IFN-gamma-induced IDO and WRS expression in microglia is differentially regulated by IL-4.
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.
Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, California 92037, USA.
Manisha C
MC
Yadav
E M E
EM
Burudi
Mehrdad
M
Alirezaei
Claudia C
CC
Flynn
Debbie D
DD
Watry
Caroline M
CM
Lanigan
Howard S
HS
Fox
D000818:Animals; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology*; D018793:Interleukin-13 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D054648:Protein Phosphatase 2; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014369:Tryptophan-tRNA Ligase / Q000235:genetics / Q000378:metabolism*
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D018793:Interleukin-13; D050794:STAT1 Transcription Factor; D050800:STAT6 Transcription Factor; C494080:Stat1 protein, mouse; C494100:Stat6 protein, mouse; D015847:Interleukin-4; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D014369:Tryptophan-tRNA Ligase