title: Decreased Tim-3 expression is associated with functional abnormalities of monocytes in decompensated cirrhosis without overt bacterial infection.
abstract: OBJECTIVE
  Patients with advanced cirrhosis usually exhibit altered monocyte function. However, the molecular mechanisms underlying the functional changes of monocytes are poorly understood.
  
  
  METHODS
  We investigated the role of T-cell immunoglobulin domain and mucin domain-containing molecule-3 (Tim-3) in regulating monocyte function in 94 patients with decompensated liver cirrhosis (DC-LC) (decompensation was defined by ascites, hepatic encephalopathy or upper gastrointestinal bleeding), 58 with compensated liver cirrhosis (C-LC) and 52 healthy controls (HC) by characterizing the frequency of Tim-3(+) monocytes, their phagocytosis capacity, HLA-DR expression, cytokine secretion and MAP kinase activation induced by lipopolysaccharide (LPS).
  
  
  RESULTS
  Tim-3 expression on CD14(+) monocytes in DC-LC group were significantly lower than that in C-LC and HC and were associated with increased levels of plasma endotoxin, enhanced cytokine production, decreased phagocytic capacity, and reduced HLA-DR expression. Tim-3 expression on monocytes and monocyte function did not differ between C-LC and HC group. Tim-3(+)CD14(+) cells had more potent phagocytic capacity, higher levels of HLA-DR, CD86, CD80, CD163, and CD206 expression, but lower levels of CD1a and CD83, related to that of Tim-3(-)CD14(+) monocytes. In addition, Tim-3(+)CD14(+) cells produced less TNF-α but higher levels of IL-10 in response to LPS. Treatment with anti-Tim-3 antibody significantly reduced phagocytic capacity, but enhanced LPS-stimulated TNF-α, IL-6, and IL-10 secretion. Furthermore, blocking Tim-3 signaling increased p38 MAP kinase phosphorylation in monocytes upon LPS stimulation.
  
  
  CONCLUSIONS
  Downregulation of Tim-3 expression was associated with endotoxemia and functional alterations of monocytes in patients with decompensated cirrhosis.
authors.affiliation: State Key Lab of Diagnostic and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Shi
authors.affiliation: State Key Lab of Diagnostic and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.affiliation: State Key Lab of Diagnostic and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Laboratory Medicine, Zhejiang Medical College, Hangzhou, China.
authors.forename: Guangzhong
authors.initials: G
authors.lastname: Song
authors.affiliation: Department of Epidemiology and Healthy Statistics, Zhejiang University School of Public Health, Hangzhou, China.
authors.forename: Yihua
authors.initials: Y
authors.lastname: Wu
authors.affiliation: State Key Lab of Diagnostic and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wei
authors.affiliation: State Key Lab of Diagnostic and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Electronic address: zju.zhichen@gmail.com.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000328:Adult; D001424:Bacterial Infections; D005260:Female; D005500:Follow-Up Studies; D006684:HLA-DR Antigens / Q000276:immunology / Q000378:metabolism; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D008103:Liver Cirrhosis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis*; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D012189:Retrospective Studies; D015398:Signal Transduction
chemical_list: C448908:HAVCR2 protein, human; D006684:HLA-DR Antigens; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins
keywords: Cirrhosis; Decompensation; Endotoxemia; Monocyte; Tim-3