Tse Hubert M, Milton Martha J, Piganelli Jon D
Diabetes Institute, Division of Immunogenetics, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA 15213-3205, USA.
Free Radic Biol Med. 2004 Jan 15;36(2):233-47. doi: 10.1016/j.freeradbiomed.2003.10.029.
Reactive oxygen species (ROS) have an indispensable role in controlling the growth of pathogens. Recent evidence also suggests that they can function as second messengers and modulators of the immune system. The identification of many redox-sensitive signal transduction pathways that are necessary for initiating the innate proinflammatory immune response suggests that modulation of these oxidation-reduction reactions may provide a means of therapeutic benefit for controlling inflammatory-mediated diseases. In order to test this hypothesis we employed two catalytic antioxidants (AEOL 10113 and 10150) for the determination of the role of oxidation-reduction reactions in innate immune system activation. Catalytic antioxidants prevented the initiation of the innate immune response in LPS-stimulated macrophages as evidenced by the suppression of proinflammatory cytokines (TNF-alpha, IL-1beta) and ROS (NO2- and O2-). The suppression of proinflammatory cytokine and ROS production correlated with the inhibition of NF-kappaB DNA binding, without any effects on the mitogen-activated protein kinase signaling pathway. Catalytic antioxidants prevented NF-kappaB from binding DNA by an oxidation mechanism that was reversible with the addition of DTT. Although the primary use of these agents was to reduce and scavenge ROS, surprisingly, we also observed the ability of these compounds to exhibit oxidoreductase activity and oxidize redox-sensitive transcription factors such as NF-kappaB. Catalytic antioxidants exhibit antioxidant and pro-oxidant activities and our data further demonstrate the importance of redox balance for the initiation of proinflammation. The coupling of the innate with the adaptive immune response is dependent on TNF-alpha, IL-1beta, NO2-, and O2- generation; therefore, agents like catalytic antioxidants that decrease proinflammatory cytokines and ROS may provide protective effects in diseases in which chronic inflammation plays a pathogenic role.
活性氧（ROS）在控制病原体生长中起着不可或缺的作用。最近的证据还表明，它们可作为免疫系统的第二信使和调节剂。许多对氧化还原敏感的信号转导途径是启动先天性促炎免疫反应所必需的，这表明调节这些氧化还原反应可能为控制炎症介导的疾病提供一种治疗益处的手段。为了验证这一假设，我们使用了两种催化抗氧化剂（AEOL 10113和10150）来确定氧化还原反应在先天性免疫系统激活中的作用。催化抗氧化剂可防止脂多糖刺激的巨噬细胞中先天性免疫反应的启动，这可通过促炎细胞因子（TNF-α、IL-1β）和ROS（NO2-和O2-）的抑制来证明。促炎细胞因子和ROS产生的抑制与NF-κB DNA结合的抑制相关，而对丝裂原活化蛋白激酶信号通路没有任何影响。催化抗氧化剂通过一种氧化机制阻止NF-κB与DNA结合，加入二硫苏糖醇（DTT）后这种机制是可逆的。尽管这些试剂的主要用途是减少和清除ROS，但令人惊讶的是，我们还观察到这些化合物具有氧化还原酶活性并能氧化对氧化还原敏感的转录因子，如NF-κB。催化抗氧化剂表现出抗氧化和促氧化活性，我们的数据进一步证明了氧化还原平衡对促炎反应启动的重要性。先天性免疫反应与适应性免疫反应的耦合依赖于TNF-α、IL-1β、NO2-和O2-的产生；因此，像催化抗氧化剂这样能减少促炎细胞因子和ROS的试剂可能在慢性炎症起致病作用的疾病中提供保护作用。
