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

  • Organ Toxicity and Mechanisms
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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.

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Acknowledgements

This work was supported by the KRIBB Research Initiative Program of the Republic of Korea, by the Development of Platform Technology for Innovative Medical Measurements Program (No. KRISS-2019-GP2019-0013) from the Korea Research Institute of Standards and Science and by the National Research Foundation of Korea (NRF) and the Korean government (MSIP) (NRF-2019R1C1C1005319).

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  1. Jung-Ran Noh and Jae-Hoon Kim contributed equally to this work.

Authors and Affiliations

  1. Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, South Korea

    Jung-Ran Noh, Jae-Hoon Kim, In Bok Lee, Yun Jeong Seo, Jung Hyeon Choi, Yong-Hoon Kim & Chul-Ho Lee

  2. National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, 61186, South Korea

    Soon-Young Na & Hueng-Sik Choi

  3. Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Chungcheongbuk-do, Cheongju-si, 28116, South Korea

    Youngwon Seo

  4. Center for Nano-Bio Measurement, Korea Research Institute of Standard and Science, 267 Gajeong-ro, Yuseong-gu, Daejeon, 34113, South Korea

    Tae Geol Lee

  5. University of Science and Technology (UST), Daejeon, 34113, South Korea

    Yong-Hoon Kim & Chul-Ho Lee

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Contributions

JRN, JHK, YHK and CHL designed the study, and drafted the manuscript. JRN, JHK, SYN, IBL, YJS, JHC, YS and YHK performed experiments, and collected and analyzed data for the study. TGL, HSC and CHL contributed to critical revisions of the text.

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Correspondence to Yong-Hoon Kim or Chul-Ho Lee.

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All animal experiments were approved by the Institutional Animal Care and Use Committee of the KRIBB.

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Noh, JR., Kim, JH., Na, SY. et al. Hepatocyte CREBH deficiency aggravates inflammatory liver injury following chemokine-dependent neutrophil infiltration through upregulation of NF-κB p65 in mice. Arch Toxicol 94, 509–522 (2020). https://doi.org/10.1007/s00204-019-02633-0

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