IL-1β secreted by macrophages in response to commensal bacteria acts together with bone morphogenetic protein signals to increase hepcidin expression in hepatocytes (MUC5P.758)

Abstract

Abstract Elevated expression of the iron regulating hormone hepcidin leads to abnormalities of iron metabolism in inflammatory diseases. The mechanisms involved in inflammation-associated hepcidin upregulation are not well understood. We have shown in mouse IBD models that the commensal microbiota significantly influences hepcidin expression. Here we describe experiments to elucidate how commensal bacteria upregulate hepcidin. Differentiated THP-1 macrophages were infected with the commensal Bifidobacterium infantis. Sterile supernatants of the infected, but not uninfected, THP-1 cells increased hepcidin expression in HuH7 human hepatocytes, whereas direct infection of HuH7 cells failed to induce hepcidin. The infected THP-1 cells secreted IL-1β, neutralization of which significantly inhibited induction of hepcidin expression in the HuH7 cells. Pretreatment of the HuH7 cells with inhibitors of the bone morphogenetic protein (BMP) signaling pathway also prevented the upregulation of hepcidin by the supernatant of B. infantis-infected THP-1 cells. Our findings demonstrate that IL-1β secreted by macrophages in response to commensal bacteria can induce increased expression of hepcidin in hepatocytes. An activator of the BMP signaling pathway is also involved but the identity and source of this molecule are yet to be determined. Furthermore, our results suggest that neutralization of IL-1β may be useful in preventing or treating the dysregulation of iron homeostasis associated with IBD.