Potential role for 8-oxoguanine DNA glycosylase in regulating inflammation
Potential role for 8-oxoguanine DNA glycosylase in regulating inflammation
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DOI：
10.1096/fj.04-2278fje
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发表时间：
2004-12-01
期刊：
影响因子：
4.8
通讯作者：
Szabó, C
中科院分区：
文献类型：
--
作者：
Mabley, JG;Pacher, P;Szabó, C
OGG-1糖基酶(OGG-1)是一种参与DNA修复的酶。它去除了7，8-二氢-8-氧鸟嘌呤，后者是由鸟嘌呤氧化损伤形成的。我们用三种炎症模型研究了OGG-1在炎症中的作用：内毒素休克、糖尿病和接触性超敏反应。我们发现，与野生型对照(OGG(+/+))相比，OGG-1(-/-)小鼠对内毒素(脂多糖，LPS)诱导的器官功能障碍、中性粒细胞渗透和氧化应激具有抵抗力。此外，Ogg-1基因的缺失与血清细胞因子和趋化因子水平的降低以及内毒素治疗后生存期的延长有关。I型糖尿病采用多次小剂量链脲佐菌素治疗。与Ogg-1(+/+)小鼠相比，Ogg-1(-/-)小鼠的血糖水平和糖尿病发病率显著降低。对胰腺的生化分析显示，Ogg-1(-/-)小鼠的胰岛素含量较高，这表明β细胞质量较大，而趋化因子MIP-1α和Th1细胞因子IL-12和TNF-α的水平较低。Ogg-1(-/-)小鼠胰腺保护性Th2细胞因子、IL-4和IL-10水平显著高于野生型小鼠。在恶唑酮诱导的接触性超敏反应中，Ogg-1(-/-)小鼠的耳朵组织中性粒细胞聚集减少，趋化因子减少，Th1和Th2细胞因子水平降低。目前的研究揭示了Ogg-1在炎症调节中的作用。
OGG-1 DNA glycosylase (OGG-1) is an enzyme involved in DNA repair. It excises 7,8-dihydro-8-oxoguanine, which is formed by oxidative damage of guanine. We have investigated the role of OGG-1 in inflammation using three models of inflammation: endotoxic shock, diabetes, and contact hypersensitivity. We found that OGG-1(-/-) mice are resistant to endotoxin ( lipopolysaccharide, LPS)-induced organ dysfunction, neutrophil infiltration and oxidative stress, when compared with the response seen in wild-type controls ( OGG(+/+)). Furthermore, the deletion of the OGG-1 gene was associated with decreased serum cytokine and chemokine levels and prolonged survival after LPS treatment. Type I diabetes was induced by multiple low-dose streptozotocin treatment. OGG-1(-/-) mice were found to have significantly lower blood glucose levels and incidence of diabetes as compared with OGG-1(+/+) mice. Biochemical analysis of the pancreas showed that OGG-1(-/-) mice had greater insulin content, indicative of a greater beta-cell mass coupled with lower levels of the chemokine MIP-1alpha and Th1 cytokines IL-12 and TNF-alpha. Levels of protective Th2 cytokines, IL-4 and IL-10 were significantly higher in the pancreata of OGG-1(-/-) mice as compared with the levels measured in wild-type mice. In the contact hypersensitivity induced by oxazolone, the OGG-1(-/-) mice showed reduced neutrophil accumulation, chemokine, and Th1 and Th2 cytokine levels in the ear tissue. The current studies unveil a role for OGG-1 in the regulation of inflammation.