Zeng Shan, Dun Hao, Ippagunta Nikalesh, Rosario Rosa, Zhang Qing Y, Lefkowitch Jay, Yan Shi F, Schmidt Ann Marie, Emond Jean C
Division of Liver Diseases and Transplantation, Department of Surgery, College of Physicians & Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA.
J Hepatol. 2009 May;50(5):929-36. doi: 10.1016/j.jhep.2008.11.022. Epub 2009 Jan 14.
BACKGROUND/AIMS: We previously showed that blockade of RAGE significantly attenuates hepatic ischemia/reperfusion (I/R) injury in mice. Here, we identify that early growth response-1 (Egr-1) is a downstream target of RAGE in hepatic I/R injury.
Hepatic I/R was induced in male mice. Liver remnants were analyzed for induction of Egr-1 and cytokines, as well as regulation of apoptotic pathways after reperfusion.
Egr-1 was upregulated in the liver remnants after hepatic I/R injury and was suppressed by administration of soluble RAGE or deletion of the RAGE gene. RAGE-mediated increased expression of Egr-1 upregulates a central downstream gene, MIP2. In contrast, RAGE-stimulated Egr-1-independent pathways regulate TNF-alpha production and apoptosis in response to I/R. Consistent with these findings, phospho-p44/42 and phospho-JNK MAPK and c-Jun were strikingly suppressed in RAGE(-/-) versus WT mice, but not in Egr-1(-/-) mice. RAGE ligand HMGB1 was upregulated after I/R in the liver remnants. In vitro, incubation of RAGE-expressing liver dendritic cells (DCs) with recombinant HMGB-1 resulted in increased Egr-1 transcripts, in a manner suppressed by RAGE gene deletion, soluble RAGE and inhibitors of p44/p42 or JNK MAP kinase.
Suppression of Egr-1 may contribute to the protective mechanisms underlying the beneficial impact of RAGE blockade or deletion.
背景/目的：我们之前的研究表明，阻断晚期糖基化终末产物受体（RAGE）可显著减轻小鼠肝脏缺血/再灌注（I/R）损伤。在此，我们确定早期生长反应因子-1（Egr-1）是肝脏I/R损伤中RAGE的下游靶点。
对雄性小鼠进行肝脏I/R诱导。分析再灌注后肝组织中Egr-1和细胞因子的诱导情况，以及凋亡途径的调控。
肝脏I/R损伤后，肝组织中Egr-1上调，可溶性RAGE给药或RAGE基因缺失可抑制其上调。RAGE介导的Egr-1表达增加上调了一个核心下游基因MIP2。相反，RAGE刺激的不依赖Egr-1的途径调节I/R诱导的肿瘤坏死因子-α（TNF-α）产生和细胞凋亡。与这些发现一致，与野生型（WT）小鼠相比，RAGE基因敲除小鼠中磷酸化-p44/42、磷酸化-JNK丝裂原活化蛋白激酶（MAPK）和c-Jun明显受到抑制，但Egr-1基因敲除小鼠中未受抑制。肝脏I/R损伤后，肝组织中RAGE配体高迁移率族蛋白B1（HMGB1）上调。在体外，用重组HMGB-1孵育表达RAGE的肝脏树突状细胞（DCs），可导致Egr-1转录本增加，RAGE基因缺失、可溶性RAGE以及p44/p42或JNK MAP激酶抑制剂可抑制这种增加。
抑制Egr-
