title: Anti-inflammatory effects of hepatocyte growth factor: induction of interleukin-1 receptor antagonist.
abstract: Hepatocyte growth factor (HGF) prevents liver failure in various animal models including endotoxin-induced acute liver failure. We were interested to find out whether human HGF exerts anti-inflammatory effects by modulation of cytokine synthesis. Therefore, human HepG2 cells were cultured with increasing concentrations of HGF. HGF dose-dependently upregulated the production of interleukin-1 receptor antagonist (IL-1Ra). Incubation of HepG2 cells with interleukin-1beta (IL-1beta) caused an increase in IL-1Ra levels, while interleukin-6 (IL-6) had no effect on IL-1Ra synthesis. Co-stimulation of HepG2 cells with HGF + IL-1beta resulted in a synergistic effect on IL-1Ra mRNA and protein expression. Stimulation of freshly isolated mouse hepatocytes from male C57 BL/6 mice with HGF increased IL-1Ra mRNA and protein synthesis dose-dependently. A co-stimulation with HGF and IL-1beta had a synergistic effect on IL-1Ra mRNA expression but only a partially additive effect on IL-1Ra protein synthesis. HGF-induced IL-1Ra production was significantly decreased by the mitogen-activated protein kinase (MAPK) inhibitor PD98059. Accordingly, HGF stimulation specifically increased MAPK-dependent signalling pathway (p42/44). In contrast, in preactivated PBMC mRNA expression and protein synthesis of IL-1Ra, interleukin-10 (IL-10) and tumor necrosis factor-alpha (TNF-alpha) were unaffected after stimulation with HGF. In conclusion, our data suggest that HGF exerts anti-inflammatory effects by modulating the signal transduction cascade leading to increased expression of IL-1Ra, which might explain the protective and regenerative properties of this cytokine in animal models of liver failure.
authors.affiliation: Clinical Division of General Internal Medicine, Clinical Department of Internal Medicine, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
authors.forename: Clemens
authors.initials: C
authors.lastname: Molnar
authors.forename: Elena R
authors.initials: ER
authors.lastname: Garcia-Trevijano
authors.forename: Othmar
authors.initials: O
authors.lastname: Ludwiczek
authors.forename: Dominique
authors.initials: D
authors.lastname: Talabot
authors.forename: Arthur
authors.initials: A
authors.lastname: Kaser
authors.forename: Jose M
authors.initials: JM
authors.lastname: Mato
authors.forename: Gernot
authors.initials: G
authors.lastname: Fritsche
authors.forename: Günter
authors.initials: G
authors.lastname: Weiss
authors.forename: Cem
authors.initials: C
authors.lastname: Gabay
authors.forename: Matias A
authors.initials: MA
authors.lastname: Avila
authors.forename: Herbert
authors.initials: H
authors.lastname: Tilg
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000494:pharmacology; D017093:Liver Failure / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D012795:Sialoglycoproteins / Q000096:biosynthesis*
chemical_list: C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012795:Sialoglycoproteins; D017228:Hepatocyte Growth Factor