FoxO1 links insulin resistance to proinflammatory cytokine IL-1beta production in macrophages.
FoxO1 links insulin resistance to proinflammatory cytokine IL-1beta production in macrophages.
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FOXO1将胰岛素耐药性与巨噬细胞中促炎性细胞因子IL-1Beta产生联系起来。
作者：
Su D;Coudriet GM;Hyun Kim D;Lu Y;Perdomo G;Qu S;Slusher S;Tse HM;Piganelli J;Giannoukakis N;Zhang J;Dong HH
巨噬细胞通过产生促炎细胞因子在胰岛素抵抗的发病机制中发挥重要作用。我们的目标是破译巨噬细胞中促炎细胞因子产生和胰岛素抵抗之间的分子联系。我们测定了培养的巨噬细胞中的细胞因子谱，并将白细胞介素（IL）-1β基因鉴定为FoxO 1的潜在靶点，FoxO 1是介导胰岛素对基因表达作用的关键转录因子。我们研究了FoxO 1介导培养的巨噬细胞中IL-1β表达的胰岛素依赖性调节的机制，并将腹膜巨噬细胞中FoxO 1活性与轻度炎症或胰岛素抵抗小鼠的IL-1β产生谱相关联。FoxO 1选择性促进巨噬细胞产生IL-1β。这种作用与FoxO 1结合和增强IL-1β启动子活性的能力相关。IL-1β启动子内FoxO 1结合位点的突变消除了FoxO 1对IL-1β表达的诱导。来自胰岛素抵抗肥胖db/db小鼠或脂多糖损伤小鼠的巨噬细胞与FoxO 1产生增加相关，与巨噬细胞中IL-1β mRNA和血浆中IL-1β蛋白水平升高相关。在未受刺激的巨噬细胞中，FoxO 1保持惰性，对IL-1β表达有良性影响。在炎症刺激的反应中，FoxO 1活性增强，因为胰岛素磷酸化FoxO 1和促进其核排斥的能力受损。这种作用沿着核因子-κB，刺激活化巨噬细胞产生IL-1β。通过核因子-κB的FoxO 1信号传导在肥胖和糖尿病的促炎细胞因子产生与胰岛素抵抗的偶联中起重要作用。
Macrophages play an important role in the pathogenesis of insulin resistance via the production of proinflammatory cytokines. Our goal is to decipher the molecular linkage between proinflammatory cytokine production and insulin resistance in macrophages. We determined cytokine profiles in cultured macrophages and identified interleukin (IL)-1β gene as a potential target of FoxO1, a key transcription factor that mediates insulin action on gene expression. We studied the mechanism by which FoxO1 mediates insulin-dependent regulation of IL-1β expression in cultured macrophages and correlated FoxO1 activity in peritoneal macrophages with IL-1β production profiles in mice with low-grade inflammation or insulin resistance. FoxO1 selectively promoted IL-1β production in cultured macrophages. This effect correlated with the ability of FoxO1 to bind and enhance IL-1β promoter activity. Mutations of the FoxO1 binding site within the IL-1β promoter abolished FoxO1 induction of IL-1β expression. Macrophages from insulin-resistant obese db/db mice or lipopolysaccharide-inflicted mice were associated with increased FoxO1 production, correlating with elevated levels of IL-1β mRNA in macrophages and IL-1β protein in plasma. In nonstimulated macrophages, FoxO1 remained inert with benign effects on IL-1β expression. In response to inflammatory stimuli, FoxO1 activity was augmented because of an impaired ability of insulin to phosphorylate FoxO1 and promote its nuclear exclusion. This effect along with nuclear factor-κB acted to stimulate IL-1β production in activated macrophages. FoxO1 signaling through nuclear factor-κB plays an important role in coupling proinflammatory cytokine production to insulin resistance in obesity and diabetes.
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