Induction of Mn SOD in human monocytes without inflammatory cytokine production by a mutant endotoxin
Induction of Mn SOD in human monocytes without inflammatory cytokine production by a mutant endotoxin
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DOI：
10.1152/ajpcell.1998.275.3.c740
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发表时间：
1998-09-01
影响因子：
5.5
通讯作者：
Tsan, MF
中科院分区：
文献类型：
--
作者：
Tian, LC;White, JE;Tsan, MF
内毒素选择性诱导单核细胞锰超氧化物歧化酶（SOD），而不影响铜，锌SOD，过氧化氢酶，谷胱甘肽过氧化物酶的水平。然而，很少有人知道的构效关系和机制，内毒素诱导锰超氧化物歧化酶。在这项研究中，我们证明了在脂质A部分的3' R-3-羟基肉豆蔻酸酯位置缺少肉豆蔻酰脂肪酸的突变大肠杆菌内毒素与野生型大肠杆菌相比保留了其完全凝固鲎变形细胞裂解物的能力。大肠杆菌内毒素能显著激活人单核细胞核因子-κ B（NF-κ B）B，诱导Mn SOD mRNA表达和酶活性。然而，与野生型内毒素相反，它不能诱导单核细胞显著产生肿瘤坏死因子-α和巨噬细胞炎性蛋白-1 α，也不能诱导丝裂原活化蛋白激酶的磷酸化和核转位。这些结果表明：1）脂质A肉豆蔻酰脂肪酸虽然对诱导人单核细胞产生炎性细胞因子很重要，但对Mn SOD的诱导不是必需的，2）内毒素介导的Mn SOD和炎性细胞因子的诱导至少部分通过不同的信号转导途径进行调节，和3）突变型内毒素不能诱导肿瘤坏死因子-A产生至少部分是由于其不能激活促分裂原活化蛋白激酶。
Endotoxin selectively induces monocyte Mn superoxide dismutase (SOD) without affecting levels of Cu,Zn SOD, catalase, or glutathione peroxidase. However, little is known about the structure-activity relationship and the mechanism by which endotoxin induces Mn SOD. In this study we demonstrated that a mutant Escherichia coli endotoxin lacking myristoyl fatty acid at the 3' R-3-hydroxymyristate position of the lipid A moiety retained its full capacity to coagulate Limulus amoebocyte lysate compared with the wild-type E. coli endotoxin and markedly stimulated the activation of human monocyte nuclear factor-kappa B and the induction of Mn SOD mRNA and enzyme activity. However, in contrast to the wild-type endotoxin, it failed to induce significant production of tumor necrosis factor-a: and macrophage inflammatory protein-1 alpha by monocytes and did not induce the phosphorylation and nuclear translocation of mitogen-activated protein kinase. These results suggest that 1) lipid A myristoyl fatty acid, although it is important for the induction of inflammatory cytokine production by human monocytes, is not necessary for the induction of Mn SOD, 2) endotoxin-mediated induction of Mn SOD and inflammatory cytokines are regulated, at least in part, through different signal transduction pathways, and 3) failure of the mutant endotoxin to induce tumor necrosis factor-a production is, at least in part, due to its inability to activate mitogen-activated protein kinase.