Open Access

ARTICLE

Anti-inflammatory effects of hepatocyte growth factor: induction of interleukin-1 receptor antagonist

Clemens Molnar¹, Elena R. Garcia-Trevijano², Othmar Ludwiczek¹, Dominique Talabot³, Arthur Kaser¹, Jose M. Mato², Gernot Fritsche¹, Günter Weiss¹, Cem Gabay³, Matias A. Avila², Herbert Tilg¹

1 Clinical Division of General Internal Medicine, Clinical Department of Internal Medicine, Innsbruck Medical University, ANICHSTRAßE 35, 6020 INNSBRUCK, Austria
2 Division of Hepatology and Gene Therapy, School of Medicine, University of Navarra, Pamplona, Spain
3 Division of Rheumatology, University Hospital of Geneva, Geneva, Switzerland

* Corresponding Author: H. Tilg,

European Cytokine Network 2004, 15(4), 303-311.

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-1β (IL-1β) 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-1β 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-1β 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-α (TNF-α) 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.

---

Keywords

---