Matrix metalloproteinase 8 contributes to solubilization of IL-13 receptor α2 in vivo
Matrix metalloproteinase 8 contributes to solubilization of IL-13 receptor α2 in vivo
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DOI：
10.1016/j.jaci.2008.06.022
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发表时间：
2008-09-01
影响因子：
14.2
通讯作者：
Hershey, Gurjit K. Khurana
中科院分区：
文献类型：
--
作者：
Chen, Weiguo;Tabata, Yasuhiro;Hershey, Gurjit K. Khurana
背景：IL-13受体α 2（IL-13 R α 2）是11，43的高亲和力受体，11，43是过敏性哮喘的中枢介质。它主要作为诱饵受体发挥作用，但在某些条件下也可促进IL-13应答。IL-13 R α 2以可溶性和膜形式存在，其可以结合IL-13并调节其活性。目的：探讨基质金属蛋白酶（matrix metalloproteinases，MMPs）在可溶性IL-13 R α 2产生中的作用。方法：采用小鼠或人IL-13 R α 2的谷胱甘肽-S-转移酶融合蛋白，进行MMPs的非细胞切割实验。IL-13 R α 2稳定转染的细胞用于分析可溶性IL-13 R α 2的表面表达和释放。用野生型和MMP-8缺陷小鼠分析变应原诱导的气道高反应性和IL-13 R α 2的增溶作用。结果：在所测试的几种MMP中，仅MMP-8切割IL-13 R α 2。用MMP-8处理表达高水平表面IL-13 R α 2的转染的人或鼠细胞导致可溶性IL-13 R α 2释放到上清液中，同时表面IL-13 R α 2水平降低。MMP-8溶解的IL-13 R α 2保留了IL-13结合活性。在哮喘模型中，MMP-8缺陷小鼠表现出气道高反应性增加和支气管肺泡灌洗液中可溶性IL-13 R α 2蛋白水平降低，与野生型小鼠相比，在屋尘螨challenge.Conclusion：MMP-8在体外切割IL-13 R α 2，并有助于IL-13 R α 2在体内的溶解。
Background: IL-13 receptor alpha 2 (IL-13R alpha 2) is a high-affinity receptor for 11,43, a central mediator of allergic asthma. It acts predominantly as a decoy receptor but can also contribute to IL-13 responses under certain conditions. IL-13R alpha 2 exists in soluble and membrane forms, which can both bind IL-13 and modulate its activity. Yet the proteolytic processes that contribute to the generation of soluble IL-13R alpha 2 are largely unknown.Objective: We sought to investigate the role of matrix metalloproteinases (MMPs) in the generation of soluble IL-13R alpha 2.Methods: Acellular cleavage assays by MMPs were performed by using glutathione-S-transferase fusion proteins of murine or human IL-13R alpha 2. IL-13R alpha 2 stable-transfected cells were used for analysis of surface expression and release of soluble IL-13R alpha 2. Wild-type and MMP-8-deficient mice were used for analysis of allergen-induced airway hyperresponsiveness and solubilization of IL-13R alpha 2.Results: Among several MMPs tested, only MMP-8 cleaved IL-13R alpha 2. Treatment of transfected human or murine cells expressing high levels of surface IL-13R alpha 2 with MMP-8 resulted in release of soluble IL-13R alpha 2 into the supernatants, with a concomitant decrease in surface IL-13R alpha 2 levels. The IL-13R alpha 2 solubilized by MMP-8 retained IL-13 binding activity. In an asthma model MMP-8-deficient mice displayed increased airway hyperresponsiveness and decreased soluble IL-13R alpha 2 protein levels in bronchoalveolar lavage fluid compared with those seen in wild-type mice after house dust mite challenge.Conclusion: MMP-8 cleaves IL-13R alpha 2 in vitro and contributes to the solubilization of IL-13R alpha 2 in vivo.