Angiopoietin-like protein 2 mediates endotoxin-induced acute inflammation in the eye
Angiopoietin-like protein 2 mediates endotoxin-induced acute inflammation in the eye
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DOI：
10.1038/labinvest.2012.111
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发表时间：
2012-11-01
影响因子：
5
通讯作者：
Ishida, Susumu
中科院分区：
文献类型：
--
作者：
Kanda, Atsuhiro;Noda, Kousuke;Ishida, Susumu
血管生成素样蛋白（Angptl）2是将肥胖与慢性脂肪组织炎症和全身性胰岛素抵抗联系起来的关键介质，并且越来越多的证据表明Angptl2与各种慢性炎性疾病如癌症和皮肌炎相关;然而，仍不清楚Angptl2在急性炎症中起作用。在这项研究中，我们研究了Angptl2是否在患有内毒素诱导的葡萄膜炎（EIU）的眼睛中的急性炎症中起作用。Angptl2在正常小鼠视网膜中广泛表达，而Angptl2（-/-）小鼠在视网膜细胞标志物表达和形态学分析中未表现出任何变化。用脂多糖（LPS）处理刺激视网膜Angptl2 mRNA在体内和体外的表达。我们通过腹腔内注射LPS在野生型（C57BL/6）和Angptl2（-/-）小鼠中产生EIU。与野生型动物相比，Angptl2（-/-）小鼠显著降低了各种EIU相关的细胞和分子参数，包括白细胞粘附至视网膜血管和浸润至玻璃体腔以及单核细胞趋化蛋白-1、细胞间粘附分子-1、白细胞介素（IL）-6和肿瘤坏死因子（TNF）-α的视网膜mRNA表达水平，同时伴有核因子（NF）-κ B B p65亚单位的核转位。在体外，基于抗体的α 5 β 1整联蛋白（Angptl2的受体）的抑制显著地抑制了LPS诱导的IL-6和TNF-α的表达，IL-6和TNF-α两者都是来源于巨噬细胞的主要炎性细胞因子。本研究结果表明，Angptl2通过激活NF-κ B信号通路介导内毒素诱导的视网膜炎症，并表明Angptl2作为治疗急性炎症的新分子靶标的潜在有效性。实验室调查（2012）92，1553 - 1563; doi：10.1038/labinvest.2012.111;在线发表2012年8月6日
Angiopoietin-like protein (Angptl) 2 is a key mediator linking obesity to chronic adipose-tissue inflammation and systemic insulin resistance, and increasing evidence has shown that Angptl2 is associated with various chronic inflammatory diseases such as cancer and dermatomyositis; however, it remains unclear that Angptl2 functions in acute inflammation. In this study, we investigate whether Angptl2 has a role in acute inflammation in the eye with endotoxin-induced uveitis (EIU). Angptl2 was widely expressed in the normal mouse retina, while Angptl2(-/-) mice did not exhibit any changes in retinal cell marker expression and morphological analyses. Treatment with lipopolysaccharide (LPS) stimulated retinal Angptl2 mRNA expression in vivo and in vitro. We generated EIU in wild-type (C57BL/6) and Angptl2(-/-) mice by injecting LPS intraperitoneally. Compared with wild-type animals, Angptl2(-/-) mice significantly reduced various EIU-associated cellular and molecular parameters including leukocyte adhesion to the retinal vessels and infiltration into the vitreous cavity and retinal mRNA expression levels of monocyte chemotactic protein-1, intercellular adhesion molecule-1, interleukin (IL)-6, and tumor necrosis factor (TNF)-alpha, together with nuclear translocation of nuclear factor (NF)-kappa B p65 subunit. In vitro, antibody-based inhibition of alpha 5 beta 1 integrin, a receptor for Angptl2, significantly repressed LPS-induced expression of IL-6 and TNF-alpha, both of which are the major inflammatory cytokines derived from macrophages. The present findings indicate that Angptl2 mediates endotoxin-induced retinal inflammation through the activation of NF-kappa B signaling pathway and suggest a potential validity of Angptl2 as a new molecular target for the treatment of acute inflammation. Laboratory Investigation (2012) 92, 1553-1563; doi:10.1038/labinvest.2012.111; published online 6 August 2012