Interleukin-1 Receptor Antagonist Modulates the Early Phase of Liver Regeneration after Partial Hepatectomy in Mice

Abstract

BackgroundCytokine administration is a potential therapy for acute liver failure by reducing inflammatory responses and favour hepatocyte regeneration. The aim of this study was to evaluate the role of interleukin-1 receptor antagonist (IL-1ra) during liver regeneration and to study the effect of a recombinant human IL-1ra on liver regeneration.MethodsWe performed 70%-hepatectomy in wild type (WT) mice, IL-1ra knock-out (KO) mice and in WT mice treated by anakinra. We analyzed liver regeneration at regular intervals by measuring the blood levels of cytokines, the hepatocyte proliferation by bromodeoxyuridin (BrdU) incorporation, proliferating cell nuclear antigen (PCNA) and Cyclin D1 expression. The effect of anakinra on hepatocyte proliferation was also tested in vitro using human hepatocytes.ResultsAt 24h and at 48h after hepatectomy, IL-1ra KO mice had significantly higher levels of pro-inflammatory cytokines (IL-6, IL-1β and MCP-1) and a reduced and delayed hepatocyte proliferation measured by BrdU incorporation, PCNA and Cyclin D1 protein levels, when compared to WT mice. IGFBP-1 and C/EBPβ expression was significantly decreased in IL-1ra KO compared to WT mice. WT mice treated with anakinra showed significantly decreased levels of IL-6 and significantly higher hepatocyte proliferation at 24h compared to untreated WT mice. In vitro, primary human hepatocytes treated with anakinra showed significantly higher proliferation at 24h compared to hepatocytes without treatment.ConclusionIL1ra modulates the early phase of liver regeneration by decreasing the inflammatory stress and accelerating the entry of hepatocytes in proliferation. IL1ra might be a therapeutic target to improve hepatocyte proliferation.

IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice

“…Our data showed a protective effect of IL-1Ra in the development of ALD. A protective effect of the blockade of IL-1 signaling has also been shown in TLR9-associated liver injury (14), recovery after partial hepatectomy in mice (36), and liver failure induced by d-galactosamine (37). Moreover, we demonstrated, for the first time to our knowledge, that administration of IL-1Ra inhibited progression of already established ALD and facilitated recovery from acute-on-chronic alcoholic liver injury, a scenario observed in the majority of patients presenting with acute alcoholic hepatitis (1).…”

Amniotic-Fluid–Derived Mesenchymal Stem Cells Overexpressing Interleukin-1 Receptor Antagonist Improve Fulminant Hepatic Failure

“…Recent studies have shown that FHF is an inflammatory disease; this conclusion is supported clinically by elevated serum levels of immuno-inflammatory cytokines, including IL-1, TNF, IL-6 [7], and IL-8 [8]. Uncontrolled hepatic immunoactivation is regarded as the primary pathological mechanism of FHF [9].…”

Spontaneous and LPS-Induced Production of 26 Cytokines Secreted by Blood Cells of Patients With Liver Cirrhosis During of Cell Therapy

“…Поскольку воспалительная реакция яв-ляется триггером и поддерживает развитие фи-броза, значительный интерес в лечении ЦП отво-дится противовоспалительным стратегиям [41]. Действительно, подавление воспаления благо-приятствует регенерации печени при острой пе-ченочной недостаточности [47,57] и позитивно сказывается на функциях печени при тяжелых формах алкогольной болезни [7,52].…”