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IFN-gamma-induced IDO and WRS expression in microglia is differentially regulated by IL-4

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Title IFN-gamma-induced IDO and WRS expression in microglia is differentially regulated by IL-4
 
Creator Yadav, M.C.
Burudi, E.M.E.
Alirezaei, M.
Flynn, C.C.
Watry, D.D.
Lanigan, C.M.
Fox, H.S.
 
Subject GENETICS
ANIMAL DISEASES
 
Description Indoleamine 2,3-dioxygenase (IDO), a tryptophan catabolizing enzyme, has been implicated in the pathogenesis of various neurological disorders. IDO expression is induced by IFN-gamma and leads to neurotoxicity by generating quinolinic acid. Additionally, it inhibits the immune response through both tryptophan depletion and generating other tryptophan catabolites. IL-4 and IL-13 have been shown to control IDO expression by antagonizing the effects of IFN-gamma in different cell types. Here, we investigated the effects of these cytokines on IDO expression in microglia. Interestingly, we observed that both IL-4 and IL-13 greatly enhanced IFN-gamma-induced IDO expression. However, tryptophanyl-tRNA synthetase (WRS), which is coinduced with IDO by IFN-gamma, is downregulated by IL-4 and IL-13. The effect of IL-4 and IL-13 was independent of STAT-6. Modulation of IDO but not WRS was eliminated by inhibition of protein phosphatase 2A (PP2A) activity. The phosphatidylinositol 3-kinase (PI3K) pathway further differentiated the regulation of these two enzymes, as inhibiting the PI3K pathway eliminated IFN-gamma induction of IDO, whereas such inhibition greatly enhanced WRS expression. These findings show discordance between modulations of expression of two distinct enzymes utilizing tryptophan as a common substrate, and raise the possibility of their involvement in regulating immune responses in various neurological disorders.
 
Date 2010-06-13T16:00:50Z
2010-06-13T16:00:50Z
2007-07-27
 
Type Journal Article
 
Identifier Yadav, M.C.; Burudi, E.M.; Alirezaei, M.; Flynn, C.C.; Watry, D.D.; Lanigan, C.M., Fox, H.S. 2007. IFN-gamma-induced IDO and WRS expression in microglia is differentially regulated by IL-4. Glia 55(13):1385-1396.
http://hdl.handle.net/10568/1864
 
Language en
 
Source Glia