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Role of the ERK Pathway for Oxidant-Induced Parthanatos in Human Lymphocytes

Journal article
Authors Aliasghar Akhiani
Olle Werlenius
Johan Aurelius
Charlotta Movitz
Anna Martner
Kristoffer Hellstrand
Fredrik Bergh Thorén
Published in Plos One
Volume 9
Issue 2
ISSN 1932-6203
Publication year 2014
Published at Sahlgrenska Cancer Center
Institute of Medicine
Institute of Biomedicine, Department of Infectious Medicine
Language en
Links dx.doi.org/10.1371/journal.pone.008...
https://gup.ub.gu.se/file/127280
Keywords INDUCED CELL-DEATH, ACTIVATED PROTEIN-KINASE, ACUTE MYELOID-LEUKEMIA, NATURAL-KILLER-CELLS, REACTIVE OXYGEN METABOLITES, SIGNAL-REGULATED, KINASE, PERIPHERAL T-CELLS, HYDROGEN-PEROXIDE, NK CELLS, HISTAMINE, DIHYDROCHLORIDE
Subject categories Cancer and Oncology

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.

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