Regulation of Leukotriene C4-and B4-synthesis in allergic diseases

我们提出了一种假设，即LTC4和LTB4的产生受四种LT合成酶--磷脂酶A2(PLA2)、5-脂氧合酶(5-LO)、LTC4合成酶和LTA4水解酶通过不同的机制调节。我们利用培养的大鼠嗜碱性白血病细胞来研究这些可能的调控机制，这些细胞是癌变的粘膜型肥大细胞。我们证明，维生素A的混合物维甲酸可以特异性地诱导LTC4合成酶活性，但不能诱导LTA4水解酶、5-LO或PLA2的活性。这种对LTC4合成酶活性的诱导被地塞米松抑制。我们进一步研究了维甲酸是否增加了LTC4合成酶的mRNA丰度。维甲酸没有改变LTC4合成酶的mRNA水平，表明维甲酸诱导的LTC4合成酶活性是转录后调节的。我们还使用相同的细胞，研究了各种抗炎和抗过敏药物如环孢菌素、FK506、氮卓斯汀、和厚朴酚和厚朴酚是否以及如何抑制这些LT合成酶的活性。这些药物大多抑制LTC4和LTB4的合成。然而，不同的药物抑制机制是不同的。还需要进一步的调查。

We have proposed a hypothesis that the production of LTC4 and LTB4, important chemical mediators in allergic and inflammatory diseases, are regulated at four LT-synthetic enzymes, phospholipase A2 (PLA2), 5-lipoxygenase (5-LO), LTC4 synthase and LTA4 hydrolase, by various different mechanisms. We investigated to clarify these possible regulatory mechanisms by using cultured rat basophilic leukemia cells which were cancerous mucosal type mast cells. We demonstrated that retinoic acid, a deliberative of vitamin A,specifically induced the activity of LTC4 synthase activity but not LTA4 hydrolase, 5-LO or PLA2. This induction of the LTC4 synthase activity was suppressed by dexamethasone. We further investigated whether mRNA abundance of LTC4 synthase was increased by retinoic acid. Retinoic acid did not change mRNA level of the LTC4 synthase, indicating that retinoic acid induced LTC4 synthase activity was post-transcriptionally regulated.We also investigated whether and how activities of these LT synthetic enzymes are inhibited by various kinds of anti-inflammatory and anti-allergic agents such as cyclosporin, FK506, azerastine, honokiol and Kanpo-medicines by using the same cells. Most of these drugs inhibited the synthesis of LTC4 and LTB4. However, the inhibitory mechanisms are varied from one agent to others. Further investigations are needed.