Mer tyrosine kinase (MerTK) promotes macrophage survival following exposure to oxidative stress
Mer tyrosine kinase (MerTK) promotes macrophage survival following exposure to oxidative stress
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DOI：
10.1189/jlb.0608334
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发表时间：
2009-07-01
影响因子：
5.5
通讯作者：
Graham, Douglas K.
中科院分区：
文献类型：
--
作者：
Anwar, Adil;Keating, Amy K.;Graham, Douglas K.
MerTK在正常的巨噬细胞生理中起着几个重要的作用，包括调节细胞因子的分泌和清除凋亡细胞。其他类型细胞中的MER信号，包括异位过度表达RTK的恶性肿瘤细胞，会导致下游生存通路的激活。我们探索了Mer在暴露于氧化应激的巨噬细胞中具有生存作用的假设。H_2O_2处理小鼠巨噬细胞和J774细胞后，以浓度依赖的方式迅速刺激Mer的磷酸化。Mer的磷酸化依赖于配体Gas6，华法林或MerFc(Mer胞外区与人Ig Fc部分的融合蛋白)是Gas6活性的抑制剂，可阻断H_2O_2介导的Mer的激活。与H_2O_2刺激的Mer-KO巨噬细胞相比，WT-Mer阳性巨噬细胞的抗凋亡信号包括PACT和PERK_(1/2)显著增加(分别是3倍和4.5倍)。以一致的方式，Mer的表达导致促凋亡指标PARP和Caspase-3的切割减少。此外，MER使暴露于过氧化氢的原代巨噬细胞的细胞存活率提高了一倍。这些数据代表了氧化应激反应中Mer激活的第一个报告，并证明了Mer RTK在涉及氧化应激环境的疾病状态下促进巨噬细胞存活的能力。J.Leukoc。比奥尔。86：73-79；2009。
The MerTK plays several important roles in normal macrophage physiology, including regulation of cytokine secretion and clearance of apoptotic cells. Mer signaling in other cell types, including malignant cells that ectopically overexpress the RTK, leads to downstream prosurvival pathway activation. We explored the hypothesis that Mer has a prosurvival role in macrophages exposed to oxidative stress. H2O2 treatment of peritoneal exudate murine macrophages and J774 cells rapidly stimulated Mer phosphorylation in a concentration- dependent manner. Mer phosphorylation was dependent on the ligand Gas6, as treatment with warfarin or MerFc (a fusion protein of the extracellular domain of Mer and the Fc portion of human Ig), inhibitors of Gas6 activity, blocked H2O2-mediated activation of Mer. Antiapoptotic signals including pAkt and pErk 1/2 were increased dramatically (threefold and 4.5-fold, respectively) in WT Mer-positive macrophages compared with Mer KO macrophages stimulated with H2O2. In a consistent manner, Mer expression led to decreased cleavage of proapoptotic indicators PARP and Caspase-3. Furthermore, Mer provided up to twofold enhanced cellular survival to primary macrophages exposed to H2O2. These data represent the first report of Mer activation in response to oxidative stress and demonstrate the ability of Mer RTK to promote macrophage survival in disease states that involve an oxidative stress environment. J. Leukoc. Biol. 86: 73-79; 2009.