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 by the kit ligand.
Mouse bone marrow-derived mast cells (BMMC) store and release serotonin whose synthesis is initiated by tryptophan 5-monooxygenase. (6R)-H4biopterin serves as the natural cofactor for this reaction. GTP cyclohydrolase I catalyzes the first and rate-limiting step of its synthesis. In this study we demonstrate that among a panel of growth-promoting cytokines including kit ligand (KL), interleukin 3 (IL-3), IL-4, IL-9, and nerve growth factor, KL selectively enhances the synthesis of H4biopterin through up-regulation of GTP cyclohydrolase I activity to 6.2-fold levels. The activities of the subsequent enzymes 6-pyruvoyl-H4pterin synthase and sepiapterin reductase remain unaffected. The activity of tryptophan 5-monooxygenase was selectively enhanced 4.5-fold by the combination of IL-3 with KL. All other factors could not substitute for KL. The constitutive high activity of aromatic L-amino acid decarboxylase is not different in cells cultured in IL-3 and/or KL. In consequence, 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 causes 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.
Ziegler
I
I
GSF-Institut für Klinische Molekularbiologie und Tumorgenetik, München, Germany.
Hültner
L
L
Egger
D
D
Kempkes
B
B
Mailhammer
R
R
Gillis
S
S
Rödl
W
W
D006916:5-Hydroxytryptophan / Q000302:isolation & purification / Q000378:metabolism; D000818:Animals; D001708:Biopterins / Q000302:isolation & purification / Q000378:metabolism; D001853:Bone Marrow / Q000201:enzymology*; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D006136:GTP Cyclohydrolase / Q000378:metabolism*; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology*; D007377:Interleukin-3 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology; D007700:Kinetics; D008407:Mast Cells / Q000166:cytology / Q000201:enzymology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D011994:Recombinant Proteins / Q000494:pharmacology; D012701:Serotonin / Q000096:biosynthesis / Q000302:isolation & purification / Q000378:metabolism*; D019089:Stem Cell Factor; D014365:Tryptophan Hydroxylase / Q000378:metabolism*
D016298:Hematopoietic Cell Growth Factors; D007377:Interleukin-3; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D015847:Interleukin-4; D001708:Biopterins; D012701:Serotonin; D006916:5-Hydroxytryptophan; D014365:Tryptophan Hydroxylase; D006136:GTP Cyclohydrolase