Role of the ERK pathway for oxidant-induced parthanatos in human lymphocytes

PLoS One. 2014 Feb 21;9(2):e89646. doi: 10.1371/journal.pone.0089646. eCollection 2014.

Abstract

Reactive oxygen species (ROS) are formed by myeloid cells as a defense strategy against microorganisms. ROS however also trigger poly(ADP-ribose) polymerase 1- (PARP-1) dependent cell death (parthanatos) in adjacent lymphocytes, which has been forwarded as a mechanism of immune escape in several forms of cancer. The present study assessed the role of mitogen-activated protein kinases (MAPKs), in particular the extracellular signal-regulated kinase (ERK), in ROS-induced signal transduction leading to lymphocyte parthanatos. We report that inhibitors of ERK1/2 phosphorylation upheld natural killer (NK) cell-mediated cytotoxicity under conditions of oxidative stress and rescued NK cells and CD8(+) T lymphocytes from cell death induced by ROS-producing monocytes. ERK1/2 phosphorylation inhibition also protected lymphocytes from cell death induced by exogenous hydrogen peroxide (H2O2) and from ROS generated by xanthine oxidase or glucose oxidase. Phosphorylation of ERK1/2 was observed in lymphocytes shortly after exposure to ROS. ROS-generating myeloid cells and exogenous H2O2 triggered PARP 1-dependent accumulation of poly ADP-ribose (PAR), which was prevented by ERK pathway inhibitors. ERK1/2 phosphorylation was induced by ROS independently of PARP-1. Our findings are suggestive of a role for ERK1/2 in ROS-induced lymphocyte parthanatos, and that the ERK axis may provide a therapeutic target for the protection of lymphocytes against oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Cells, Cultured
  • Coculture Techniques
  • Cytotoxicity, Immunologic
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Flavonoids / pharmacology
  • Humans
  • Hydrogen Peroxide / pharmacology*
  • Killer Cells, Natural / metabolism
  • MAP Kinase Signaling System*
  • Oxidants / pharmacology*
  • Oxidants / physiology
  • Oxidative Stress
  • Phosphorylation
  • Poly (ADP-Ribose) Polymerase-1
  • Poly Adenosine Diphosphate Ribose / metabolism
  • Poly(ADP-ribose) Polymerases / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Protein Processing, Post-Translational
  • T-Lymphocytes / physiology*

Substances

  • Flavonoids
  • Oxidants
  • Protein Kinase Inhibitors
  • Poly Adenosine Diphosphate Ribose
  • Hydrogen Peroxide
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • Extracellular Signal-Regulated MAP Kinases
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Grant support

This study was supported by the Swedish Cancer Foundation (Cancerfonden), the Torsten and Ragnar Söderberg Foundation, the Swedish Research Council/Medicine, ALF Funds at Sahlgrenska University Hospital, the Ingabritt and Arne Lundberg Foundation, the Assar Gabrielsson Foundation, the Lundgren Research Foundation, and by the Royal Society of Arts and Sciences in Göteborg. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.