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

Manisha C. Yadav, E. M.E. Burudi, Mehrdad Alirezaei, Claudia C. Flynn, Debbie D. Watry, Caroline M. Lanigan, Howard S. Fox

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

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-γ 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-γ 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-γ-induced IDO expression. However, tryptophanyl-tRNA synthetase (WRS), which is coinduced with IDO by IFN-γ, 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 phosphatidyl-inositol 3-kinase (PI3K) pathway further differentiated the regulation of these two enzymes, as inhibiting the PI3K pathway eliminated IFN-γ 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.

Original languageEnglish (US)
Pages (from-to)1385-1396
Number of pages12
JournalGlia
Volume55
Issue number13
DOIs
StatePublished - Oct 2007

Keywords

  • Cytokine
  • Indoleamine 2,3-dioxygenase
  • Tryptophanyl-tRNA synthetase

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

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    Yadav, M. C., Burudi, E. M. E., Alirezaei, M., Flynn, C. C., Watry, D. D., Lanigan, C. M., & Fox, H. S. (2007). IFN-γ-induced IDO and WRS expression in microglia is differentially regulated by IL-4. Glia, 55(13), 1385-1396. https://doi.org/10.1002/glia.20544