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

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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.