IL-12 p40 homodimer-dependent macrophage chemotaxis and respiratory viral inflammation are mediated through IL-12 receptor β1
IL-12 p40 homodimer-dependent macrophage chemotaxis and respiratory viral inflammation are mediated through IL-12 receptor β1
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DOI：
10.4049/jimmunol.171.12.6866
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发表时间：
2003-12-15
影响因子：
4.4
通讯作者：
Walter, MJ
中科院分区：
文献类型：
--
作者：
Russell, TD;Yan, QY;Walter, MJ
白细胞聚集到气道腔是哮喘和呼吸道病毒感染等炎症性疾病的主要特征。在这些情况下调节白细胞募集的介质的特征表明，IL-12p40同源二聚体(P80)水平的增加与气道巨噬细胞聚集的增加有关。为了检验这种联系，我们使用了体内和体外试验来证明p80，而不是IL-12或p40，提供了巨噬细胞趋化信号。来自基因缺陷小鼠的巨噬细胞表明，p80依赖的趋化作用不依赖于IL-12，需要IL-12Rbeta1(Rbeta1)的表达。此外，对小鼠细胞系和原代培养的巨噬细胞的分析表明，Rbeta1的表达以及完整的细胞质尾巴对于介导p80依赖的趋化是必要的和充分的。为了检验Rbeta1在体内介导巨噬细胞聚集中的作用，我们对比了野生型和Rbeta1缺陷小鼠中仙台病毒驱动的呼吸道炎症。尽管病毒载量和巨噬细胞趋化因子p80的产生相似，但Rbeta1缺陷小鼠在呼吸道巨噬细胞聚集和对病毒依赖性死亡的抵抗力方面表现出选择性的减少。因此，Rbeta1介导p80依赖的巨噬细胞趋化作用，抑制p80-Rbeta1的相互作用可能为控制哮喘和呼吸道病毒感染相关的炎症提供一种新的抗炎策略。
Leukocyte recruitment to the airway lumen is a central feature of inflammatory conditions such as asthma and respiratory viral infection. Characterization of mediators that regulate leukocyte recruitment in these conditions revealed increased IL-12 p40 homodimer (p80) levels were associated with enhanced airway macrophage accumulation. To examine this association, we used in vivo and in vitro assays to demonstrate p80, but not IL-12 or p40, provided a macrophage chemoattractant signal. Macrophages from genetically deficient mice indicated p80-dependent chemotaxis was independent of IL-12 and required IL-12Rbeta1 (Rbeta1) expression. Furthermore, analysis of murine cell lines and primary culture macrophages revealed Rbeta1 expression, with an intact cytoplasmic tail, was necessary and sufficient to mediate p80-dependent chemotaxis. To examine the role for Rbeta1 in mediating macrophage accumulation in vivo, we contrasted Sendai virus-driven airway inflammation in wild-type and Rbeta1-deficient mice. Despite similar viral burden and production of the macrophage chemoattractant p80, the Rbeta1-deficient mice displayed a selective decrease in airway macrophage accumulation and resistance to viral-dependent mortality. Thus, Rbeta1 mediates p80-dependent macrophage chemotaxis and inhibition of the p80-Rbeta1 interaction may provide a novel anti-inflammatory strategy to manipulate the inflammation associated with asthma and respiratory viral infection.