Inhibition of airway inflammation by amino-terminally modified RANTES/CC chemokine ligand 5 analogues is not mediated through CCR3
Inhibition of airway inflammation by amino-terminally modified RANTES/CC chemokine ligand 5 analogues is not mediated through CCR3
复制标题
DOI：
10.4049/jimmunol.171.10.5498
复制
发表时间：
2003-11-15
影响因子：
4.4
通讯作者：
Wells, TNC
中科院分区：
文献类型：
--
作者：
Chvatchko, Y;Proudfoot, AEI;Wells, TNC
在呼吸道炎症动物模型中，趋化因子在活化的CD4(+)T细胞和嗜酸性粒细胞向肺内募集中发挥关键作用。N末端修饰的趋化因子对炎症的抑制在几个模型中都得到了很好的证明，但经常在有限剂量的方案中报道。我们评价了两种CC趋化因子受体拮抗剂Met-RANTES/CC趋化因子配体5(CCL5)和氨氧戊烷-RANTES/CCL5在预防OVA致敏小鼠哮喘模型炎症中的作用。在人类系统中，氨氧戊烷-RANTES/CCL5是CCR5的完整激动剂，但在小鼠系统中，这两个变体都不能诱导细胞募集。在过敏原刺激后，两种拮抗剂都显示出相反的钟形抑制细胞向呼吸道的渗透和肺部粘液的产生。在较高剂量下，抑制作用的丧失似乎不是由于部分激动剂活性，因为在这些剂量下，两个变异体都没有表现出将细胞重新招募到腹膜腔中的活性。令人惊讶的是，两者都不能与嗜酸性粒细胞上表达的主要CCR结合，CCR3。然而，观察到嗜酸性粒细胞募集明显受到抑制。两个类似物都与小鼠CCR1和小鼠CCR5保持了高亲和力结合。它们在体内外均能抑制RANTES/CCL5和巨噬细胞炎性蛋白-1β/CCL4的募集，而对eoaxin/CCL11诱导的RANTES/CCL5和巨噬细胞炎性蛋白-1β/CCL4的募集均无影响，表明它们能拮抗CCR1和CCR5而不能拮抗CCR3。这些结果提示CCR1和/或CCR5可能是哮喘治疗的潜在靶点。
Chemokines play a key role in the recruitment of activated CD4(+) T cells and eosinophils into the lungs in animal models of airway inflammation. Inhibition of inflammation by N-terminally modified chemokines is well-documented in several models but is often reported with limited dose regimens. We have evaluated the effects of doses ranging from 10 ng to 100 mug of two CC chemokine receptor antagonists, Met-RANTES/CC chemokine ligand 5 (CCL5) and aminooxypentane-RANTES/CCL5, in preventing inflammation in the OVA-sensitized murine model of human asthma. In the human system, aminooxypentane-RANTES/CCL5 is a full agonist of CCR5, but in the murine system neither variant is able to induce cellular recruitment. Both antagonists showed an inverse bell-shaped inhibition of cellular infiltration into the airways and mucus production in the lungs following allergen provocation. The loss of inhibition at higher doses did not appear to be due to partial agonist activity because neither variant showed activity in recruiting cells into the peritoneal cavity at these doses. Surprisingly, neither was able to bind to the major CCR expressed on eosinophils, CCR3. However, significant inhibition of eosinophil recruitment was observed. Both analogues retained high affinity binding for murine CCR1 and murine CCR5. Their ability to antagonize CCR1 and CCR5 but not CCR3 was confirmed by their ability to prevent RANTES/CCL5 and macrophage inflammatory protein-1beta/CCL4 recruitment in vitro and in vivo, while they had no effect on that induced by eotaxin/CCL11. These results suggest that CCR1 and/or CCR5 may be potential targets for asthma therapy.