Human placental indoleamine 2,3-dioxygenase: cellular localization and characterization of an enzyme preventing fetal rejection.
In order to test the hypothesis (Munn, Zhou, Attwood, Bondarev, Conway, Marshall, Brown, Mellor, Science 281 (1998) 1191-1193) that localized placental tryptophan catabolism prevents immune rejection of the mammalian fetus, the cellular localization and characteristics of human placental indoleamine 2,3-dioxygenase (EC 1.13.11.42) were studied. The localization of indoleamine 2, 3-dioxygenase activity was determined quantitatively using cell fractionation by differential and discontinuous sucrose gradient centrifugation. Enzyme activity was looked for in isolated brush border microvillous plasma membranes of placental syncytiotrophoblast. We found that this membrane preparation (which showed a 32.4-fold purification from the starting homogenate with reference to the activity of a membrane marker enzyme, alkaline phosphatase (EC 3.1.3.1)) was strongly negatively enriched with indoleamine 2,3-dioxygenase (which showed a one twenty-fifth decrease in its specific activity). Placental indoleamine 2, 3-dioxygenase is thus not expressed in the maternal facing brush border membrane of syncytiotrophoblast. 1-Methyl-DL-tryptophan which was used by Munn et al. as a key experimental tool for inhibiting indoleamine 2,3-dioxygenase in the murine model showed a competitive inhibition of human placental indoleamine 2,3-dioxygenase with L-tryptophan. The hypothesis, based on experiments performed in mouse, may therefore be applicable to avoidance of immune rejection of the fetus in human pregnancy.
Kudo
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Y
Department of Human Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, UK. yoshiki.kudo@anat.ox.ac.uk
Boyd
C A
CA
D001205:Ascorbic Acid / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D002374:Catalase / Q000494:pharmacology; D003593:Cytoplasm / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005333:Fetus / Q000276:immunology; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007527:Isoenzymes / Q000378:metabolism; D007737:Kynurenine / Q000031:analogs & derivatives / Q000096:biosynthesis; D008751:Methylene Blue / Q000494:pharmacology; D008871:Microvilli / Q000201:enzymology; D010920:Placenta / Q000201:enzymology* / Q000276:immunology; D013347:Subcellular Fractions / Q000201:enzymology; D013379:Substrate Specificity; D014327:Trophoblasts / Q000201:enzymology / Q000648:ultrastructure; D014364:Tryptophan / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D014366:Tryptophan Oxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism*
D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007527:Isoenzymes; C007772:N'-formylkynurenine; D007737:Kynurenine; D014364:Tryptophan; D002374:Catalase; D014366:Tryptophan Oxygenase; D001205:Ascorbic Acid; D008751:Methylene Blue