Department of Pediatrics, Instituto Fernandes Figueira, Rio de Janeiro, Brazil.
J Leukoc Biol. 2010 May;87(5):885-93. doi: 10.1189/jlb.1108709. Epub 2010 Mar 10.
IL-13 and eotaxin play important, inter-related roles in asthma models. In the lungs, CysLT, produced by the 5-LO-LTC4S pathway, mediate some local responses to IL-13 and eotaxin; in bone marrow, CysLT enhance IL-5-dependent eosinophil differentiation. We examined the effects of IL-13 and eotaxin on eosinophil differentiation. Semi-solid or liquid cultures were established from murine bone marrow with GM-CSF or IL-5, respectively, and the effects of IL-13, eotaxin, or CysLT on eosinophil colony formation and on eosinophil differentiation in liquid culture were evaluated, in the absence or presence of: a) the 5-LO inhibitor zileuton, the FLAP inhibitor MK886, or the CysLT1R antagonists, montelukast and MK571; b) mutations that inactivate 5-LO, LTC4S, or CysLT1R; and c) neutralizing mAb against eotaxin and its CCR3 receptor. Both cytokines enhanced GM-CSF-dependent eosinophil colony formation and IL-5-stimulated eosinophil differentiation. Although IL-13 did not induce eotaxin production, its effects were abolished by anti-eotaxin and anti-CCR3 antibodies, suggesting up-regulation by IL-13 of responses to endogenous eotaxin. Anti-CCR3 blocked eotaxin completely. The effects of both cytokines were prevented by zileuton, MK886, montelukast, and MK571, as well as by inactivation of the genes coding for 5-LO, LTC4S, and CysLT1R. In the absence of either cytokine, these treatments or mutations had no effect. These findings provide evidence for: a) a novel role of eotaxin and IL-13 in regulating eosinophilopoiesis; and b) a role for CysLTRs in bone marrow cells in transducing cytokine regulatory signals.
白细胞介素 13（IL-13）和嗜酸性粒细胞趋化因子（eotaxin）在哮喘模型中发挥着重要的、相互关联的作用。在肺部，5-脂氧合酶（5-LO）-白三烯 C4 合酶（LTC4S）途径产生的半胱氨酰白三烯（CysLT）介导了 IL-13 和 eotaxin 对某些局部反应；在骨髓中，CysLT 增强了白细胞介素 5（IL-5）依赖性嗜酸性粒细胞分化。我们研究了 IL-13 和 eotaxin 对嗜酸性粒细胞分化的影响。使用 GM-CSF 或 IL-5 分别建立了来自鼠骨髓的半固体或液体培养物，并评估了 IL-13、eotaxin 或 CysLT 对嗜酸性粒细胞集落形成和液体培养物中嗜酸性粒细胞分化的影响，同时存在或不存在：a）5-LO 抑制剂齐留通（zileuton）、FLAP 抑制剂 MK886 或 CysLT1R 拮抗剂孟鲁司特（montelukast）和 MK571；b）失活 5-LO、LTC4S 或 CysLT1R 的突变；c）针对 eotaxin 和其 CCR3 受体的中和单克隆抗体。两种细胞因子均增强了 GM-CSF 依赖性嗜酸性粒细胞集落形成和 IL-5 刺激的嗜酸性粒细胞分化。虽然 IL-13 没有诱导 eotaxin 的产生，但抗 eotaxin 和抗 CCR3 抗体可使其作用消失，这表明 IL-13 可上调对内源性 eotaxin 的反应。抗 CCR3 完全阻断了 eotaxin。齐留通、MK886、孟鲁司特和 MK571 以及失活编码 5-LO、LTC4S 和 CysLT1R 的基因均可预防这两种细胞因子的作用。在没有这两种细胞因子的情况下，这些治疗方法或突变没有任何影响。这些发现为：a）eotaxin 和白细胞介素 13 在调节嗜酸性粒细胞生成中的新作用；b）半胱氨酰白三烯受体（CysLTRs）在骨髓细胞中传递细胞因子调节信号的作用。
