Differential regulation of human eosinophil IL-3, IL-5, and GM-CSF receptor α-chain expression by cytokines:: IL-3, IL-5, and GM-CSF down-regulate IL-5 receptor α expression with loss of IL-5 responsiveness, but up-regulate IL-3 receptor a expression
Differential regulation of human eosinophil IL-3, IL-5, and GM-CSF receptor α-chain expression by cytokines:: IL-3, IL-5, and GM-CSF down-regulate IL-5 receptor α expression with loss of IL-5 responsiveness, but up-regulate IL-3 receptor a expression
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DOI：
10.4049/jimmunol.170.11.5359
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发表时间：
2003-06-01
影响因子：
4.4
通讯作者：
Robinson, DS
中科院分区：
文献类型：
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作者：
Gregory, B;Kirchem, A;Robinson, DS
我们最近的数据表明，组织嗜酸性粒细胞可能对抗IL-5治疗相对不敏感。我们研究了IL-3、IL-5、GM-CSF和嗜酸性粒细胞趋化因子对嗜酸性粒细胞细胞因子受体表达的交叉调节和功能影响。用IL-3、IL-5或GM-CSF孵育嗜酸性粒细胞导致IL-5 R α表达降低，并持续长达5天。与IL-5或IL-3孵育的嗜酸性粒细胞显示呼吸爆发和丝裂原活化蛋白激酶激酶磷酸化减少，以响应进一步的IL-5刺激。与这些发现相反，IL-3、IL-5和GM-CSF增加了IL-3R α的嗜酸性粒细胞表达，而GM-CSF受体α被GM-CSF下调，但不受IL-3或IL-5的影响。CCR 3表达被IL-3下调，并被IL-5和GM-CSF短暂降低，但迅速恢复至基线水平。Eotaxin对IL-3、IL-5或GM-CSF的受体表达没有影响。磷酸肌醇3-激酶抑制剂可阻止细胞因子对IL-3Ra的上调，而磷酸肌醇3-激酶抑制剂和其他信号传导抑制剂对IL-5 Ra的下调没有影响。这些数据表明细胞因子配体对IL-3、IL-5和GM-CSF的嗜酸性粒细胞受体的动态和差异调节。因为这些细胞因子。被认为参与嗜酸性粒细胞的发育和从骨髓的动员，并存在于过敏性炎症部位，组织嗜酸性粒细胞可能具有降低的IL-5 R表达和反应性，这可以解释抗IL-5治疗在降低哮喘气道嗜酸性粒细胞增多症中令人失望的效果。
Our recent data suggested that tissue eosinophils may be relatively insensitive to anti-IL-5 treatment. We examined cross-regulation and functional consequences of modulation of eosinophil cytokine receptor expression by IL-3, IL-5 GM-CSF, and eotaxin. Incubation of eosinophils with IL-3, IL-5, or GM-CSF led to reduced expression of IL-5Ralpha, which was sustained for up to 5 days. Eosinophils incubated with IL-5 or IL-3 showed diminished respiratory burst and mitogen-activated protein kinase kinase phosphorylation in response to further IL-5 stimulation. In contrast to these findings, eosinophil expression of IL-3Ralpha was increased by IL-3, IL-5, and GM-CSF, whereas GM-CSF receptor a was down-regulated by GM-CSF, but was not affected by IL-3 or IL-5. CCR3 expression was down-regulated by IL-3 and was transiently reduced by IL-5 and GM-CSF, but rapidly returned toward baseline. Eotaxin had no effect on receptor expression for IL-3, IL-5, or GM-CSF. Up-regulation of IL-3Ra by cytokines was prevented by a phosphoinositol 3-kinase inhibitor, whereas this and other signaling inhibitors had no effect on IL-5Ralpha downregulation. These data suggest dynamic and differential regulation of eosinophil receptors for IL-3, IL-5, and GM-CSF by the cytokine ligands. Since these cytokines are. thought to be involved in eosinophil development and mobilization from the bone marrow and are present at sites of allergic inflammation, tissue eosinophils may have reduced IL-5R expression and responsiveness, and this may explain the disappointing effect of anti-IL-5 therapy in reducing airway eosinophilia in asthma.