Requirements for C5a receptor-mediated IL-4 and IL-13 production and leukotriene C4 generation in human basophils
Requirements for C5a receptor-mediated IL-4 and IL-13 production and leukotriene C4 generation in human basophils
复制标题
DOI：
10.4049/jimmunol.165.4.2183
复制
发表时间：
2000-08-15
影响因子：
4.4
通讯作者：
Dahinden, CA
中科院分区：
文献类型：
--
作者：
Eglite, S;Plüss, K;Dahinden, CA
源自第五补体成分（C5a）的过敏毒素在 IL-3 存在下诱导人嗜碱性粒细胞中连续白三烯 C4 生成以及 IL-4 和 IL-13 表达，持续 16-18 小时，这表明 G 蛋白偶联 C5a 受体（C5aR）可以诱导持久的细胞反应。使用抗 N 端 C5aR 抗体、C 端 C5a 六肽类似物和百日咳毒素，我们证明 C5aR 的假定激活位点对于这些晚期细胞反应是必要且充分的。此外，在整个产品发布期间，持续的百日咳毒素敏感 G 蛋白偶联受体激活和受体-配体相互作用是持续进行的并且是必需的。然而，晚期嗜碱性粒细胞反应对最佳受体激活有更严格的要求。白三烯 C4 的生成似乎主要受受体激活方式的影响，因为最活跃的六肽是这种反应的超级激动剂。相比之下，缺乏 C 端精氨酸的 C5a(desarg) 可诱导最小程度的脂质介质形成，但具有完全活性以诱导 IL-4 产生，甚至是 IL-13 释放的超级激动剂。然而，响应 C5a(desarg) 的 IL-4/IL-13 合成可以被 C 端拮抗肽以及抗 N 端 C5aR Ab 阻断，表明 C5a 和 C5a(desarg) 之间的配体-受体相互作用仅存在微小差异。总而言之，我们的数据表明，持久且连续的信号传导是通过 C5aR 的有限激活域发生的，这可以差异性地促进单独的嗜碱性粒细胞功能。
Anaphylatoxin derived from the fifth complement component (C5a) in the presence of IL-3 induces continuous leukotriene C4 generation and IL-4 and IL-13 expression in human basophils for a period of 16-18 h, This indicates that the G protein-coupled C5a receptor (C5aR) can induce long-lasting cellular responses. Using anti-N-terminal C5aR Abs, C-terminal C5a hexapeptide analogs, and pertussis toxin, we demonstrate that the putative activation site of the C5aR is both necessary and sufficient for these late cellular responses. Furthermore, continuous pertussis toxin-sensitive G protein-coupled receptor activation and receptor-ligand interaction is ongoing and required during the entire period of product release. However, the late basophil responses have a more stringent requirement for optimal receptor activation. Leukotriene C4 generation appears to be influenced mostly by the way the receptor is activated, because the most active hexapeptide is a superagonist for this response. By contrast, C5a(desarg), lacking the C-terminal arginine, induces minimal lipid mediator formation but is fully active to induce IL-4 production and is even a superagonist for IL-13 release. Nevertheless, IL-4/IL-13 synthesis in response to C5a(desarg) could be blocked by both C-terminal antagonistic peptide as well as anti-N-terminal C5aR Abs, indicating only minor differences of ligand-receptor interactions between C5a and C5a(desarg). Taken together, our data demonstrate that long-lasting and continuous signaling occurs through a limited activation domain of the C5aR, which can differentially promote separate basophil functions.