C6orf120 gene knockout in rats mitigates concanavalin A‑induced autoimmune hepatitis via regulating NKT cells

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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Hyperproduction of Proinflammatory Cytokines by WSX-1-Deficient NKT Cells in Concanavalin A-Induced Hepatitis

The Journal of Immunology ◽

10.4049/jimmunol.172.6.3590 ◽

2004 ◽

Vol 172 (6) ◽

pp. 3590-3596 ◽

Cited By ~ 67

Author(s):

Atsushi Yamanaka ◽

Shinjiro Hamano ◽

Yoshiyuki Miyazaki ◽

Kazunari Ishii ◽

Atsunobu Takeda ◽

...

Keyword(s):

Proinflammatory Cytokines ◽

Concanavalin A ◽

Nkt Cells

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Augmentation of Vα14 Nkt Cell–Mediated Cytotoxicity by Interleukin 4 in an Autocrine Mechanism Resulting in the Development of Concanavalin a–Induced Hepatitis

Journal of Experimental Medicine ◽

10.1084/jem.191.1.105 ◽

2000 ◽

Vol 191 (1) ◽

pp. 105-114 ◽

Cited By ~ 307

Author(s):

Yoshikatsu Kaneko ◽

Michishige Harada ◽

Tetsu Kawano ◽

Masakatsu Yamashita ◽

Youichi Shibata ◽

...

Keyword(s):

Concanavalin A ◽

Molecular Mechanisms ◽

Fas Ligand ◽

Granzyme B ◽

Nkt Cells ◽

Interleukin 4 ◽

Con A ◽

Short Term Treatment ◽

Nkt Cell ◽

Hepatocyte Injury

The administration of concanavalin A (Con A) induces a rapid severe injury of hepatocytes in mice. Although the Con A–induced hepatitis is considered to be an experimental model of human autoimmune hepatitis, the precise cellular and molecular mechanisms that induce hepatocyte injury remain unclear. Here, we demonstrate that Vα14 NKT cells are required and sufficient for induction of this hepatitis. Moreover, interleukin (IL)-4 produced by Con A–activated Vα14 NKT cells is found to play a crucial role in disease development by augmenting the cytotoxic activity of Vα14 NKT cells in an autocrine fashion. Indeed, short-term treatment with IL-4 induces an increase in the expression of granzyme B and Fas ligand (L) in Vα14 NKT cells. Moreover, Vα14 NKT cells from either perforin knock-out mice or FasL-mutant gld/gld mice fail to induce hepatitis, and hence perforin–granzyme B and FasL appear to be effector molecules in Con A–induced Vα14 NKT cell–mediated hepatocyte injury.

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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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