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.
Highlights
Acute liver failure (ALF) occurs when the extent of hepatocyte death exceeds the liver’s regenerative capacity
BrdU incorporation was increased in both wild type (WT) and interleukin-1 receptor antagonist (IL-1ra) KO mice at 24 h after hepatectomy and reached maximal levels at 48 h
Western blot analysing proliferating cell nuclear antigen (PCNA) expression (Figure 1B) increased at 24 h after hepatectomy in WT and in IL-1ra KO mice but was significantly lower in IL-1ra KO mice at 48 h compared to WT mice (1.82 arbitrary unit (a. u.) 60.53 vs 0.4060.33, respectively) confirming the results obtained by BrdU incorporation
Summary
Acute liver failure (ALF) occurs when the extent of hepatocyte death exceeds the liver’s regenerative capacity. The regeneration of native liver may be impaired by accumulation of various toxic substances such as ammonia or nitric acid [1]. This clinical devastating syndrome is associated with a significant morbidity and mortality reaching 80%. Liver transplantation is currently the only effective therapy for those patients who are unlikely to recover with standard care. The improvement of liver regeneration by cytokine therapy is a potential solution to increase the number of patients in whom the native liver regenerates sufficiently to resume normal function. Cytokine 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
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