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

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.活性氧簇（reactive oxygen species，ROS）由髓系细胞产生，作为抗微生物的防御策略。然而，ROS亦可在邻近淋巴细胞中触发依赖于多聚ADP核糖聚合酶1（poly(ADP-ribose) polymerase 1，PARP-1）的帕拉托斯细胞死亡（parthanatos），这一过程被提出为多种癌症的免疫逃逸机制。本研究探讨了丝裂原活化蛋白激酶（mitogen-activated protein kinases，MAPKs），尤其是细胞外调节蛋白激酶（extracellular signal-regulated kinase，ERK）在ROS诱导的、介导淋巴细胞帕拉托斯细胞死亡的信号转导通路中的作用。我们发现，ERK1/2磷酸化抑制剂可在氧化应激条件下维持自然杀伤（natural killer，NK）细胞介导的细胞毒性，并可使NK细胞与CD8+ T淋巴细胞免受产ROS单核细胞诱导的细胞死亡。抑制ERK1/2磷酸化还可保护淋巴细胞免受外源性过氧化氢（hydrogen peroxide，H₂O₂）以及黄嘌呤氧化酶或葡萄糖氧化酶产生的ROS诱导的细胞死亡。淋巴细胞暴露于ROS后不久即可检测到ERK1/2的磷酸化。产ROS的髓系细胞与外源性H₂O₂可触发PARP-1依赖的多聚ADP核糖（poly ADP-ribose，PAR）积累，而ERK通路抑制剂可阻断这一过程。ROS诱导的ERK1/2磷酸化不依赖于PARP-1。本研究结果提示ERK1/2在ROS诱导的淋巴细胞帕拉托斯细胞死亡中发挥作用，且ERK通路或可作为保护淋巴细胞免受氧化应激损伤的治疗靶点。