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.
Yadav
Manisha C
MC
Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, California 92037, USA.
Burudi
E M E
EM
Alirezaei
Mehrdad
M
Flynn
Claudia C
CC
Watry
Debbie D
DD
Lanigan
Caroline M
CM
Fox
Howard S
HS
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