Modulation of cellular tryptophan metabolism in human fibroblasts by transforming growth factor-β: Selective inhibition of indoleamine 2,3- dioxygenase and tryptophanyl-tRNA synthetase gene expression

Weihua Yuan, Alicia Collado-Hidalgo, Tatyana Yufit, Milton Taylor, John Varga*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

Abstract

Alterations in the rate of cellular tryptophan metabolism are involved in mediating important biological activities associated with cytokines and growth factors. Indoleamine 2,3-dioxygenase (IDO) and tryptophanyl-tRNA synthetase are enzymes of tryptophan metabolism whose expression in a variety of cells and tissues is highly inducible by interferon-γ (IFN-γ). Transforming growth factor-β (TGF-β) antagonizes many cellular responses to IFN-γ. The interaction of these two cytokines plays an important role in maintaining homeostasis during inflammation and repair. In human skin and synovial fibroblasts in vitro, TGF-β caused time-and dose-dependent abrogation of IFN-γ-stimulated expression of IDO and tryptophanyl-tRNA synthetase mRNAs. The inhibition was selective and did not appear to be due to down-regulation of IFN-γ signaling by TGF-β. In parallel with its effect on IDO mRNA expression, TGF-β caused a marked reduction in intracellular IDO protein levels and abrogated IDO activity and tryptophan catabolism in these cells induced by IFN-γ. IFN-γ caused a rapid and striking increase in the amount of IDO heterogeneous nuclear pre-mRNA and induced transcription of the IDO gene, as demonstrated by transient transfection assays. TGF-β partially reversed this stimulation. IFN regulatory factor (IRF)-1 and stat1 are cellular intermediates in IFN signaling. Both are implicated in activation of IDO transcription in response to IFN-γ. The stimulation by IFN-γ of IRF-1 protein and mRNA expression was not prevented by treatment of fibroblasts with TGF-β. Furthermore, gel mobility shift assays indicated that TGF-β did not inhibit the induction of stat1 and IRF-1 binding activity to their cognate DNA recognition sites in the IDO gene promoter. In contrast, the stability of IDO mRNA transcripts was reduced in fibroblasts treated with TGF-β, as shown by determination of mRNA half-lives following blockade of transcription with 5,6-dichlorobenzimidazole riboside. The findings indicate that TGF-β prevents the induction of IDO and tryptophanyl-RNA synthetase gene expression in fibroblasts. The repression of IDO expression by TGF-β is mediated at both transcriptional and posttranscriptional levels. These results implicate TGF-β in the negative regulation of tryptophan metabolism, provide evidence for the molecular basis of this regulation, and indicate that cellular tryptophan metabolism is under tight immunological control.

Original languageEnglish (US)
Pages (from-to)174-186
Number of pages13
JournalJournal of Cellular Physiology
Volume177
Issue number1
DOIs
StatePublished - Oct 1998

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

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