Interleukin 28A aggravates Con A‐induced acute liver injury by promoting the recruitment of M1 macrophages

Abstract

AbstractImmune‐mediated acute hepatic injury is characterized by the destruction of a large number of hepatocytes and severe liver function damage. Interleukin‐28A (IL‐28A), a member of the IL‐10 family, is notable for its antiviral properties. However, despite advances in our understanding of IL‐28A, its role in immune‐mediated acute injury remains unclear. The present study investigated the role of IL‐28A in concanavalin A (Con A)‐induced acute immune liver injury. After Con A injection in mice, IL‐28A level significantly increased. IL‐28A deficiency was found to protect mice from acute liver injury, prolong survival time, and reduce serum aspartate aminotransferase and alanine aminotransferase levels. In contrast, recombinant IL‐28A aggravated liver injury in mice. The proportion of activated M1 macrophages was significantly lower in the IL‐28A‐deficiency group than in the wild‐type mouse group. In adoptive transfer experiments, M1 macrophages from WT could exacerbate mice acute liver injury symptoms in the IL‐28A deficiency group. Furthermore, the expression of proinflammatory cytokines, including tumor necrosis factor‐α (TNF‐α), IL‐12, IL‐6, and IL‐1β, by M1 macrophages decreased significantly in the IL‐28A‐deficiency group. Western blotting demonstrated that IL‐28A deficiency could limit M1 macrophage polarization by modulating the nuclear factor (NF)‐κB, mitogen‐activated protein kinase (MAPK), and interferon regulatory factor (IRF) signaling pathways. In summary, IL‐28A deletion plays an important protective role in the Con A‐induced acute liver injury model and IL‐28A deficiency inhibits the activation of M1 macrophages by inhibiting the NF‐κB, MAPK, and IRF signaling pathways. These results provide a potential new target for the treatment of immune‐related hepatic injury.