Bio-pharmacological study for the action of bioactive molecules which control the reciprocal relationship between mast cells and other inflammatory cells

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We have investigated the basic problems about the action mechanisms of bioactive molecules which control the reciprocal relation between mast cells and other inflammatory cells, focused on following three points. 1. Studies on histamine synthesis in mast cells. (1) Isolation of L-histidine decarboxylase from mouse mastocytoma P-815 cells was performed, and is cDNA-derived amino acid sequence was determined. (2) Synergistic effects of de novo synthesis of L-histidine decarboxylase and its mRNA was found in cultured mast cells treated with two different stimulants; dexamethasone and 12-O-tetradecanoylphorbol 13-acetate, or dibutyryl cAMP and calcium ionophore A23187. (3) Possible post-translational processing of L-histidine decarboxylase was suspected. 2. Studies on cellular interaction between mast cells and endothelial cells or platelets. (1) PGD_2, is metabolite DELTA^<12>-PGJ_2, from mast cells inhibited cell growth of, but induced 31kDa protein, which was hemeoxygenase, in endothelial cells. (2) PGI_2 from endothelial cells stimulated cAMP synthesis via Gs-coupled adenylate cyclase. (3) Differential regulation of thrombin- or ATP-induced mobilization of intracellular Ca_<2+> by PGI_2 receptor in mastocytoma cells. (4) PGI_2 receptors in mastocytoma cells and platelets were identified by use of irreversible specific photoaffinity probe. 3. Studies on structure and function of prostaglandin E receptor subtypes. and on their mRNA expression in various tissues. (1) Cloning and expression of cDNAs for mouse prostaglandin E receptors, EP_3 subtype and EP_2 subtypes. (2) Functional cDNA for two isoforms of PGE receptor EP_3 subtype with different C-terminal domains which were derived from alternative splicing were obtained. Two forms determined ligand-binding affinity and sensitivity of agonist-induced desensitization.