title: Interleukin-23 mediates the pathogenesis of LPS/GalN-induced liver injury in mice.
abstract: BACKGROUND
  Interleukin-23 (IL-23) is required for T helper 17 (Th17) cell responses and IL-17 production in hepatitis B virus infection. A previous study showed that the IL-23/IL-17 axis aggravates immune injury in patients with chronic hepatitis B virus infection. However, the role of IL-23 in acute liver injury remains unclear.
  
  
  OBJECTIVE
  The purpose of this study was to determine the role of the inflammatory cytokine IL-23 in lipopolysaccharide/d-galactosamine (LPS/GalN)-induced acute liver injury in mice.
  
  
  METHODS
  Serum IL-23 from patients with chronic hepatitis B virus (CHB), acute-on-chronic liver failure (ACLF) and healthy individuals who served as healthy controls (HCs) was measured by ELISA. An IL-23p19 neutralizing antibody or an IL-23p40 neutralizing antibody was administered intravenously at the time of challenge with LPS (10μg/kg) and GalN (400mg/kg) in C57BL/6 mice. Hepatic pathology and the expression of Th17-related cytokines, including IL-17 and TNF-α; neutrophil chemoattractants, including Cxcl1, Cxcl2, Cxcl9, and Cxcl10; and the stabilization factor Csf3 were assessed in liver tissue.
  
  
  RESULTS
  Serum IL-23 was significantly upregulated in ACLF patients compared with CHB patients and HCs (P<0.05 for both). Serum IL-23 was significantly upregulated in the non-survival group compared with the survival group of ACLF patients, which was consistent with LPS/GalN-induced acute hepatic injury in mice (P<0.05 for both). Moreover, after treatment, serum IL-23 was downregulated in the survival group of ACLF patients (P<0.001). Compared with LPS/GalN mice, mice treated with either an IL-23p19 neutralizing antibody or an IL-23p40 neutralizing antibody showed less severe liver tissue histopathology and significant reductions in the expression of Th17-related inflammatory cytokine, including IL-17 and TNF-α; neutrophil chemoattractants, including Cxcl1, Cxcl2, Cxcl9, and Cxcl10; and stabilization factors Csf3 within the liver tissue compared with LPS/GalN mice (P<0.05 for all).
  
  
  CONCLUSIONS
  High serum IL-23 was associated with mortality in ACLF patients and LPS/GalN-induced acute liver injury in mice. IL-23 neutralizing antibodies attenuated liver injury by reducing the expression of Th17-related inflammatory cytokines, neutrophil chemoattractants and stabilization factors within the liver tissue, which indicated that IL-23 likely functions upstream of Th17-related cytokine and chemokine expression to recruit inflammatory cells into the liver.
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Suxia
authors.initials: S
authors.lastname: Bao
authors.affiliation: Institute of Liver Diseases, Dawn Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200040, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Jianming
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Mingquan
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Mengqi
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Kangkang
authors.initials: K
authors.lastname: Yu
authors.affiliation: Institute of Liver Diseases, Dawn Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200040, China.
authors.forename: Chenghai
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China. Electronic address: gfshi@shmu.edu.cn.
authors.forename: Guangfeng
authors.initials: G
authors.lastname: Shi
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005688:Galactosamine / Q000276:immunology; D006515:Hepatitis B virus / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000276:immunology* / Q000401:mortality; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D053759:Interleukin-23 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D008099:Liver / Q000276:immunology*; D017114:Liver Failure, Acute / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018123:Receptors, Interleukin / Q000378:metabolism*; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C515500:IL23R protein, human; D020381:Interleukin-17; D053759:Interleukin-23; D008070:Lipopolysaccharides; D018123:Receptors, Interleukin; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine
keywords: Acute hepatic injury; Chemokines; IL-23; Neutralizing antibody; Th17 cells