Discovery of a polysaccharide from the fruiting bodies of Lepista sordida as potent inhibitors of indoleamine 2, 3-dioxygenase (IDO) in HepG2 cells via blocking of STAT1-mediated JAK-PKC-δ signaling pathways

Carbohydr Polym. 2018 Oct 1:197:540-547. doi: 10.1016/j.carbpol.2018.05.052. Epub 2018 May 21.

Abstract

The present study examined the role of a polysaccharide (LSP, 25 and 100 μg/ml) from the fruiting bodies of Lepista sordid on the immunosuppressive enzyme indoleamine 2, 3-dioxygenase (IDO) in HepG2 cells, and the possible mechanism of action. IDO expression and kynurenine production from LSP-treated HepG2 cells following IFN-γ stimulation were dramatically inhibited by LSP treatment. In line with this, the medium of HepG2 cells pretreated with LSP improved the survival rate of primary CD4+ and CD8+ T cells as compared with IFN-γ-treated control cells. Moreover, tyrosine 701 and serine 727 phosphorylation of STAT1 were dramatically reduced by LSP pretreatment in IFN-γ-stimulated HepG2 cells. Furthermore phosphorylation of JAK-1 and JAK-2 was also inhibited by LSP. Additionally, two IDO promoters (GAS and ISRE) were inhibited in cells pretreated with LSP prior to IFN-γ exposure. These findings suggest that LSP exerts antitumor effects on HepG2 cells by inhibiting IDO via JAK-PKC-δ-STAT1 signaling pathway.

Keywords: Hepatocellular carcinoma (HCC); IFN-γ; Indoleamine 2,3-dioxygenase (IDO); JAK-PKC-δ-STAT1 signaling pathway; Lepista sordid polysaccharide.

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Drug Discovery
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / isolation & purification
  • Enzyme Inhibitors / pharmacology*
  • Fruiting Bodies, Fungal / chemistry
  • Hep G2 Cells
  • Humans
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
  • Janus Kinase 1 / antagonists & inhibitors*
  • Janus Kinase 1 / metabolism
  • Lepisma / chemistry
  • Polysaccharides / chemistry
  • Polysaccharides / isolation & purification
  • Polysaccharides / pharmacology*
  • Protein Kinase C-delta / antagonists & inhibitors*
  • Protein Kinase C-delta / metabolism
  • STAT1 Transcription Factor / antagonists & inhibitors*
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Polysaccharides
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • JAK1 protein, human
  • Janus Kinase 1
  • Protein Kinase C-delta