IN A CONCERTED ACTION KIT-LIGAND AND INTERLEUKIN-3 CONTROL THE SYNTHESIS OF SEROTONIN IN MURINE BONE MARROW-DERIVED MAST-CELLS - UP-REGULATION OF GTP CYCLOHYDROLASE-I AND TRYPTOPHAN 5-MONOOXYGENASE ACTIVITY BYTHE KIT-LIGAND

Mouse bone marrow-derived mast cells (BMMC) store and release serotoni n whose synthesis is initiated by tryptophan 5-monooxygenase. (6R)-H4b iopterin serves as the natural cofactor for this reaction. GTP cyclohy drolase I catalyzes the first and rate-limiting step of its synthesis. In this study we demonstrate that among a panel of growth-promoting c ytokines including kit ligand (KL), interleukin 3 (IL-3), IL-4, IL-9, and nerve growth factor, KL selectively enhances the synthesis of H4bi opterin through up-regulation of GTP cyclohydrolase I activity to 6.2- fold levels. The activities of the subsequent enzymes 6-pyruvoyl-H4pte rin synthase and sepiapterin reductase remain unaffected. The activity of tryptophan 5-monooxygenase was selectively enhanced 4.5-fold by th e combination of IL-3 with KL. All other factors could not substitute for KL. The constitutive high activity of aromatic L-amino acid decarb oxylase is not different in cells cultured in IL-3 and/or KL. In conse quence, the concerted action of IL-3 and KL on the GTP cyclohydrolase I and the tryptophan 5-monooxygenase reaction enhances the production of serotonin to about 20-fold levels. Additionally, KL specifically ca uses the release of about half of total serotonin produced. Hence, our data demonstrate a novel role of these cytokines for the function of mouse BMMC and provide a coherent view of the regulation of serotonin synthesis in this cell type.