines in FFA/lipopolysaccharide-treated primary macrophages. The p65 inhibitor could abolish macrophage TCF-4 transgene-aggravated systemic inflammation, glucose intolerance and insulin resistance in HFD-treated mice. In addition, we demonstrated that the mRNA expression of TCF-4 in the peripheral blood monocytes from humans was positively correlated to the levels of interleukin (IL)-1β, tumour necrosis factor α, IL-6 and fasting plasma glucose. In summary, we identified TCF-4 as a co-activator of p65 in the potentiation of proinflammatory cytokine production in macrophages and aggravation of HFD-induced chronic inflammation and insulin resistance in mice.

KEYWORDS:

TCF-4; chronic inflammation; insulin resistance; macrophages; p65

PMID:
27129186
DOI:
10.1042/CS20160192
[Indexed for MEDLINE]

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