Oxidation of HMGB1 causes attenuation of its pro-inflammatory activity and occurs during liver ischemia and reperfusion.
Oxidation of HMGB1 causes attenuation of its pro-inflammatory activity and occurs during liver ischemia and reperfusion.
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DOI：
10.1371/journal.pone.0035379
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Dahmen U
中科院分区：
文献类型：
--
作者：
Liu A;Fang H;Dirsch O;Jin H;Dahmen U
高迁移率族蛋白1（HMGB 1）是一种核转录因子。一旦HMGB 1被受损细胞或激活的免疫细胞释放，它就充当危险分子并触发炎症信号级联反应。目前，越来越多的证据表明，翻译后修饰，如氧化可能会调节危险信号的促炎潜力。我们假设HMGB 1的氧化可能降低其促炎潜力，并可能发生在长时间缺血和再灌注时。将肝移植物冷保存24 h，每小时用盐水冲洗一次以收集流出物。将冷保存6 h的肝移植物移植到同系受者中，在开始再灌注后24 h获得血清和肝脏样品。向巨噬细胞培养物中添加流出物诱导肿瘤坏死因子-α（TNF-α）和白细胞介素（IL）-6的合成。通过免疫沉淀去除HMGB 1后，移植物流出物的刺激活性降低。用H2 O2氧化流出物HMGB 1也减弱了其刺激活性。免疫组化和ELISA法分别测定冷保存移植物的肝移植引起HMGB 1移位和释放。使用非还原条件下的Western印迹显示，在12小时后获得的肝脏样品和16小时的冷保存后的流出物样品中以及在再灌注后24小时获得的肝脏和血清样品中存在氧化的HMGB 1。这些观察结果证实HMGB 1的翻译后氧化减弱其促炎活性。体内长时间缺血和再灌注期间再氧合诱导的HMGB 1氧化也可能减弱其促炎活性。我们的研究结果也呼吁未来的研究，以探讨氧化的HMGB 1对促炎潜力的抑制作用的机制。
High mobility group box 1 (HMGB1) is a nuclear transcription factor. Once HMGB1 is released by damaged cells or activated immune cells, it acts as danger molecule and triggers the inflammatory signaling cascade. Currently, evidence is accumulating that posttranslational modifications such as oxidation may modulate the pro-inflammatory potential of danger signals. We hypothesized that oxidation of HMGB1 may reduce its pro-inflammatory potential and could take place during prolonged ischemia and upon reperfusion. Liver grafts were cold preserved for 24 h and flushed with saline in hourly intervals to collect the effluent. Liver grafts, cold-preserved for 6 h, were transplanted into syngeneic recipients to obtain serum and liver samples 24 h after initiation of reperfusion. Addition of the effluent to a macrophage culture induced the synthesis of tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6. The stimulatory activity of graft effluent was reduced after depletion of HMGB1 via immunoprecipitation. Oxidation of the effluent HMGB1 using H2O2 attenuated its stimulatory activity as well. Liver transplantation of cold preserved grafts caused HMGB1 translocation and release as determined by immunohistochemistry and ELISA-assay, respectively. Using Western blot with non-reducing conditions revealed the presence of oxidized HMGB1 in liver samples obtained after 12 h and in effluent samples after 16 h of cold preservation as well as in liver and serum samples obtained 24 h after reperfusion. These observations confirm that post-translational oxidation of HMGB1 attenuates its pro-inflammatory activity. Oxidation of HMGB1 as induced during prolonged ischemia and by reoxygenation during reperfusion in vivo might also attenuate its pro-inflammatory activity. Our findings also call for future studies to investigate the mechanism of the inhibitory effect of oxidized HMGB1 on the pro-inflammatory potential.
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HMGB1：内源性危险信号。
影响因子：
5.7
作者：
Klune, John R.;Dhupar, Rajeev;Cardinal, Jon;Billiar, Timothy R.;Tsung, Allan
通讯作者：
Tsung, Allan
影响因子：
3.8
作者：
Liu, Anding;Fang, Haoshu;Dahmen, Uta
通讯作者：
Dahmen, Uta
影响因子：
3.5
作者：
Sahu, Debashish;Debnath, Priyanka;Takayama, Yuki;Iwahara, Junji
通讯作者：
Iwahara, Junji
影响因子：
11.1
作者：
Müller, S;Ronfani, L;Bianchi, ME
通讯作者：
Bianchi, ME
影响因子：
4.6
作者：
Liu A;Jin H;Dirsch O;Deng M;Huang H;Bröcker-Preuss M;Dahmen U
通讯作者：
Dahmen U