Induction of apoptosis by 7,8-dihydroneopterin: involvement of radical formation

Immunobiology. 2001 May;203(4):629-41. doi: 10.1016/s0171-2985(01)80012-7.

Abstract

Interferon-gamma is a cytokine released in large amounts during cell-mediated immune response. It induces the expression of proinflammatory cytokines and enhances macrophage capacity to secrete reactive oxygen intermediates and the pteridines neopterin and 7,8-dihydroneopterin. To assay the role of these pteridines in the immune system several studies were performed. Thereby, 7,8-dihydroneopterin was found to induce apoptosis in T lymphocytes. In this study we report that caspases are involved in 7,8-dihydroneopterin-mediated apoptosis in Jurkat T cells. In connection with this result we found that 7,8-dihydroneopterin can increase Fas ligand expression detected in Western blot analysis and promoter reporter assays. Antioxidants potently reduced the effect of 7,8-dihydroneopterin on Fas ligand promoter activation suggesting an involvement of oxidative stress. In further investigations, ESR-measurements were performed to evaluate the role of 7,8-dihydroneopterin in the formation of radicals. We found that the pteridine in combination with the spin trap DMPO induces the production of DMPO-OH spin adducts. This reaction was sensitive to the presence of chelated metal ions and could completely be blocked by the addition of superoxide dismutase. These data suggest that 7,8-dihydroneopterin in aqueous solution leads to the formation of .OH radicals via generation of superoxide anion. We hypothesize that an overproduction of radicals caused by high levels of 7,8-dihydroneopterin is likely to be responsible for the pro-apoptotic effects observed in cell cultures and possibly contributes to the pathogenesis of diseases involving immune activation and elevated concentrations of neopterin-derivatives.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Cyclic N-Oxides
  • Electron Spin Resonance Spectroscopy
  • Fas Ligand Protein
  • Humans
  • Hydroxyl Radical / metabolism
  • Interferon-gamma / metabolism
  • Jurkat Cells
  • Membrane Glycoproteins / metabolism
  • Neopterin / analogs & derivatives
  • Pteridines / pharmacology*
  • Reactive Oxygen Species / metabolism
  • Spin Labels
  • T-Lymphocytes / cytology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism

Substances

  • Cyclic N-Oxides
  • FASLG protein, human
  • Fas Ligand Protein
  • Membrane Glycoproteins
  • Pteridines
  • Reactive Oxygen Species
  • Spin Labels
  • 7,8-dihydroneopterin
  • Hydroxyl Radical
  • 2,2-dimethyl-5-hydroxy-1-pyrrolidinyloxy
  • Neopterin
  • Interferon-gamma