INTERFERON REGULATORY FACTOR 1 MEDIATES ACETYLATION AND RELEASE OF HIGH MOBILITY GROUP BOX 1 FROM HEPATOCYTES DURING MURINE LIVER ISCHEMIA-REPERFUSION INJURY
INTERFERON REGULATORY FACTOR 1 MEDIATES ACETYLATION AND RELEASE OF HIGH MOBILITY GROUP BOX 1 FROM HEPATOCYTES DURING MURINE LIVER ISCHEMIA-REPERFUSION INJURY
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DOI：
10.1097/shk.0b013e3181f6aab0
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发表时间：
2011-03-01
期刊：
影响因子：
3.1
通讯作者：
Tsung, Allan
中科院分区：
文献类型：
--
作者：
Dhupar, Rajeev;Klune, John R.;Tsung, Allan
损伤相关分子模式（DAMP）启动无菌和感染过程常见的炎症途径。DAMP，高迁移率族蛋白1（HMGB 1），和转录因子，干扰素调节因子1（IRF-1），已独立相关的缺血-再灌注（I/R）损伤的关键球员。我们的研究表明，IRF-1有助于肝细胞释放HMGB 1，并进一步表明IRF-1是响应缺氧或肝I/R后HMGB 1释放的必要组分。我们还将IRF-1的核上调与功能性Toll样受体4（TLR 4）的存在联系起来，TLR 4是一种在不育和感染过程中也很重要的模式识别受体。使用IRF-1嵌合体小鼠，我们表明，IRF-1上调肝实质细胞，而不是在骨髓来源的免疫细胞，是负责缺血性肝损伤过程中HMGB 1的释放。最后，我们的研究还证明了IRF-1在调节乙酰化状态和随后通过组蛋白乙酰转移酶释放HMGB 1中的作用。我们发现，血清HMGB 1乙酰化后肝I/R，这一过程是依赖于IRF-1。此外，肝脏I/R诱导IRF-1与核组蛋白乙酰转移酶p300直接结合。总之，这些发现表明，I/R诱导的乙酰化HMGB 1释放是一个依赖于TLR 4介导的IRF-1上调的过程。
Damage-associated molecular patterns (DAMPs) initiate inflammatory pathways that are common to both sterile and infectious processes. The DAMP, high-mobility group box 1 (HMGB1), and the transcription factor, interferon regulatory factor 1 (IRF-1), have been independently associated as key players in ischemia-reperfusion (I/R) injury. Our study demonstrates that IRF-1 contributes to hepatocellular release of HMGB1 and further that IRF-1 is a necessary component of HMGB1 release in response to hypoxia or after liver I/R. We also link the nuclear upregulation of IRF-1 to the presence of functional Toll-like receptor 4 (TLR4), a pattern recognition receptor also important in sterile and infectious processes. Using IRF-1 chimeric mice, we show that IRF-1 upregulation in hepatic parenchymal cells, and not in the bone marrow-derived immune cells, is responsible for HMGB1 release during ischemic liver injury. Finally, our study also demonstrates a role for IRF-1 in modulating the acetylation status and subsequent release of HMGB1 through histone acetyltransferases. We found that serum HMGB1 is acetylated after liver I/R and that this process was dependent on IRF-1. Additionally, liver I/R induced a direct association of IRF-1 and the nuclear histone acetyltransferase enzyme p300. Together, these findings suggest that I/R-induced release of acetylated HMGB1 is a process that is dependent on TLR4-mediated upregulation of IRF-1.