Pathogenesis of Concanavalin A induced autoimmune hepatitis in mice

Background/Aims: Autoimmune hepatitis (AIH) is a chronic necroinflammatory disease of the liver whose pathogenic mechanisms have not yet been elucidated. Moreover, the current treatment used for the vast majority of AIH patients is largely dependent on immunosuppressant administration and liver transplantation. However, research on the pathogenesis of AIH and effective new treatments for AIH have been hampered by a lack of animal models that accurately reproduce the human condition. Methods: AIH models created by concanavalin A (ConA) injections at different times and doses. The levels of ALT, AST, LDH and inflammatory cytokines were examined at various times after 20 mg/kg ConA was administered by ELISA using commercially available kits. Moreover, liver pathological changes were observed by flow cytometry (FCM) and H&E staining. Results: Our experiments demonstrated that the levels of ALT, AST, LDH and several inflammatory cytokines, including TNF-α, IFN-γ, and IL-6, were higher in the 20 mg/kg 12 h ConA group than in the other groups. Importantly, the numbers of activated CD4+ and CD8+ T lymphocytes in the blood, spleen and liver were calculated. These results showed that ConA (20 mg/kg for 12 h)-induced hepatitis was similar to that in clinical AIH patients. Furthermore, we found that the number of MDSCs in the blood was significantly increased in the ConA (20 mg/kg for 12 h) group compared with controls. Our findings indicated that ConA (20 mg/kg for 12 h)-induced hepatitis could be used as an experimental murine model that mirrors most of the pathogenic properties of human type I AIH. Conclusion: This model [ConA (20 mg/kg for 12 h)] provides a valuable tool for studying AIH immunopathogenesis and rapidly assessing novel therapeutic approaches.

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Characterization and functional prediction of the microRNAs differentially expressed in a mouse model of concanavalin A-induced autoimmune hepatitis

International Journal of Medical Sciences ◽

10.7150/ijms.47766 ◽

2020 ◽

Vol 17 (15) ◽

pp. 2312-2327 ◽

Cited By ~ 1

Author(s):

Yang Liu ◽

Hao Chen ◽

Jianheng Hao ◽

Zhencheng Li ◽

Tiezheng Hou ◽

...

Keyword(s):

Mouse Model ◽

Autoimmune Hepatitis ◽

Concanavalin A ◽

Differentially Expressed ◽

Functional Prediction

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The farnesyltransferase inhibitor tipifarnib protects against autoimmune hepatitis induced by Concanavalin A

International Immunopharmacology ◽

10.1016/j.intimp.2020.106462 ◽

2020 ◽

Vol 83 ◽

pp. 106462

Author(s):

Jie Guo ◽

Kazuhiro Shirozu ◽

Tomohiko Akahoshi ◽

Yukie Mizuta ◽

Masaharu Murata ◽

...

Keyword(s):

Autoimmune Hepatitis ◽

Concanavalin A ◽

Farnesyltransferase Inhibitor

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Betulin from Hedyotis hedyotidea ameliorates concanavalin A-induced and T cell-mediated autoimmune hepatitis in mice

Acta Pharmacologica Sinica ◽

10.1038/aps.2016.102 ◽

2016 ◽

Vol 38 (2) ◽

pp. 201-210 ◽

Cited By ~ 10

Author(s):

Yong-qin Zhou ◽

Xiu-fang Weng ◽

Rui Dou ◽

Xiao-sheng Tan ◽

Tian-tian Zhang ◽

...

Keyword(s):

T Cell ◽

Autoimmune Hepatitis ◽

Concanavalin A

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The Protective Effect of Resveratrol on Concanavalin-A-Induced Acute Hepatic Injury in Mice

Gastroenterology Research and Practice ◽

10.1155/2015/506390 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 21

Author(s):

Yingqun Zhou ◽

Kan Chen ◽

Lei He ◽

Yujing Xia ◽

Weiqi Dai ◽

...

Keyword(s):

Autoimmune Hepatitis ◽

Sonic Hedgehog ◽

Concanavalin A ◽

Hepatic Injury ◽

Hedgehog Pathway ◽

Oral Gavage ◽

Pathway Activity ◽

Cytokine Levels ◽

Acute Hepatic Injury ◽

Gli 1

Pharmacologic Relevance.Resveratrol, an antioxidant derived from grapes, has been reported to modulate the inflammatory process. In this study, we investigated the effects of resveratrol and its mechanism of protection on concanavalin-A- (ConA-) induced liver injury in mice.Materials and Methods.Acute autoimmune hepatitis was induced by ConA (20 mg/kg) in Balb/C mice; mice were treated with resveratrol (10, 20, and 30 mg/kg) daily by oral gavage for fourteen days prior to a single intravenous injection of ConA. Eight hours after injection, histologic grading, proinflammatory cytokine levels, and hedgehog pathway activity were determined.Results.After ConA injection, the cytokines IL-2, IL-6, and TNF-αwere increased, and Sonic hedgehog (Shh), Glioblastoma- (Gli-) 1, and Patched (Ptc) levels significantly increased. Pretreatment with resveratrol ameliorated the pathologic effects of ConA-induced autoimmune hepatitis and significantly inhibited IL-2, IL-6, TNF-α, Shh, Gli-1, and Ptc. The effects of resveratrol on the hedgehog pathway were studied by western blotting and immunohistochemistry. Resveratrol decreased Shh expression, possibly by inhibiting Shh expression in order to reduce Gli-1 and Ptc expression.Conclusion.Resveratrol protects against ConA-induced autoimmune hepatitis by decreasing cytokines expression in mice. The decreases seen in Gli-1 and Ptc may correlate with the amelioration of hedgehog pathway activity.

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Formononetin protects against concanavalin-A-induced autoimmune hepatitis in mice through its anti-apoptotic and anti-inflammatory properties

Biochemistry and Cell Biology ◽

10.1139/bcb-2020-0197 ◽

2021 ◽

Vol 99 (2) ◽

pp. 231-240

Author(s):

Guangwei Liu ◽

Wenxia Zhao ◽

Jiameng Bai ◽

Jianjiao Cui ◽

Haowei Liang ◽

...

Keyword(s):

Autoimmune Hepatitis ◽

Concanavalin A ◽

Nuclear Factor Kappa B ◽

Caspase 3 ◽

Receptor Protein ◽

Dependent Manner ◽

Caspase 9 ◽

Apoptotic Protein ◽

Natural Herb ◽

Dose Dependent

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that seriously threatens the health of humans globally. Formononetin (FMN) is a natural herb extract with multiple biological functions. In this study, an experimental model of AIH was established in mice through the use of concanavalin A (ConA). To investigate the effects of FMN on ConA-induced hepatitis, the mice were pretreated with 50 or 100 mg/kg body mass of FMN. The results show that FMN alleviated ConA-induced liver injury of mice in a dose-dependent manner. Moreover, pretreatment with FMN inhibited the apoptosis of hepatocytes in the ConA-treated mice through downregulating the expression of pro-apoptotic proteins (Bax, cleaved caspase 9, and cleaved caspase 3) and upregulating the expression of anti-apoptotic protein (Bcl-2). It was also found that the levels of proinflammatory cytokines were greatly reduced in the serum and liver tissues of mice pretreated with FMN. Further studies showed that FMN reduced the level of phosphorylated nuclear factor kappa B (p-NF-κB) p65 and enhanced the level of IκBα (inhibitor of NF-κB), suggesting that FMN inhibits the activation of the NF-κB signaling pathway. In addition, FMN inhibited activation of the NOD-like receptor protein 3 (NLRP3) inflammasome. Therefore, FMN could be a promising agent for the treatment of AIH.

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