Blocking interleukin-1 receptor type 1 (IL-1R1) signaling in hepatocytes slows down diethylnitrosamine-induced liver tumor growth in obese mice

Abstract

Background: An increasing number of HCC develops in the context of metabolic dysfunction-associated steatotic liver disease and its inflammatory form, metabolic dysfunction–associated steatohepatitis, even in the absence of cirrhosis. Chronic metabolic inflammation is the driving force of metabolic dysfunction–associated steatotic liver disease progression and a key factor in hepatocarcinogenesis. Given the prominent role of IL-1 signaling in inflammation and metabolic diseases, we investigated the relevance of the hepatocyte-specific IL-1 receptor type 1 knockout in metabolic dysfunction– associated steatohepatitis–related noncirrhotic HCC. Methods: For HCC induction, Il1r1Hep−/− mice received a single i.p. injection of diethylnitrosamine at 2 weeks and were fed with high-fat plus high-carbohydrate diet, starting from 4 weeks. After 18 weeks of diet intervention, mice were sacrificed, and macroscopic and microscopic tumor loads were assessed. Results: Knockout of the hepatic IL-1 receptor type 1 pathway significantly reduced liver tumor growth. Il1r1Hep−/− mice were also less susceptible to hepatic steatosis, insulin resistance, and associated hepatic c-Jun N-terminal kinase activation than their wild-type (WT) littermates. Reduced Ki-67 and cyclin D1 levels, as well as decreased phosphorylation of signal transducer and activator of transcription 3, occur in Il1r1Hep−/− livers, lowering cancer cell proliferation and growth. Additionally, in Il1r1Hep−/− livers, the chemokine (C-X-C motif) ligand 1/2-driven accumulation of myeloid-derived suppressor cells and CD8+ T-cell infiltration were reduced compared to the wild type. Conclusions: Metabolic inflammation mediated by the hepatocytic IL-1 receptor type 1 is a cofactor in mutagenic hepatocarcinogenesis. Targeting IL-1 signaling could be an adjunct strategy to the current immunomodulatory HCC treatments.