Selective metabolism of kynurenine in the spleen in the absence of indoleamine 2,3-dioxygenase induction.
The kynurenine pathway of L-tryptophan degradation is differentially regulated dependent on the level of immune system activation. During inflammation and disease, activity of the hepatocellular enzyme tryptophan 2,3-dioxygenase (TDO) decreases and a second enzyme, indoleamine 2,3-dioxygenase (IDO), is induced in extrahepatic sites. Substantial formation of a metabolise downstream of this step, quinolinic acid (Quin), subsequently occurs only in select regions of the lymphoid tissues, such as spleen, in a temporally restricted manner. The goal of this study was to determine the localization of Quin in unstimulated mice under conditions where rate-limiting control of the pathway by both TDO and IDO was by-passed. Supplementation of drinking water with L-kynurenine, a pathway intermediate that lies between tryptophan and Quin, resulted in a dose-dependent increase in Quin immunoreactivity in the follicles and discontinuous regions of the marginal zones of the spleen. Strongly immunoreactive cells in the periarteriole lymphoid sheaths adopted a highly reactive morphology despite the lack of immunostimulation and IDO induction. In contrast, a patchy to diffuse pallor of staining was observed in the liver parenchyma with 1 and 10 mM L-kynurenine ingestion, respectively. These data show that selective tryptophan metabolism can occur in discrete subcompartments of the lymphoid tissues beyond the level of IDO. In vivo manipulation of Quin synthesis in the absence of IDO induction may serve as a model for studying regulation and function of the kynurenine pathway activation in the immune system.
Espey
M G
MG
Radiation Biology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA. sp@nih.gov
Namboodiri
M A
MA
D000818:Animals; D004790:Enzyme Induction; D005260:Female; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine / Q000008:administration & dosage / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011817:Rabbits; D013154:Spleen / Q000378:metabolism*; D014366:Tryptophan Oxygenase / Q000096:biosynthesis*
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine; D014366:Tryptophan Oxygenase