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

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.

Endoplasmic reticulum stress regulates oxygen‐glucose deprivation‐induced parthanatos in human SH‐SY5Y cells via improvement of intracellular ROS

“…On the one hand, ROS could lead to DNA strand breaks via causing oxidative damage of nucleic acids . On the other hand, ROS could induce ERK phosphorylation, and the phosphorylated ERK has direct regulatory effect on DNA damage‐induced PARP‐1 activation . In this study, we found that OGD induced time‐dependent overproduction of intracellular ROS, and suppression of ROS prevented markedly expressional upregulation of PARP‐1 and PAR polymer.…”

“…Zheng et al reported that exogenous H 2 O 2 induced expressional upregulation of PARP‐1 and obvious accumulation of PAR polymer in glioma cells . Moreover, Akhiani et al found that exogenous H 2 O 2 could trigger PARP‐1‐dependent accumulation of PAR polymer in myeloid cells . Although it is still elusive why ROS could activate PARP‐1, previous studies suggest ROS might overactivate PARP‐1 via two pathways.…”

“…of PAR polymer in myeloid cells. 28 Although it is still elusive why ROS could activate PARP-1, previous studies suggest ROS might overactivate PARP-1 via two pathways. On the one hand, ROS could lead to DNA strand breaks via causing oxidative damage of nucleic acids.…”

Vanadium pentoxide increased PTEN and decreased SHP1 expression in NK-92MI cells, affecting PI3K-AKT-mTOR and Ras-MAPK pathways

“…All these results suggest that cell death in vanadium-exposed NK cells is secondary to non-caspase-dependent signaling. Consequently, NK cell death observed here might be a consequence of increased ERK and MEK activation (as noted in Akhiani et al 2014), since phosphorylation of BAD could not be initiated by Akt/protein kinase B (since V 2 O 5 decreased Akt expression).…”

Adenanthin, a new inhibitor of thiol‐dependent antioxidant enzymes, impairs the effector functions of human natural killer cells

“…7 Reactive oxygen species (ROS)-induced NK cell dysfunction is considered one of the mechanisms of 'immune escape' at sites of solid tumour progression. 8 Furthermore, tumour-associated monocytes/macrophages 9 or myeloid cells 10 suppress NK cells in an oxidant-dependent manner. Oxidative stress is also responsible for the suppression of NK cell functions in non-malignant pathological conditions, such as uraemia 11,12 or atherosclerosis.…”