Targeted gene disruption reveals the role of cysteinyl leukotriene 1 receptor in the enhanced vascular permeability of mice undergoing acute inflammatory responses
Targeted gene disruption reveals the role of cysteinyl leukotriene 1 receptor in the enhanced vascular permeability of mice undergoing acute inflammatory responses
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DOI：
10.1074/jbc.m203163200
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发表时间：
2002-06-07
影响因子：
4.8
通讯作者：
Kanaoka, Y
中科院分区：
文献类型：
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作者：
Maekawa, A;Austen, KF;Kanaoka, Y
半胱氨酰白三烯（cysLTs），即白三烯（LT）C - 4、LTD4和LTE4，是由小鼠体内诸如巨噬细胞和肥大细胞等造血细胞产生的促炎脂质介质。cysLTs有两种小鼠受体，即半胱氨酰白三烯1型受体（CysLT₁R）和半胱氨酰白三烯2型受体（CysLT₂R），它们有38%的同源性，分别位于小鼠的X染色体和14号染色体上。为了阐明CysLT₁R和CysLT₂R在体内炎症反应中的不同作用，我们通过靶向基因敲除技术培育了CysLT₁R缺陷型小鼠。这些小鼠发育正常且具有生育能力。在用呋喃 - 2乙酰氧基甲酯进行的细胞内钙动员试验中，来自野生型同窝小鼠的腹腔巨噬细胞（同时表达CysLT₁R和CysLT₂R）对1×10⁻⁶ M的LTD4有显著反应，对1×10⁻⁶ M的LTC4有轻微反应，而来自CysLT₁R缺陷型小鼠的巨噬细胞对LTD4和LTC4均无反应。在酵母聚糖A诱导的腹腔炎症中，CysLT₁R缺陷型小鼠的血浆蛋白渗出显著减少，但中性粒细胞浸润未减少。与野生型小鼠相比，在发生IgE介导的被动皮肤过敏反应的CysLT₁R缺陷型小鼠中，血浆蛋白渗出也显著减少。因此，由单核细胞/巨噬细胞或肥大细胞在体内产生的半胱氨酰白三烯在急性炎症中利用CysLT₁R来引起微血管的反应。
The cysteinyl leukotrienes (cysLTs), leukotriene (LT) C-4, LTD4, and LTE4, are proinflammatory lipid mediators generated in the mouse by hematopoietic cells such as macrophages and mast cells. There are two mouse receptors for the cysLTs, CysLT, receptor (CysLT(1)R) and CysLT(2)R, which are 38% homologous and are located on mouse chromosomes X and 14, respectively. To clarify the different roles of the CysLT1R and CysLT2R in inflammatory responses in vivo, we generated CysLT,R-deficient mice by targeted gene disruption. These mice developed normally and were fertile. In an intracellular calcium mobilization assay with fura-2 acetoxymethyl ester, peritoneal macrophages from wild-type littermates, which express both CysLT(1)R and CysLT(2)R, responded substantially to 1 X 10(-6) M LTD4 and slightly to 1 x 10(-6) M LTC4, whereas the macrophages from CysLT(1)R-deficient mice did not respond to either LTD4 or LTC4. Plasma protein extravasation, but not neutrophil infiltration, was significantly reduced in CysLT(1)R-deficient mice subjected to zymosan A-induced peritoneal inflammation. Plasma protein extravasation was also significantly diminished in CysLT(1)R-deficient mice undergoing IgE-mediated passive cutaneous anaphylaxis as compared with the wild-type mice. Thus, the cysLTs generated in vivo by either monocytes/macrophages or mast cells utilize CysLT(1)R for the response of the microvasculature in acute inflammation.