T helper cell type 2 cytokines coordinately regulate immunoglobulin E-dependent cysteinyl leukotriene production by human cord blood-derived mast cells: profound induction of leukotriene C(4) synthase expression by interleukin 4.
T helper cell type 2 cytokines coordinately regulate immunoglobulin E-dependent cysteinyl leukotriene production by human cord blood-derived mast cells: profound induction of leukotriene C(4) synthase expression by interleukin 4.
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DOI：
10.1084/jem.193.1.123
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发表时间：
2001-01-01
影响因子：
15.3
通讯作者：
Boyce, J A
中科院分区：
文献类型：
--
作者：
Hsieh, F H;Lam, B K;Penrose, J F;Austen, K F;Boyce, J A
体外培养的脐血单个核细胞来源的人肥大细胞(HMCs)对辅助性T细胞2型(Th2)细胞因子具有依赖干细胞因子(SCF)的共生反应。由于半胱氨酰白三烯(Cys-LT)的生物合成是免疫球蛋白(Ig)激活的粘膜HMCS的特征，我们推测Th2细胞因子可能调节HMCS产生二十烷类化合物。在干细胞因子存在下，经IgE被动致敏5d后，抗IgE刺激的HMCs产生极少量的Cys-LT(0.1±0.1 ng/106HMCs)和丰富的前列腺素D2(16.2±10.3 ng/106HMCs)。在被动致敏过程中，用白细胞介素4(IL-4)和干细胞因子(SCF)共同作用于HMCs，可增强其抗IgE依赖组胺的胞吐能力，并使其产生Cys-LT(增加27倍)和PGD2(增加2.5倍)。尽管单独用IL-3或IL-5与SCF共同作用5d对抗IgE介导的Cys-LT的生成有微弱的促进作用，但在IL-4和SCF的共同作用下，这些细胞因子对IgE依赖的Cys-LT的生成分别诱导了6倍和4倍的增加；与单独使用IL-4相比，这并不改变PGD2的生成或组胺的胞吐。这些细胞因子单独或联合应用均不能显著改变HMCS胞浆磷脂酶A2(CPLA2)、5-脂氧合酶(5-LO)或5-LO激活蛋白(FIFP)蛋白的表达水平。与之相反，IL-4可在6h内显著诱导白三烯C4合成酶(LTC4S)mRNA的稳定表达，并以剂量和时间依赖的方式增加LTC4S蛋白的表达和功能活性，平台期分别为10 ng/ml和5d。IL-3或IL-5单独或联合IL-4均可支持5-LO定位于HMCs的胞核。因此，不同的Th2来源的细胞因子针对5-LO/LTC4S生物合成途径中的不同步骤(分别诱导LTC4S表达和5-LO的核导入)，每一步都是对IgE依赖的激活的完全整合的功能反应所必需的，从而调节成熟HMCs的效应表型。
Human mast cells (hMCs) derived in vitro from cord blood mononuclear cells exhibit stem cell factor (SCF)-dependent comitogenic responses to T helper cell type 2 (Th2) cytokines. As cysteinyl leukotriene (cys-LT) biosynthesis is a characteristic of immunoglobulin (Ig)E-activated mucosal hMCs, we speculated that Th2 cytokines might regulate eicosanoid generation by hMCs. After passive sensitization for 5 d with IgE in the presence of SCF, anti-IgE–stimulated hMCs elaborated minimal cys-LT (0.1 ± 0.1 ng/106 hMCs) and abundant prostaglandin (PG)D2 (16.2 ± 10.3 ng/106 hMCs). Priming of hMCs by interleukin (IL)-4 with SCF during passive sensitization enhanced their anti-IgE–dependent histamine exocytosis and increased their generation of both cys-LT (by 27-fold) and PGD2 (by 2.5-fold). Although priming with IL-3 or IL-5 alone for 5 d with SCF minimally enhanced anti-IgE–mediated cys-LT generation, these cytokines induced further six- and fourfold increases, respectively, in IgE-dependent cys-LT generation when provided with IL-4 and SCF; this occurred without changes in PGD2 generation or histamine exocytosis relative to hMCs primed with IL-4 alone. None of these cytokines, either alone or in combination, substantially altered the levels of cytosolic phospholipase A2 (cPLA2), 5-lipoxygenase (5-LO), or 5-LO activating protein (FLAP) protein expression by hMCs. In contrast, IL-4 priming dramatically induced the steady-state expression of leukotriene C4 synthase (LTC4S) mRNA within 6 h, and increased the expression of LTC4S protein and functional activity in a dose- and time-dependent manner, with plateaus at 10 ng/ml and 5 d, respectively. Priming by either IL-3 or IL-5, with or without IL-4, supported the localization of 5-LO to the nucleus of hMCs. Thus, different Th2-derived cytokines target distinct steps in the 5-LO/LTC4S biosynthetic pathway (induction of LTC4S expression and nuclear import of 5-LO, respectively), each of which is necessary for a full integrated functional response to IgE-dependent activation, thus modulating the effector phenotype of mature hMCs.