Context: In nonallergic (naive) mice, type I cysteinyl-leukotriene receptors (CysLT1R) mediate the stimulatory effects of cytokines (eotaxin/CCL11, interleukin[IL] - 13), and nonsteroidal anti-inflammatory drugs (NSAID; indomethacin, aspirin) on eosinophil production by IL-5-stimulated bone-marrow. In ovalbumin (OVA)-sensitized mice, airway challenge-induced bone-marrow eosinophilia and eosinopoiesis are prevented by pretreatment with blockers of adrenal glucocorticoid signaling (RU486, metyrapone) or cysteinyl-leukotriene (CysLT) signaling (montelukast).Objective: To define whether allergen challenge modifies subsequent bone-marrow responses to CysLT, NSAID, and cytokines which act through type 1 CysLT receptor (CysLT1R).Methods: We examined the effects of sensitization/challenge, and of in vivo blockade of endogenous glucocorticoid or CysLT signaling, on ex vivo responses to CysLT1R-dependent stimuli.Results and discussion: Challenge abolished the stimulatory ex vivo responses to CysLT1R-dependent agents in the eosinophil lineage. In cultured bone-marrow of naive, sensitized and sensitized/challenged mice, responses to leukotriene D4 (LTD4) in eosinophil differentiation ex vivo shifted from stimulatory (without challenge) to suppressive (following challenge). Both stimulatory and suppressive LTD4 effects were blocked by montelukast. The suppressive LTD4 effect was accounted for by accelerated maturation followed by apoptosis of eosinophils. RU486/metyrapone or montelukast pretreatments before challenge prevented the challenge-induced change in subsequent responses to all these agents. Hence, allergen challenge has two separate effects on bone-marrow: (a) it enhances eosinopoiesis in vivo and upregulates ex vivo responses to IL-5; (b) it promotes a faster, but self-limiting, response to LTD4 and CysLT1R-dependent stimuli.Conclusion: Allergen challenge modifies eosinopoiesis through systemic (glucocorticoid- and CysLT1R-dependent) mechanisms, increasing responses to IL-5 but restricting responses to subsequent CysLT1R stimulation.

中文翻译：

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变应原激发引起的对白三烯D4，非甾体类抗炎药和细胞因子的骨髓反应变化。

背景：在非变态反应（天真）小鼠中，I型半胱氨酰-白三烯受体（CysLT1R）介导细胞因子（eotaxin / CCL11，白介素[IL]-13）和非甾体抗炎药（NSAID；消炎痛，阿司匹林）的刺激作用IL-5刺激的骨髓对嗜酸性粒细胞产生的影响。在卵清蛋白（OVA）致敏的小鼠中，通过用肾上腺糖皮质激素信号传导剂（RU486，甲吗啡酮）或半胱氨酰白三烯（CysLT）信号传导剂（孟鲁司特）进行预处理可以预防气道挑战引起的骨髓嗜酸性粒细胞增多和嗜酸性粒细胞增多。过敏原攻击是否会改变随后对通过1型CysLT受体（CysLT1R）起作用的CysLT，NSAID和细胞因子的骨髓反应。方法：我们研究了敏化/挑战，结果和讨论：挑战消除了嗜酸性粒细胞谱系中对CysLT1R依赖性药物的体外离体反应。体内和内源性糖皮质激素或CysLT信号传导的阻断。在幼稚，致敏和致敏/挑战小鼠的培养的骨髓中，离体嗜酸性粒细胞分化中对白三烯D4（LTD4）的反应从刺激性（无挑战）变为抑制性（继挑战）。孟鲁司特可阻断LTD4的刺激和抑制作用。LTD4的抑制作用是由于加速成熟，随后嗜酸性粒细胞凋亡所致。攻击前的RU486 /甲吡酮或孟鲁司特预处理可防止攻击诱导的对所有这些药物的反应发生改变。因此，变应原激发对骨髓有两个单独的作用：（a）它增强体内的嗜曙红细胞生成并上调对IL-5的离体反应；（b）它促进对LTD4和CysLT1R依赖性刺激的更快但自限的反应。结论：过敏原激发通过全身性机制（糖皮质激素和CysLT1R依赖性）改变了嗜酸性粒细胞生成，增加了对IL-5的反应，但限制了对随后的CysLT1R刺激。