College of Pharmacy, Yeungnam University, Gyeongsan, Korea.
College of Pharmacy, Yeungnam University, Gyeongsan, Korea; School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
J Allergy Clin Immunol. 2014 Sep;134(3):714-721.e7. doi: 10.1016/j.jaci.2014.05.001. Epub 2014 Jun 17.
Extracellular signal-regulated kinases 1/2 (ERK1/2) make important contributions to allergic responses via their regulation of degranulation, eicosanoid production, and cytokine expression by mast cells, yet the mechanisms underlying their positive effects on FcεRI-dependent signaling are not fully understood. Recently, we reported that mast cell activation and anaphylaxis are negatively regulated by AMP-activated protein kinase (AMPK). However, little is known about the relationship between ERK1/2-mediated positive and the AMPK-mediated negative regulation of FcεRI signaling in mast cells.
We investigated possible interactions between ERK1/2 and AMPK in the modulation of mast cell signaling and anaphylaxis.
Wild-type or AMPKα2(-/-) mice, or bone marrow-derived mast cells obtained from these mice, were treated with either chemical agents or small interfering RNAs that modulated the activity or expression of ERK1/2 or AMPK to evaluate the functional interplay between ERK1/2 and AMPK in FcεRI-dependent signaling.
The ERK1/2 pathway inhibitor U0126 and the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside similarly inhibited FcεRI-mediated mast cell signals in vitro and anaphylaxis in vivo. ERK1/2-specific small interfering RNA also mimicked this effect on FcεRI signals. Moreover, AMPKα2 knockdown or deficiency led to increased FcεRI-mediated mast cell activation and anaphylaxis that were insensitive to U0126 or activator 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside, suggesting that the suppression of FcεRI signals by the inhibition of the ERK1/2 pathway relies largely on AMPK activation. ERK1/2 controlled AMPK activity by regulating its subcellular translocation.
ERK1/2 ablated the AMPK-dependent negative regulatory axis, thereby activating FcεRI signals in mast cells.
细胞外信号调节激酶 1/2（ERK1/2）通过调节肥大细胞的脱颗粒、类花生酸的产生和细胞因子的表达，对过敏反应做出重要贡献，但ERK1/2 对 FcεRI 依赖性信号的正向作用的机制尚不完全清楚。最近，我们报道了肥大细胞的激活和过敏反应受到 AMP 激活的蛋白激酶（AMPK）的负调控。然而，ERK1/2 介导的正调节和 AMPK 介导的肥大细胞 FcεRI 信号负调节之间的关系知之甚少。
我们研究了 ERK1/2 与 AMPK 在调节肥大细胞信号和过敏反应中的相互作用。
用化学试剂或调节 ERK1/2 或 AMPK 活性或表达的小干扰 RNA 处理野生型或 AMPKα2（-/-）小鼠或从小鼠骨髓中获得的肥大细胞，以评估 ERK1/2 和 AMPK 在 FcεRI 依赖性信号转导中的功能相互作用。
ERK1/2 途径抑制剂 U0126 和 AMPK 激活剂 5-氨基咪唑-4-甲酰胺-1-β-4-核糖呋喃苷在体外同样抑制 FcεRI 介导的肥大细胞信号和体内过敏反应。ERK1/2 特异性小干扰 RNA 也模拟了这种对 FcεRI 信号的作用。此外，AMPKα2 敲低或缺失导致 FcεRI 介导的肥大细胞激活和过敏反应增加，对 U0126 或激活剂 5-氨基咪唑-4-甲酰胺-1-β-4-核糖呋喃苷不敏感，表明 ERK1/2 途径的抑制主要依赖于 AMPK 的激活来抑制 FcεRI 信号。ERK1/2 通过调节其亚细胞易位来控制 AMPK 活性。
ERK1/2 通过调节 AMPK 依赖性负向调节轴，从而激活肥大细胞中的 FcεRI 信号。
