Inhibition of the translocation and extracellular release of high-mobility group box 1 alleviates liver damage in fibrotic mice in response to D-galactosamine/lipopolysaccharide challenge

Bai,Li; Kong,Ming; Zheng,Qingfen; Zhang,Xiaohui; Liu,Xin; Zu,Kejia; Chen,Yu; Zheng,Sujun; Li,Junfeng; Ren,Feng; Lou,Jinli; Liu,Shuang; Duan,Zhongping

doi:10.3892/mmr.2016.5003

Inhibition of the translocation and extracellular release of high-mobility group box 1 alleviates liver damage in fibrotic mice in response to D-galactosamine/lipopolysaccharide challenge

Authors:
- Li Bai
- Ming Kong
- Qingfen Zheng
- Xiaohui Zhang
- Xin Liu
- Kejia Zu
- Yu Chen
- Sujun Zheng
- Junfeng Li
- Feng Ren
- Jinli Lou
- Shuang Liu
- Zhongping Duan
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Affiliations: Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, P.R. China, Clinical Laboratory Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, P.R. China, Department of Pathology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, P.R. China, Research Department, Beijing Institute of Liver Diseases, Beijing 100069, P.R. China
Published online on: March 18, 2016 https://doi.org/10.3892/mmr.2016.5003
Pages: 3835-3841
Copyright: © Bai et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Acute liver injury in the setting of fibrosis is an area of interest in investigations, and remains to be fully elucidated. Previous studies have suggested the beneficial effects of liver fibrosis induced by thioacetamide and partial bile duct ligation against Fas‑mediated acute liver injury. The activation of AKT and extracellular signal-regulated kinase signaling is considered to be crucial in this hepatoprotection. To demonstrate the protection of CCl4‑induced liver fibrosis against lethal challenge, the present study compared the reactivity to lethal doses of D‑galactosamine (D-GalN)/lipopolysaccharide (LPS) between fibrotic mice and control mice groups. The extent of hepatic damage was assessed by survival rate and histopathological analysis. The molecular basis of the fibrosis‑based hepatoprotection was examined, with a particular focus on the translocation and release of high‑mobility group box (HMGB)1 and the inflammatory response triggered by HMGB1. Hepatoprotection induced by fibrosis was demonstrated by improved survival rates (100%, vs. 20%) and improved preservation of liver architecture in fibrotic mice subjected to D‑GalN/LPS, compared with control mice treated in the same way. D‑GalN/LPS evoked the translocation and release of HMGB1, detected by immunohistochemistry, in the control mice, which was significantly inhibited in the fibrotic mice. The gene expression levels of HMGB1‑associated proinflammatory cytokines, including interleukin (IL)‑1β, IL‑6, tumor necrosis factor‑α and IL‑12p40, were markedly inhibited in the fibrotic mice when exposed to D‑GalN/LPS. These findings confirmed that CCl4‑based fibrosis induced hepatoprotection, and provided evidence that fibrosis inhibited the translocation and release of HMGB1, and the proinflammatory response triggered by HMGB1. This alleviated liver damage following exposure to D‑GalN/LPS challenge.

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1	Friedman SL: Mechanisms of hepatic fibrogenesis. Gastroenterology. 134:1655–1669. 2008. View Article : Google Scholar : PubMed/NCBI
2	Friedman SL: Evolving challenges in hepatic fibrosis. Nat Rev Gastroenterol Hepatol. 7:425–436. 2010. View Article : Google Scholar : PubMed/NCBI
3	Bataller R and Brenner DA: Liver fibrosis. J Clin Invest. 115:209–218. 2005. View Article : Google Scholar : PubMed/NCBI
4	White ES and Mantovani AR: Inflammation, wound repair and fibrosis: Reassessing the spectrum of tissue injury and resolution. J Pathol. 229:141–144. 2013. View Article : Google Scholar
5	Wynn TA and Ramalingam TR: Mechanisms of fibrosis: Therapeutic translation for fibrotic disease. Nat Med. 18:1028–1040. 2012. View Article : Google Scholar : PubMed/NCBI
6	Osawa Y, Hannun YA, Proia RL and Brenner DA: Roles of AKT and sphingosine kinase in the antiapoptotic effects of bile duct ligation in mouse liver. Hepatology. 42:1320–1328. 2005. View Article : Google Scholar : PubMed/NCBI
7	Bourbonnais E, Raymond VA, Ethier C, Nguyen BN, El-Leil MS, Meloche S and Bilodeau M: Liver fibrosis protects mice from acute hepatocellular injury. Gastroenterology. 142:130–139.e4. 2012. View Article : Google Scholar
8	Javaherian K, Liu JF and Wang JC: Nonhistone proteins HMG1 and HMG2 change the DNA helical structure. Science. 199:1345–1346. 1978. View Article : Google Scholar : PubMed/NCBI
9	Chen R, Hou W, Zhang Q, Kang R, Fan XG and Tang D: Emerging role of high-mobility group box 1 (HMGB1) in liver diseases. Mol Med. 19:357–366. 2013. View Article : Google Scholar : PubMed/NCBI
10	Li LC, Gao J and Li J: Emerging role of HMGB1 in fibrotic diseases. J Cell Mol Med. 18:2331–2339. 2014. View Article : Google Scholar : PubMed/NCBI
11	Kang R, Chen R, Zhang Q, Hou W, Wu S, Cao L, Huang J, Yu Y, Fan XG, Yan Z, et al: HMGB1 in health and disease. Mol Aspects Med. 40:1–116. 2014. View Article : Google Scholar : PubMed/NCBI
12	Andersson U and Tracey KJ: HMGB1 is a therapeutic target for sterile inflammation and infection. Annu Rev Immunol. 29:139–162. 2011. View Article : Google Scholar : PubMed/NCBI
13	Huang H, Nace GW, McDonald KA, Tai S, Klune JR, Rosborough BR, Ding Q, Loughran P, Zhu X, Beer-Stolz D, et al: Hepatocyte-specific high-mobility group box 1 deletion worsens the injury in liver ischemia/reperfusion: A role for intracellular high-mobility group box 1 in cellular protection. Hepatology. 59:1984–1997. 2014. View Article : Google Scholar : PubMed/NCBI
14	Kamo N, Ke B, Ghaffari AA, Shen XD, Busuttil RW, Cheng G and Kupiec-Weglinski JW: ASC/caspase-1/IL-1β signaling triggers inflammatory responses by promoting HMGB1 induction in liver ischemia/reperfusion injury. Hepatology. 58:351–362. 2013. View Article : Google Scholar : PubMed/NCBI
15	Sims GP, Rowe DC, Rietdijk ST, Herbst R and Coyle AJ: HMGB1 and RAGE in inflammation and cancer. Annu Rev Immunol. 28:367–388. 2010. View Article : Google Scholar : PubMed/NCBI
16	Yanai H, Ban T, Wang Z, Choi MK, Kawamura T, Negishi H, Nakasato M, Lu Y, Hangai S, Koshiba R, et al: HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses. Nature. 462:99–103. 2009. View Article : Google Scholar : PubMed/NCBI
17	Albayrak A, Uyanik MH, Cerrah S, Altas S, Dursun H, Demir M and Uslu H: Is HMGB1 a new indirect marker for revealing fibrosis in chronic hepatitis and a new therapeutic target in treatment? Viral Immunol. 23:633–638. 2010. View Article : Google Scholar : PubMed/NCBI
18	Wang FP, Li L, Li J, Wang JY, Wang LY and Jiang W: High mobility group box-1 promotes the proliferation and migration of hepatic stellate cells via TLR4-dependent signal pathways of PI3K/Akt and JNK. PLoS One. 8:e643732013. View Article : Google Scholar : PubMed/NCBI
19	Gong Q, Zhang H, Li JH, Duan LH, Zhong S, Kong XL, Zheng F, Tan Z, Xiong P, Chen G, et al: High-mobility group box 1 exacerbates concanavalin A-induced hepatic injury in mice. J Mol Med (Berl). 88:1289–1298. 2010. View Article : Google Scholar
20	Zhou RR, Zhao SS, Zou MX, Zhang P, Zhang BX, Dai XH, Li N, Liu HB, Wang H and Fan XG: HMGB1 cytoplasmic translocation in patients with acute liver failure. BMC Gastroenterol. 11(21)2011. View Article : Google Scholar
21	Kuroda N, Inoue K, Ikeda T, Hara Y, Wake K and Sato T: Apoptotic response through a high mobility box 1 protein-dependent mechanism in LPS/GalN-induced mouse liver failure and glycyrrhizin-mediated inhibition. PLoS One. 9:e928842014. View Article : Google Scholar : PubMed/NCBI
22	Antoine DJ, Jenkins RE, Dear JW, Williams DP, McGill MR, Sharpe MR, Craig DG, Simpson KJ, Jaeschke H and Park BK: Molecular forms of HMGB1 and keratin-18 as mechanistic biomarkers for mode of cell death and prognosis during clinical acetaminophen hepatotoxicity. J Hepatol. 56:1070–1079. 2012. View Article : Google Scholar : PubMed/NCBI
23	Tsung A, Klune JR, Zhang X, Jeyabalan G, Cao Z, Peng X, Stolz DB, Geller DA, Rosengart MR and Billiar TR: HMGB1 release induced by liver ischemia involves toll-like receptor 4 dependent reactive oxygen species production and calcium-mediated signaling. J Exp Med. 204:2913–2923. 2007. View Article : Google Scholar : PubMed/NCBI
24	National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals: Guide for the Care and Use of Laboratory Animals. 8th edition. National Academies Press; Washington (DC): 2011
25	Lefkowitch JH: Pathologic diagnosis of liver disease. Hepatology - A Textbook of Liver Disease. Zakim D and Boyer TD: W.B. Saunders Company; Philadelphia: pp. 844–871. 1996
26	Untergrasser A, Cutcutache I, Koressaar T, Ye J, Faircloth BC, Remm M and Rozen SG: Primer 3 - new capabilities and interfaces. Nucleic Acids Res. 40:e1152012. View Article : Google Scholar
27	Dechêne A, Sowa JP, Gieseler RK, Jochum C, Bechmann LP, El Fouly A, Schlattjan M, Saner F, Baba HA, Paul A, et al: Acute liver failure is associated with elevated liver stiffness and hepatic stellate cell activation. Hepatology. 52:1008–1016. 2010. View Article : Google Scholar : PubMed/NCBI
28	He Y, Jin L, Wang J, Yan Z, Chen T and Zhao Y: Mechanisms of fibrosis in acute liver failure. Liver Int. 35:1877–1885. 2015. View Article : Google Scholar
29	Yang H, Hreggvidsdottir HS, Palmblad K, Wang H, Ochani M, Li J, Lu B, Chavan S, Rosas-Ballina M, Al-Abed Y, et al: A critical cysteine is required for HMGB1 binding to Toll-like receptor 4 and activation of macrophage cytokine release. Proc Natl Acad Sci USA. 107:11942–11947. 2010. View Article : Google Scholar : PubMed/NCBI
30	Jung JH, Park JH, Jee MH, Keum SJ, Cho MS, Yoon SK and Jang SK: Hepatitis C virus infection is blocked by HMGB1 released from virus-infected cells. J Virol. 85:9359–9368. 2011. View Article : Google Scholar : PubMed/NCBI
31	Youn JH and Shin JS: Nucleocytoplasmic shuttling of HMGB1 is regulated by phosphorylation that redirects it toward secretion. J Immunol. 177:7889–7897. 2006. View Article : Google Scholar : PubMed/NCBI
32	Bonaldi T, Talamo F, Scaffidi P, Ferrera D, Porto A, Bachi A, Rubartelli A, Agresti A and Bianchi ME: Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J. 22:5551–5560. 2003. View Article : Google Scholar : PubMed/NCBI