Marikovsky Moshe, Ziv Vered, Nevo Nava, Harris-Cerruti Catherine, Mahler Ori
Department of Animal Sciences, Faculty of Agricultural, Food, and Environmental Quality Sciences, Hebrew University of Jerusalem, Rehovot, Israel.
J Immunol. 2003 Mar 15;170(6):2993-3001. doi: 10.4049/jimmunol.170.6.2993.
Activation of macrophages leads to the secretion of cytokines and enzymes that shape the inflammatory response and increase metabolic processes. This, in turn, results in increased production of reactive oxygen species. The role of Cu/Zn superoxide dismutase (SOD-1), an important enzyme in cellular oxygen metabolism, was examined in activated peritoneal elicited macrophages (PEM) and in several inflammatory processes in vivo. LPS and TNF-alpha induced SOD-1 in PEM. SOD-1 induction by LPS was mainly via extracellular signal-regulated kinase-1 activation. Transgenic mice overexpressing SOD-1 demonstrated a significant increase in the release of TNF-alpha and of the metalloproteinases MMP-2 and MMP-9 from PEM. Disulfiram (DSF), an inhibitor of SOD-1, strongly inhibited the release of TNF-alpha, vascular endothelial growth factor, and MMP-2 and MMP-9 from cultured activated PEM. These effects were prevented by addition of antioxidants, further indicating involvement of reactive oxygen species. In vivo, transgenic mice overexpressing SOD-1 demonstrated a 4-fold increase in serum TNF-alpha levels and 2-fold stronger delayed-type hypersensitivity reaction as compared with control nontransgenic mice. Conversely, oral administration of DSF lowered TNF-alpha serum level by 4-fold, lowered the delayed-type hypersensitivity response in a dose-dependent manner, and significantly inhibited adjuvant arthritis in Lewis rats. The data suggest an important role for SOD-1 in inflammation, establish DSF as a potential inhibitor of inflammation, and raise the possibility that regulation of SOD-1 activity may be important in the treatment of immune-dependent pathologies.
巨噬细胞的激活会导致细胞因子和酶的分泌，这些细胞因子和酶会塑造炎症反应并增加代谢过程。反过来，这又会导致活性氧的产生增加。细胞氧代谢中的一种重要酶——铜/锌超氧化物歧化酶（SOD-1），在活化的腹腔诱导巨噬细胞（PEM）以及体内的几种炎症过程中的作用得到了研究。脂多糖（LPS）和肿瘤坏死因子-α（TNF-α）可诱导PEM中的SOD-1。LPS对SOD-1的诱导主要通过细胞外信号调节激酶-1的激活。过表达SOD-1的转基因小鼠显示，PEM中TNF-α、金属蛋白酶MMP-2和MMP-9的释放显著增加。SOD-1的抑制剂双硫仑（DSF）强烈抑制培养的活化PEM中TNF-α、血管内皮生长因子以及MMP-2和MMP-9的释放。添加抗氧化剂可阻止这些效应，进一步表明活性氧的参与。在体内，与对照非转基因小鼠相比，过表达SOD-1的转基因小鼠血清TNF-α水平增加了4倍，迟发型超敏反应增强了2倍。相反，口服DSF可使TNF-α血清水平降低4倍，以剂量依赖的方式降低迟发型超敏反应，并显著抑制Lewis大鼠的佐剂性关节炎。这些数据表明SOD-1在炎症中起重要作用，确立了DSF作为一种潜在的炎症抑制剂，并提出调节SOD-1活性在免疫依赖性疾病的治疗中可能很重要的可能性。
