中国神经再生研究(英文版) ›› 2019, Vol. 14 ›› Issue (8): 1430-1437.doi: 10.4103/1673-5374.253529

• 原著:退行性病与再生 • 上一篇    下一篇

过氧化氢介导促炎细胞-细胞信号传导:炎症的新治疗靶点?

  

  • 出版日期:2019-08-15 发布日期:2019-08-15
  • 基金资助:

    澳大利亚西悉尼大学研究生奖(APA)

Hydrogen peroxide mediates pro-inflammatory cell-to-cell signaling: a new therapeutic target for inflammation?

Dhanushka Gunawardena, Ritesh Raju, Gerald Münch   

  1. Department of Pharmacology, School of Medicine, Western Sydney University, Penrith, NSW, Australia
  • Online:2019-08-15 Published:2019-08-15
  • Contact: Gerald Münch, PhD, g.muench@westernsydney.edu.au.
  • Supported by:

    Australian Postgraduate Award (APA) Ph.D. fellowship by Western Sydney University to DG.

摘要:

长期以来已知过氧化氢在细胞内信号转导途径中起第二信使的作用,过氧化氢作为第二信使的这种性质被称为“氧化还原敏感的”信号转导。实验假设过氧化氢可以作为细胞外信号分子,因为它可以通过细胞膜扩散,能够将促炎信号从一个细胞转移到另一个细胞,从而充当真正的第一(细胞间)信使。实验结果显示,RAW 264.7巨噬细胞中响应于3种配体/配体组合干扰素-γ,脂多糖和鸡蛋清蛋白衍生的晚期糖基化终产物(CEA-AGE)的NO和TNF-α水平随过氧化氢清除剂过氧化氢酶浓度增高而降低;过氧化氢酶在最高浓度下抑制100%NO和40%TNF-α的产生。实验结果表明过氧化氢通过细胞膜进入细胞外空间并激活相邻细胞发挥了上述作用。由此认为,作为过氧化氢清除剂的化合物甚至可能不需要进入细胞即可起到对抗炎症的作用。

orcid: 0000-0002-4873-7779 (Gerald Münch)

关键词: 炎症, 糖化, 氧化还原信号, 细胞因子, 消炎药, 膜透性, 过氧化氢, 脂多糖, 干扰素-&gamma

Abstract:

Nitric oxide is now universally recognized as an extracellular signaling molecule. Nitric oxide, produced in one cell, diffuses across the extracellular space and acts with targets in an adjoining cell. In this study, we present proof that hydrogen peroxide – like nitric oxide – acts as a true first (intercellular) messenger for a multitude of pro-inflammatory ligands. RAW 264.7 macrophages were activated with three different ligands, lipopolysaccharide, interferon-gamma or advanced glycation end products in the presence of increasing concentrations of (hydrogen peroxide scavenging) catalase. As inflammatory readouts, nitric oxide and tumor necrosis factor were determined. We hypothesize that hydrogen peroxide travels between cells propagating the signal, then a certain percentage of the readout should be inhibited by catalase in a concentration-dependent manner. The experiment showed concentration-dependent inhibition of nitric oxide and tumor necrosis factor-α production in response to all three ligands/ligand combinations (interferon-gamma, lipopolysaccharide, and chicken egg albumin-derived advanced glycation end product) in the presence of increasing concentration of catalase. For example, catalase inhibited 100% of nitric oxide and 40% of tumor necrosis factor-α production at its highest concentration. Our results suggest that hydrogen peroxide travels through cell membranes into the extracellular space and enters and activates adjacent cells. Like nitric oxide, we suggest that it is a ubiquitous first messenger, able to transmit cell-to-cell pro-inflammatory signals such as nitric oxide and tumor necrosis factor-α. In a therapeutic setting, our data suggest that compounds acting as hydrogen peroxide scavengers might not even need to enter the cell to act as anti-inflammatory drugs.

Key words: Inflammation, glycation, redox signaling, cytokines, anti-inflammatory drugs, hydrogen peroxide, membrane permeable, lipopolysaccharide, Interferon-gamma, signaling