An inhibitor of interleukin-6 trans-signalling, sgp130, contributes to impaired acute phase response in human chronic liver disease.
In chronic liver disease, high circulating interleukin (IL)-6 contrasts with a poor acute phase response. We evaluated the impact of liver and circulating IL-6-receptor (IL-6R) forms on IL-6 bioactivity in chronic liver disease. IL-6, soluble IL-6-receptor and sgp130 levels were assayed in plasma from 45 patients with alcoholic liver disease, 84 with hepatitis C virus (HCV) infection undergoing transjugular liver biopsies and 15 healthy subjects. IL-6R mRNA was quantified on liver extracts from 54 patients with alcoholic liver disease with or without cirrhosis and 18 HCV-infected patients. The effect of gp130-Fc on fibrinogen secretion induced by IL-6 trans-signalling was evaluated on hepatocyte cultures. Levels of plasma IL-6 and sgp130, but not soluble IL-6R, increased with the stage of chronic liver disease, and correlated significantly with disease severity. Alcoholic liver disease patients had higher plasma IL-6 levels than hepatitis C, but lower liver IL-6R expression. In alcoholic and HCV-related liver diseases, liver IL-6R expression decreased with advanced fibrosis stage. In vitro, on hepatocytes, gp130-Fc blunted the acute phase response while soluble IL-6R enhanced IL-6 stimulation. In advanced chronic liver disease, high plasma IL-6 is associated with low liver IL-6R expression. This situation enables high plasma sgp130 to act as a major negative regulator of liver IL-6 trans-signalling, as demonstrated functionally here on hepatocytes. This might explain the poor acute phase response induced by IL-6 in chronic liver disease.
Lemmers
A
A
Department of Gastroenterology, Hepato-Pancreatology and Digestive Oncology, Erasme Hospital, Universite Libre de Bruxelles (ULB), Bruxelles, Belgium. arnaud.lemmers@erasme.ulb.ac.be
Gustot
T
T
Durnez
A
A
Evrard
S
S
Moreno
C
C
Quertinmont
E
E
Vercruysse
V
V
Demetter
P
P
Franchimont
D
D
Le Moine
O
O
Geerts
A
A
Devière
J
J
D000210:Acute-Phase Reaction / Q000276:immunology*; D000328:Adult; D015415:Biomarkers / Q000097:blood; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130 / Q000097:blood* / Q000235:genetics; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D019698:Hepatitis C, Chronic / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology; D006801:Humans; D006975:Hypertension, Portal / Q000276:immunology; D015850:Interleukin-6 / Q000097:blood*; D008108:Liver Diseases, Alcoholic / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics; D019947:Receptors, Interleukin-6 / Q000097:blood / Q000235:genetics; D014407:Tumor Cells, Cultured
D015415:Biomarkers; D015850:Interleukin-6; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6; D050822:Cytokine Receptor gp130