IL-16 promotes leukotriene C4 and IL-4 release from human eosinophils via CD4-and autocrine CCR3-chemokine-mediated signaling
IL-16 promotes leukotriene C4 and IL-4 release from human eosinophils via CD4-and autocrine CCR3-chemokine-mediated signaling
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DOI：
10.4049/jimmunol.168.9.4756
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发表时间：
2002-05-01
影响因子：
4.4
通讯作者：
Weller, PF
中科院分区：
文献类型：
--
作者：
Bandeira-Melo, C;Sugiyama, K;Weller, PF
人嗜酸性粒细胞是炎症和免疫调节介质的潜在来源，包括半胱氨酰白三烯、趋化因子和细胞因子，其与过敏性炎症有关。我们评估了IL-16（一种公认的嗜酸性粒细胞化学引诱物）可能作用于嗜酸性粒细胞以影响其释放白三烯C-4（LTC 4）或其预先储存的趋化因子（嗜酸性粒细胞趋化因子，RANTES）或Th 1（IL-12）或Th 2（IL-4）细胞因子的能力的方法。IL-16剂量依赖性地（0.01-100 nM）引起新的脂质体形成、在脂质体处的细胞内LTC 4形成以及引发增强的钙离子载体激活的LTC 4释放。IL-16还引起了布雷菲德菌素A-可降解的，囊泡转运介导的释放预制IL-4，但不是IL-12，从嗜酸性粒细胞。CD 4是公认的IL-16 R，因此抗CD 4 Fab、可溶性CD 4和基于CD 4结构域4的1h-16阻断肽抑制IL-16对嗜酸性粒细胞的作用。虽然CD 4不是G蛋白偶联的，但百日咳毒素抑制IL-16诱导的嗜酸性粒细胞活化。IL-16的作用被认为是介导的自分泌活性，而不是血小板活化因子，而是内源性CCR 3作用趋化因子。IL-16诱导快速囊泡转运介导的RANTES释放。IL-16的作用被CCR 3抑制剂（met-RANTES，抗CCR 3 mAb）和中和抗嗜酸性粒细胞趋化因子和抗RANTES mAb阻断，但不被血小板活化因子受体拮抗剂（CV 6209，BN 52021）阻断。RANTES和eotaxin各自增强LTC 4和IL-4（但不增强IL-12）的释放。因此，IL-16对嗜酸性粒细胞的活化是CD 4介导的，以引起预先形成的RANTES和嗜酸性粒细胞活化趋化因子的细胞外释放，然后以自分泌方式作用于质膜CCR 3受体，以刺激增强的LTC 4产生和从嗜酸性粒细胞内优先释放IL-4，而不是IL-12。
Human eosinophils are potential sources of inflammatory and immunomodulatory mediators, including cysteinyl leukotrienes, chemokines, and cytokines, which are pertinent to allergic inflammation. We evaluated the means by which IL-16, a recognized eosinophil chemoattractant, might act on eosinophils to affect their capacity to release leukotriene C-4 (LTC4) or their preformed stores of chemokines (eotaxin, RANTES) or Th1 (IL-12) or Th2 (IL-4) cytokines. IL-16 dose dependently (0.01-100 nM) elicited new lipid body formation, intracellular LTC4 formation at lipid bodies, and priming for enhanced calcium ionophore-activated LTC4 release. IL-16 also elicited brefeldin A-inhibitable, vesicular transport-mediated release of preformed IL-4, but not IL-12, from eosinophils. CD4 is a recognized IL-16R, and accordingly anti-CD4 Fab, soluble CD4, and a CD4 domain 4-based 1h-16 blocking peptide inhibited the actions of IL-16 on eosinophils. Although CD4 is not G-protein coupled, pertussis toxin inhibited IL-16-induced eosinophil activation. IL-16 actions were found to be mediated by the autocrine activity, not of platelet-activating factor, but rather of endogenous CCR3-acting chemokines. IL-16 induced the rapid vesicular transport-mediated release of RANTES. The effects of IL-16 were blocked by CCR3 inhibitors (met-RANTES, anti-CCR3 mAb) and by neutralizing anti-eotaxin and anti-RANTES mAbs, but not by platelet-activating factor receptor antagonists (CV6209, BN52021). RANTES and eotaxin each enhanced LTC4 and IL-4 (but not IL-12) release. Therefore, IL-16 activation of nosinophils is CD4-mediated to elicit the extracellular release of preformed RANTES and eotaxin, which then in an autocrine fashion act on plasma membrane CCR3 receptors to stimulate both enhanced LTC4 production and the preferential release of IL-4, but not IL-12, from within eosinophils.