Kurimoto Y, de Weck A L, Dahinden C A
Institute of Clinical Immunology, Inselspital, Bern, Switzerland.
J Exp Med. 1989 Aug 1;170(2):467-79. doi: 10.1084/jem.170.2.467.
The anaphylatoxin C5a is a potent trigger for basophil degranulations, but in contrast to IgE-dependent basophil activation, it does not result in the synthesis of sulfidoleukotrienes (leukotriene C4/D4/E4). Thus, degranulation and the generation of lipid mediators are separately regulated cellular responses. Exposure of human blood basophils to the cytokine IL-3 alone does not induce the release of histamine in cells from most donors and never leads to the generation of LTC4, indicating that IL-3 is not a direct agonist for basophil mediator release. However, preincubation of basophils with IL-3 enhances the degranulation response to C5a. Most importantly, IL-3 "primes" basophils to release large amounts of leukotriene C4 after challenge with C5a (mean of 50 gp LTC4 per nanograms cellular histamine), while neither peptide alone is capable of inducing the formation of bioactive lipids. This effect is dose dependent, occurring at IL-3 concentrations considerably lower than are required to stimulate the growth of bone marrow progenitor cells. IL-3 affects the extent but not the time course of basophil degranulation, and leukotriene release of cells sequentially exposed to IL-3 and C5a occurs very rapidly concomitant with degranulation. A preincubation of the basophils with IL-3 is strictly required for C5a-induced LTC4 synthesis, but not for an enhancement of degranulation. Priming for C5a-induced lipid mediator generation occurs rapidly after exposure of the cells to IL-3, starting at 1 min and reaching maximal effects at 5 min, but this altered state of responsiveness is relatively long lasting. Cell fractionation studies indicate that the basophil is the source of lipid mediators and that IL-3 affects the basophil response directly. This study demonstrates that IL-3 is a potent modifier of effector functions of mature basophils; this is possibly of greater in vivo significance than its growth factor properties. The large amounts of LTC4 formed after triggering of IL-3-primed basophils may not only enhance but also qualitatively change the pathophysiological consequences of complement activation, and this might be important in the pathogenesis of immediate type hypersensitivity reactions, shock syndromes, and inflammation.
过敏毒素C5a是嗜碱性粒细胞脱颗粒的有效触发因素，但与IgE依赖的嗜碱性粒细胞激活不同，它不会导致硫代白三烯（白三烯C4/D4/E4）的合成。因此，脱颗粒和脂质介质的产生是分别调节的细胞反应。单独将人血嗜碱性粒细胞暴露于细胞因子IL-3不会诱导大多数供体的细胞释放组胺，也不会导致LTC4的产生，这表明IL-3不是嗜碱性粒细胞介质释放的直接激动剂。然而，用IL-3预孵育嗜碱性粒细胞可增强对C5a的脱颗粒反应。最重要的是，IL-3使嗜碱性粒细胞“致敏”，使其在受到C5a刺激后释放大量白三烯C4（每纳克细胞组胺平均为50 gp LTC4），而单独的两种肽都不能诱导生物活性脂质的形成。这种效应是剂量依赖性的，在比刺激骨髓祖细胞生长所需浓度低得多的IL-3浓度下就会出现。IL-3影响嗜碱性粒细胞脱颗粒的程度，但不影响其时间进程，依次暴露于IL-3和C5a的细胞的白三烯释放与脱颗粒同时非常迅速地发生。用IL-3预孵育嗜碱性粒细胞是C5a诱导的LTC4合成所必需的，但不是增强脱颗粒所必需的。在细胞暴露于IL-3后，对C5a诱导的脂质介质产生的致敏作用迅速发生，从1分钟开始，在5分钟时达到最大效果，但这种改变的反应状态持续时间相对较长。细胞分级分离研究表明，嗜碱性粒细胞是脂质介质的来源，IL-3直接影响嗜碱性粒细胞的反应。这项研究表明IL-3是成熟嗜碱性粒细胞效应功能的有效调节剂；这在体内可能比其生长因子特性具有更大的意义。IL-3致敏的嗜碱性粒细胞被触发后形成的大量LTC4不仅可能增强补体激活的病理生理后果，而且可能在质上改变其后果，这在速发型过敏反应、休克综合征和炎症的发病机制中可能很重要。
