Fulminant hepatitis is a serious inflammatory condition of the liver characterized by massive necrosis of liver parenchyma following excessive immune cell infiltration into the liver, and possibly causing sudden hepatic failure and medical emergency. However, the underlying mechanisms are not fully understood. Here, we investigated the role of cyclic AMP-responsive element-binding protein, hepatocyte specific (CREBH) in concanavalin A (ConA)-driven hepatitis-evoked liver injury. C57BL/6J (WT) and Crebh knockout (KO) mice injected with ConA (7.5 or 25 mg/kg) and bone marrow (BM) chimeric mice, generated by injection of BM cells into sub-lethally irradiated recipients followed by ConA injection (22.5 or 27.5 mg/kg) 8 weeks later, were used for in vivo study. Primary mouse hepatocytes and HEK293T cells were used for a comparative in vitro study. Crebh KO mice are highly susceptible to ConA-induced liver injury and prone to death due to increased neutrophil infiltration driven by enhanced hepatic expression of neutrophil-attracting chemokines. Notably, BM chimera experiment demonstrated that Crebh-deficient hepatocytes have an enhanced ability of recruiting neutrophils to the liver, thereby promoting hepatotoxicity by ConA. Intriguingly, in vitro assays showed that p65, a subunit of NF-κB and common transcription factor for various chemokines, dependent transactivation was inhibited by CREBH. Furthermore, p65 expression was inversely correlated with CREBH level in ConA-treated mice liver and TNFα-stimulated primary mouse hepatocytes. This is the first demonstration that CREBH deficiency aggravates inflammatory liver injury following chemokine-dependent neutrophil infiltration via NF-κB p65 upregulation. CREBH is suggested to be a novel therapeutic target for treatment of fulminant hepatitis.

中文翻译：

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肝细胞CREBH缺乏会通过上调NF-κBp65的表达而加剧趋化因子依赖性中性粒细胞浸润后的炎症性肝损伤。

暴发性肝炎是一种严重的肝脏炎症性疾病，其特征是免疫细胞过度渗透进入肝脏后，肝实质大量坏死，并可能导致突然的肝衰竭和医疗紧急情况。但是，尚未完全理解其基本机制。在这里，我们调查了环状AMP反应元件结合蛋白，肝细胞特异性（CREBH）在伴刀豆球蛋白A（ConA）驱动的肝炎诱发的肝损伤中的作用。注射了ConA（7.5或25 mg / kg）的C57BL / 6J（WT）和Crebh敲除（KO）小鼠以及骨髓（BM）嵌合小鼠，这些小鼠是通过将BM细胞注射到次致死剂量的受者体内，然后再注射ConA（ 8周后，将22.5或27.5mg / kg）用于体内研究。原代小鼠肝细胞和HEK293T细胞用于体外比较研究。Crebh KO小鼠高度易受ConA诱导的肝损伤，并且由于吸引中性粒细胞的趋化因子在肝脏中的表达增强而导致中性粒细胞浸润增加，因此容易死亡。值得注意的是，BM嵌合体实验表明，缺乏Crebh的肝细胞具有将嗜中性白细胞募集到肝脏的能力，从而通过ConA促进了肝毒性。有趣的是，体外试验显示CR65H抑制p65（NF-κB的亚基和多种趋化因子的共同转录因子）的依赖性反式激活。此外，在经ConA处理的小鼠肝脏和TNFα刺激的原代小鼠肝细胞中，p65的表达与CREBH水平呈负相关。这是第一个证明CREBH缺乏加剧了通过NF-κBp65上调趋化因子依赖性中性粒细胞浸润后炎症性肝损伤的方法。CREBH被认为是治疗暴发性肝炎的新型治疗靶标。