Decreased expression of membrane IL-5 receptor α on human eosinophils:: II.: IL-5 down-modulates its receptor via a proteinase-mediated process
Decreased expression of membrane IL-5 receptor α on human eosinophils:: II.: IL-5 down-modulates its receptor via a proteinase-mediated process
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DOI：
10.4049/jimmunol.169.11.6459
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发表时间：
2002-12-01
影响因子：
4.4
通讯作者：
Kelly, EAB
中科院分区：
文献类型：
--
作者：
Liu, LY;Sedgwick, JB;Kelly, EAB
在随后的研究中，我们证明了Ag激发后，支气管肺泡灌洗液嗜酸性粒细胞的膜（m）IL-5 R α表达减弱，在sIL-5 R α mRNA稳态水平不增加的情况下，在BAL液中可检测到可溶性（s）IL-5 R α，并且BAL嗜酸性粒细胞对IL-5的离体脱粒不敏感。我们假设IL-5通过蛋白水解释放mIL-5 R α调节其受体，而mIL-5 R α反过来又促进sIL-5 R α的存在。纯化的人外周血嗜酸性粒细胞与IL-5在各种条件下孵育，并在存在不同的药理学试剂。mIL-5 R α呈剂量依赖性降低，同时上清液中sIL-5 R α升高。IL-5对mIL-5 R α或sIL-5 R α mRNA水平无配体特异性影响。基质金属蛋白酶特异性抑制剂BB-94和GM 6001以及金属蛋白酶组织抑制剂3部分抑制IL-5介导的mIL-5 R α的丢失，表明sIL-5 R α可能通过mIL-5 R α的蛋白水解裂解产生。IL-5可短暂降低β链的表达，但对GM-CSF受体α的表达无影响。用下调mIL-5 R α的IL-5预处理嗜酸性粒细胞，使这些细胞不能对进一步的IL-5刺激作出应答，但它们对GM-CSF完全应答。这些发现表明，IL-5激活的嗜酸性粒细胞可能在体内丢失mIL-5 R α并释放sIL-5 Ra，这可能限制哮喘等疾病中的IL-5依赖性炎症事件。
In the accompanying study, we demonstrated that following Ag challenge, membrane (m)IL-5Ralpha expression is attenuated on bronchoalveolar lavage eosinophils, soluble (s)IL-5Ralpha is detectable in BAL fluid in the absence of increased steady state levels of sIL-5Ralpha mRNA, and BAL eosinophils become refractory to IL-5 for ex vivo degranulation. We hypothesized that IL-5 regulates its receptor through proteolytic release of mIL-5Ralpha, which in turn contributes to the presence of sIL-5Ralpha. Purified human peripheral blood eosinophils were incubated with IL-5 under various conditions and in the presence of different pharmacological agents. A dose-dependent decrease in mIL-5Ralpha was accompanied by an increase in sIL-5Ralpha in the supernatant. IL-5 had, no ligand-specific effect on mIL-5Ralpha or sIL-5Ralpha mRNA levels. The matrix metalloproteinase-specific inhibitors BB-94 and GM6001 and tissue inhibitor of metalloproteinase-3 partially inhibited IL-5-mediated loss of mIL-5Ralpha, suggesting that sIL-5Ralpha may be produced by proteolytic cleavage of mIL-5Ralpha. IL-5 transiently reduced surface expression of beta-chain, but had no effect on the expression of GM-CSFRalpha. Pretreatment of eosinophils with a dose of IL-5 that down-modulated mIL-5Ralpha rendered these cells unable to degranulate in response to further IL-5 stimulation, but they were fully responsive to GM-CSF. These findings suggest that IL-5-activated eosinophils may lose mIL-5Ralpha and release sIL-5Ra in vivo, which may limit IL-5-dependent inflammatory events in diseases such as asthma.