期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 290, 期 51, 页码 30637-30647出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M115.689190
关键词
-
资金
- National Institutes of Health [R01 AI089700]
- China Scholarship Council
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 up-regulate 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 up-regulated hepcidin when added to a human hepatocyte cell line. This activity was abrogated by neutralization of IL-1 beta. Moreover, purified IL-1 beta increased hepcidin expression when added to the hepatocyte line or primary human hepatocytes and when injected into mice. IL-1 beta activated the bone morphogenetic protein (BMP) signaling pathway in hepatocytes and in mouse liver, as indicated by increased phosphorylation of small mothers against decapentaplegic proteins. Activation of BMP signaling correlated with IL-1 beta -induced expression of BMP2in human hepatocytes and activinBin mouse liver. Treatment of hepatocytes with two different chemical inhibitors of BMP signaling or with a neutralizing antibody to BMP2 prevented IL-1 beta-induced up-regulation of hepcidin. Our results clarify how commensal bacteria affect hepcidin expression and reveal a novel connection between IL-1 beta 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-1 beta up-regulates hepcidin.
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