Negative regulation of eosinophil recruitment to the lung by the chemokine monokine induced by IFN-γ (Mig, CXCL9)
Negative regulation of eosinophil recruitment to the lung by the chemokine monokine induced by IFN-γ (Mig, CXCL9)
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DOI：
10.1073/pnas.0308544100
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发表时间：
2004-02-17
影响因子：
11.1
通讯作者：
Rothenberg, ME
中科院分区：
文献类型：
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作者：
Fulkerson, PC;Zimmermann, N;Rothenberg, ME
动物和人类过敏性呼吸道炎症(AAI)的实验分析与协同基因诱导有关。利用DNA微阵列分析，我们已经确定了一大组AAI标志性基因。出乎意料的是，变应原攻击的肺(T辅助2微环境)被发现与T辅助1相关的CXCR3配体、LFN-γ诱导的单核细胞因子(Mig)和干扰素-γ诱导的10 kDa蛋白(IP-10)的表达有关。在此，我们报道了Mig对小鼠嗜酸性粒细胞的负性调节作用。虽然Mig不能诱导嗜酸性粒细胞趋化，但Mig对趋化因子诱导的嗜酸性粒细胞体外迁移有剂量依赖性的抑制作用。此外，静脉注射。给予低剂量的Mig(约10-30µg/kg)可诱导强烈而特异的抑制趋化因子、IL-13和变应原诱导的嗜酸性粒细胞聚集，反之，在变应原攻击前中和Mig可增加气道嗜酸性粒细胞增多。重要的是，Mig还抑制了CCR3介导的嗜酸性粒细胞的功能反应。这些结果表明，炎症细胞在过敏性肺内的最终分布和功能是由正向和负向调节性趋化因子之间的平衡决定的。体内自然产生的嗜酸性粒细胞抑制性趋化因子途径的鉴定为未来的治疗考虑提供了战略基础。
Experimental analysis of allergic airway inflammation (AAI) in animals and humans is associated with coordinate gene induction. Using DNA microarray analysis, we have identified a large panel of AAI signature genes. Unexpectedly, the allergen-challenged lung (a T helper 2 microenvironment) was found to be associated with the expression of T helper 1-associated CXCR3 ligands, monokine induced by lFN-gamma(Mig),and IFN-gamma-inducible protein of 10 kDa(IP-10). Here we report that Mig functions as a negative regulator of murine eosinophils. Whereas Mig was not able to induce chemotaxis of eosinophils, pretreatment with Mig induced a dose-dependent inhibition of chemoattractant-induced eosinophil transmigration in vitro. Moreover, i.v. administration of low doses of Mig (approximate to10-30 mug/kg) induced strong and specific dose-dependent inhibition of chemokine-, IL-13-, and allergen-induced eosinophil recruitment and, conversely, neutralization of Mig before allergen challenge increased airway eosinophilia. Importantly, Mig also inhibited a CCR3-mediated functional response in eosinophils. These results indicate that the ultimate distribution and function of inflammatory cells within the allergic lung is dictated by a balance between positively and negatively regulatory chemokines. The identification of a naturally occurring eosinophil inhibitory chemokine pathway in vivo provides a strategic basis for future therapeutic consideration.