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Interleukin-1 Receptor Antagonist Modulates Liver Inflammation and Fibrosis in Mice in a Model-Dependent Manner.

Meier, Raphael P H; Meyer, Jeremy; Montanari, Elisa; Lacotte, Stephanie; Balaphas, Alexandre; Muller, Yannick D; Clément, Sophie; Negro, Francesco; Toso, Christian; Morel, Philippe; Buhler, Leo H.
Int J Mol Sci; 20(6)2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30875826

BACKGROUND:

Interleukin-1 (IL-1)ß and IL-1 receptor antagonist (IL-1Ra) have been proposed as important mediators during chronic liver diseases. We aimed to determine whether the modulation of IL-1ß signaling with IL-1Ra impacts on liver fibrosis.

METHODS:

We assessed the effects of IL-1ß on human hepatic stellate cells (HSC) and in mouse models of liver fibrosis induced by bile duct ligation (BDL) or carbon tetrachloride treatment (CCl-4).

RESULTS:

Human HSCs treated with IL-1ß had increased IL-1ß, IL-1Ra, and MMP-9 expressions in vitro. HSCs treated with IL-1ß had reduced α-smooth muscle actin expression. These effects were all prevented by IL-1Ra treatment. In the BDL model, liver fibrosis and Kuppfer cell numbers were increased in IL-1Ra KO mice compared to wild type mice and wild type mice treated with IL-1Ra. In contrast, after CCl-4 treatment, fibrosis, HSC and Kupffer cell numbers were decreased in IL-1Ra KO mice compared to the other groups. IL-1Ra treatment provided a modest protective effect in the BDL model and was pro-fibrotic in the CCl-4 model.

CONCLUSIONS:

We demonstrated bivalent effects of IL-1Ra during liver fibrosis in mice. IL-1Ra was detrimental in the CCl-4 model, whereas it was protective in the BDL model. Altogether these data suggest that blocking IL-1-mediated inflammation may be beneficial only in selective liver fibrotic disease.
Selo DaSilva