Vol.:(0123456789) 1 3 Archives of Toxicology https://doi.org/10.1007/s00204-019-02633-0 ORGAN TOXICITY AND MECHANISMS Hepatocyte CREBH defciency aggravates infammatory liver injury following chemokine‑dependent neutrophil infltration through upregulation of NF‑κB p65 in mice Jung‑Ran Noh 1  · Jae‑Hoon Kim 1  · Soon‑Young Na 2  · In Bok Lee 1  · Yun Jeong Seo 1  · Jung Hyeon Choi 1  · Youngwon Seo 3  · Tae Geol Lee 4  · Hueng‑Sik Choi 2  · Yong‑Hoon Kim 1,5  · Chul‑Ho Lee 1,5 Received: 7 August 2019 / Accepted: 26 November 2019 © Springer-Verlag GmbH Germany, part of Springer Nature 2019 Abstract Fulminant hepatitis is a serious infammatory condition of the liver characterized by massive necrosis of liver parenchyma fol- lowing excessive immune cell infltration 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 specifc (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 compara- tive in vitro study. Crebh KO mice are highly susceptible to ConA-induced liver injury and prone to death due to increased neutrophil infltration driven by enhanced hepatic expression of neutrophil-attracting chemokines. Notably, BM chimera experiment demonstrated that Crebh-defcient 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 frst demonstration that CREBH defciency aggravates infammatory liver injury following chemokine-dependent neutrophil infltration via NF-κB p65 upregulation. CREBH is suggested to be a novel therapeutic target for treatment of fulminant hepatitis. Keywords CREBH · Concanavalin A · Infammation · Liver injury · Neutrophil · NF-κB Jung-Ran Noh and Jae-Hoon Kim contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00204-019-02633-0) contains supplementary material, which is available to authorized users. * Yong-Hoon Kim yhoonkim@kribb.re.kr * Chul-Ho Lee chullee@kribb.re.kr 1 Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, South Korea 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 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 4 Center for Nano-Bio Measurement, Korea Research Institute of Standard and Science, 267 Gajeong-ro, Yuseong-gu, Daejeon 34113, South Korea 5 University of Science and Technology (UST), Daejeon 34113, South Korea