title: Interleukin 6/gp130-dependent pathways are protective during chronic liver diseases.
abstract: The contribution of the acute phase inducer interleukin 6 (IL-6) in the pathogenesis of liver diseases is yet unclear. Our analysis showed enhanced expression of IL-6 in livers derived from patients with acute and chronic liver diseases. Additionally, IL-6 plasma levels were significantly increased in patients with chronic liver diseases and showed an inverse correlation with biochemical markers of liver function and a positive correlation with inflammatory markers, signs of portal hypertension, and the degree of liver fibrosis. To prove the relevance of these clinical findings, we applied the tetrachlorcarbonide (CCl(4)) model to conditional knockout animals (Cre/loxP system) for gp130, the common signal transducer of IL-6 family cytokines. Cre recombinases were expressed through a hepatocyte (AlfpCre) and a ubiquitous (MxCre) control element. Gp130 deleted mice had a totally abolished STAT3 activation and acute phase response induction, but gp130 deletion had no effect on the degree of acute liver injury and subsequent hepatocyte proliferation. In contrast, during chronic liver injury induced by biweekly application of CCl(4), deletion of the gp130 receptor in nonparenchymal liver cells and not hepatocytes resulted in fibrosis progression. In conclusion, our experiments indicate an involvement of IL-6 in the pathogenesis of liver diseases and suggest a protective role of IL-6/gp130-dependent pathways in nonparenchymal liver cells during fibrosis progression in chronic liver diseases. (Hepatology 2003;38:218-229).
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: Konrad L
authors.initials: KL
authors.lastname: Streetz
authors.forename: Frank
authors.initials: F
authors.lastname: Tacke
authors.forename: Ludger
authors.initials: L
authors.lastname: Leifeld
authors.forename: Torsten
authors.initials: T
authors.lastname: Wüstefeld
authors.forename: Andrea
authors.initials: A
authors.lastname: Graw
authors.forename: Christian
authors.initials: C
authors.lastname: Klein
authors.forename: Kenjii
authors.initials: K
authors.lastname: Kamino
authors.forename: Ulrich
authors.initials: U
authors.lastname: Spengler
authors.forename: Hans
authors.initials: H
authors.lastname: Kreipe
authors.forename: Stefan
authors.initials: S
authors.lastname: Kubicka
authors.forename: Werner
authors.initials: W
authors.lastname: Müller
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D002251:Carbon Tetrachloride; D002455:Cell Division / Q000502:physiology; D002908:Chronic Disease; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D022781:Hepatocytes / Q000166:cytology; D006801:Humans; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood* / Q000235:genetics; D008099:Liver / Q000502:physiology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D017093:Liver Failure / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D004268:DNA-Binding Proteins; C494199:IL6ST protein, human; C494200:Il6st protein, mouse; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014764:Viral Proteins; D050822:Cytokine Receptor gp130; D002251:Carbon Tetrachloride; C045073:Cre recombinase; D019426:Integrases