Hepatocyte CREBH deficiency aggravates inflammatory liver injury following chemokine-dependent neutrophil infiltration through upregulation of NF-κB p65 in mice

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Title
Hepatocyte CREBH deficiency aggravates inflammatory liver injury following chemokine-dependent neutrophil infiltration through upregulation of NF-κB p65 in mice
Author(s)
Jung-Ran Noh; Jae-Hoon Kim; S Y Na; In-Bok LeeYun-Jeong SeoJung-Hyeon ChoiYoungwon Seo; T G Lee; H S Choi; Yong-Hoon KimChul Ho Lee
Bibliographic Citation
Archives of Toxicology, vol. 94, no. 2, pp. 509-522
Publication Year
2020
Abstract
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.
Keyword
CREBHConcanavalin AInflammationLiver injuryNF-κBNeutrophil
ISSN
0340-5761
Publisher
Springer
DOI
http://dx.doi.org/10.1007/s00204-019-02633-0
Type
Article
Appears in Collections:
Ochang Branch Institute > Division of Bioinfrastructure > Laboratory Animal Resource Center > 1. Journal Articles
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