Miz1介导NF-kB通路激活调控巨噬细胞相关爆发性肝炎的机制研究

爆发性肝炎是以肝细胞大面积死亡为发病基础的肝脏疾患，以高达80%的死亡率严重威胁人们的生命健康。在爆发性肝炎中肿瘤坏死因子α（TNF-α）起到了核心作用。TNF-α主要由活化的单核-巨噬细胞及其他多种细胞产生，参与炎症、细胞凋亡、趋化因子的产生，同时巨噬细胞通过自分泌和（或）旁分泌的方式表现出对TNF-α等产物的高敏感性，从而加剧了炎症反应，这其中的机制尚不完全清楚。转录因子Miz1广泛参与了细胞周期，自噬，增殖分化，有研究发现研究表明小鼠急性肺损伤模型中，胞核中Miz1通过降低Cebpd转录活性抑制LPS诱导的持续性炎症反应。TNF-α刺激可使Miz1在蛋白水平发生泛素化，并大量降解，这个结果与我们的研究基础相结合，可能预示了一个调控TNF-α大量分泌进而加重炎症反应的正反馈调节机制。

Fulminant hepatitis (FH), also known as acute liver failure, is a deadly liver dysfunctional syndrome with mortality up to nearly 80%, which pose a great threat to the public health. Tumor necrosis factor α (TNF-α) is a central cytokine during liver damage, mainly secreted by activated monocytes and macrophages and other inflammatory cells. As a highly pleiotropic cytokines, TNF-α is engaged in inflammation, cell death and survival. Through paracrine or autocrine, TNF-α released by macrophages and inflammatory cells could in turn activated macrophages itself, triggering more cytokines or chemokines production, a positive feedback leading to the subsequent augmentation of inflammation, the potential mechanism remains unclear, however. Transcriptional factor Miz1 was initially identified as a binding partner of c-myc, involving in regulation of cell cycle, autophage, cell proliferation and differentiation. Hanh Chi Do-Umehara discovered that phosphorylation of nuclear Miz1 could repress transcription of the gene encoding C/EBP-d, consequently terminating lipopolysaccharide (LPS)-induced inflammation. Researchers also found that cytoplasmic Miz1 could inhibit the ubiquitin ligase (E3) activity of TRAF2 and suppress TNF-α induced JNK activation thus regulating the cytokine producing in macrophages. We found that Miz1 regulates NF-κB in hepatocytes during HCC tumorigenesis. Based on these findings, we hypothesize that macrophages Miz1 go through K48-linked polyubiquitination and degradation upon TNF-α stimulation, so repression of TNF-α induced JNK and NF-κB activation by Miz1 is de-repressed by its own site-specific ubiquitination and degradation, causing more cytokines production, thus amplifying the inflammation during the progression of FH.