Free Fatty Acids Induce a Proinflammatory Response in Islets via the Abundantly Expressed Interleukin-1 Receptor I
Free Fatty Acids Induce a Proinflammatory Response in Islets via the Abundantly Expressed Interleukin-1 Receptor I
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DOI：
10.1210/en.2009-0543
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发表时间：
2009-12-01
期刊：
影响因子：
4.8
通讯作者：
Donath, Marc Y.
中科院分区：
文献类型：
--
作者：
Boeni-Schnetzler, Marianne;Boller, Simone;Donath, Marc Y.
2型糖尿病（T2 DM）患者的胰岛显示出炎症过程的特征，包括细胞因子IL-1 β、各种趋化因子和巨噬细胞水平升高。IL-1 β是炎症的主要调节因子，IL-1 I型受体（IL-1 RI）阻断可改善T2 DM患者和高脂喂养小鼠的胰岛和胰岛素分泌，这表明IL-1 RI活性在胰岛内炎症中起关键作用。鉴于血脂异常与2型糖尿病的相关性，我们检测了游离脂肪酸（FFA）是否促进人类和小鼠胰岛中促炎因子的表达，并研究了IL-1 RI在这种反应中的作用。比较22个小鼠组织，发现胰岛和MIN 6 β细胞中IL-1 RI表达水平最高。FFA在人胰岛中诱导IL-1 β、IL-6和IL-8，在小鼠胰岛中诱导IL-1 β和KC。升高的葡萄糖浓度增强FFA诱导的人胰岛促炎因子。用IL-1 R拮抗剂（IL-1 Ra）阻断IL-1 RI强烈抑制FFA介导的人和小鼠胰岛中促炎因子的表达。IL-1 β的抗体抑制显示FFA通过诱导受体配体刺激IL-1 RI活性。FFA诱导的小鼠胰岛中IL-1 β和KC表达完全依赖于IL-1 R/Toll样受体（TLR）对接蛋白Myd 88，部分依赖于TLR 2和-4。纯化的人β细胞和胰岛中TLR 2的活化刺激促炎因子的表达，IL-1 RI活性增加人胰岛中TLR 2的反应。我们的结论是FFA和TLR刺激诱导胰岛中的促炎因子，IL-1 RI参与导致信号放大。（内分泌学150：5218-5229，2009）
Islets of patients with type 2 diabetes mellitus (T2DM) display features of an inflammatory process including elevated levels of the cytokine IL-1 beta, various chemokines, and macrophages. IL-1 beta is a master regulator of inflammation, and IL-1 receptor type I (IL-1RI) blockage improves glycemia and insulin secretion in humans with T2DM and in high-fat-fed mice pointing to a pivotal role of IL-1RI activity in intra-islet inflammation. Given the association of dyslipidemia and T2DM, we tested whether free fatty acids (FFA) promote the expression of proinflammatory factors in human and mouse islets and investigated a role for the IL-1RI in this response. Acomparison of 22 mouse tissues revealed the highest IL-1RI expression levels in islets and MIN6 beta-cells. FFA induced IL-1 beta, IL-6, and IL-8 in human islets and IL-1 beta and KC in mouse islets. Elevated glucose concentrations enhanced FFA-induced proinflammatory factors in human islets. Blocking the IL-1RI with the IL-1R antagonist (IL-1Ra) strongly inhibited FFA-mediated expression of proinflammatory factors in human and mouse islets. Antibody inhibition of IL-1 beta revealed that FFA stimulated IL-1RI activity via the induction of the receptor ligand. FFA-induced IL-1 beta and KC expression in mouse islets was completely dependent on the IL-1R/Toll-like receptor (TLR) docking protein Myd88 and partly dependent on TLR2 and -4. Activation of TLR2 in purified human beta-cells and islets stimulated the expression of proinflammatory factors, and IL-1RI activity increased the TLR2 response in human islets. We conclude that FFA and TLR stimulation induce proinflammatory factors in islets and that IL-1RI engagement results in signal amplification. (Endocrinology 150: 5218-5229, 2009)