Iron activates NF-κB in Kupffer cells
Iron activates NF-κB in Kupffer cells
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DOI：
10.1152/ajpgi.00108.2002
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发表时间：
2002-09-01
影响因子：
4.5
通讯作者：
Tsukamoto, H
中科院分区：
文献类型：
--
作者：
She, HY;Xiong, SG;Tsukamoto, H
铁会加重各种类型的肝损伤，其中涉及核因子(NF)-kappaB驱动的基因。这项研究验证了一种假说，即铁直接诱导Kupffer细胞中激活核因子-kappaB和刺激肿瘤坏死因子(TNF)-α基因表达所需的信号。在培养的大鼠Kupffer细胞中加入Fe2+而不是Fe3+(类似于5-50微米)，以一种依赖于核因子-kappaB的方式增加了肿瘤坏死因子-α的释放和肿瘤坏死因子-α的启动子活性。C+对肿瘤坏死因子-α蛋白的释放和启动子活性无明显刺激作用，但作用强度较小。Fe2+使胞质抑制物kappaBalpha消失，核p65蛋白增加，p50/p50和p65/p50的DNA结合增加，但不影响激活蛋白-1的结合。细胞中加入Fe2+后，电子顺磁共振检测到的·OH增加，在15min达到峰值，先于核因子-kappaB的激活，但与抑制kappaB激酶(Ikk)的激活一致，但不与c-jun NH2-末端激酶的激活相一致。总之，Fe2+作为一种直接激动剂，以氧化还原状态依赖的方式激活IKK、NF-kappaB和TNF-α启动子活性，并诱导培养的Kupffer细胞释放TNF-α蛋白。我们认为，这一发现为铁介导的肿瘤坏死因子-α依赖性肝损伤的加重提供了分子基础。
Iron exacerbates various types of liver injury in which nuclear factor (NF)-kappaB-driven genes are implicated. This study tested a hypothesis that iron directly elicits the signaling required for activation of NF-kappaB and stimulation of tumor necrosis factor (TNF)-alpha gene expression in Kupffer cells. Addition of Fe2+ but not Fe3+ (similar to5-50 muM) to cultured rat Kupffer cells increased TNF-alpha release and TNF-alpha promoter activity in a NF-kappaB-dependent manner. C+ but not Cu2+ stimulated TNF-alpha protein release and promoter activity but with less potency. Fe2+ caused a disappearance of the cytosolic inhibitor kappaBalpha, a concomitant increase in nuclear p65 protein, and increased DNA binding of p50/p50 and p65/p50 without affecting activator protein-1 binding. Addition of Fe2+ to the cells resulted in an increase in electron paramagnetic resonance-detectable .OH peaking at 15 min, preceding activation of NF-kappaB but coinciding with activation of inhibitor kappaB kinase (IKK) but not c-Jun NH2-terminal kinase. In conclusion, Fe2+ serves as a direct agonist to activate IKK, NF-kappaB, and TNF-alpha promoter activity and to induce the release of TNF-alpha protein by cultured Kupffer cells in a redox status-dependent manner. We propose that this finding offers a molecular basis for iron-mediated accentuation of TNF-alpha-dependent liver injury.