ACS DIVISION OF BIOLOGICAL CHEMISTRY

October 29th, 2015 by Shanmugam, N. K. N., Chen, K., Cherayil, B. J.

The liver hormone hepcidin is the central regulator of systemic iron metabolism. Its increased expression in inflammatory states leads to hypoferremia and anemia. Elucidation of the mechanisms that upregulate hepcidin during inflammation is essential for developing rational therapies for this anemia. Using mouse models of inflammatory bowel disease, we have shown previously that colitis-associated hepcidin induction is influenced by intestinal microbiota composition. Here, we investigate how two commensal bacteria, Bifidobacterium longum and Bacteroides fragilis, representative members of the gut microbiota, affect hepcidin expression. We found that supernatants of a human macrophage cell line infected with either of the bacteria upregulated hepcidin when added to a human hepatocyte cell line. This activity was abrogated by neutralization of IL-1β. Moreover, purified IL-1β increased hepcidin expression when added to the hepatocyte line or primary human hepatocytes, and when injected into mice. IL-1β activated the bone morphogenetic protein (BMP) signaling pathway in the hepatocytes and in mouse liver as indicated by increased phosphorylation of small-mothers against decapentaplegic (SMAD) proteins. Activation of BMP signaling correlated with IL-1β-induced expression of BMP2 in human hepatocytes and activin B in mouse liver. Treatment of hepatocytes with two different chemical inhibitors of BMP signaling, or with a neutralizing antibody to BMP2, prevented IL-1β-induced upregulation of hepcidin. Our results clarify how commensal bacteria affect hepcidin expression, and reveal a novel connection between IL-1β and activation of BMP signaling. They also suggest that there may be differences between mice and humans with respect to the mechanism by which IL-1β upregulates hepcidin.