Anti-inflammatory effects of hepatocyte growth factor: induction of interleukin-1 receptor antagonist.
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.
Molnar
Clemens
C
Clinical Division of General Internal Medicine, Clinical Department of Internal Medicine, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
Garcia-Trevijano
Elena R
ER
Ludwiczek
Othmar
O
Talabot
Dominique
D
Kaser
Arthur
A
Mato
Jose M
JM
Fritsche
Gernot
G
Weiss
Günter
G
Gabay
Cem
C
Avila
Matias A
MA
Tilg
Herbert
H
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*
C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012795:Sialoglycoproteins; D017228:Hepatocyte Growth Factor