Anemia of inflammation (AI, anemia of chronic disease) is a common occurrence in the ICU and in pulmonary inflammatory diseases. The principal finding of AI is decreased serum iron with preserved tissue stores. The iron regulatory hormone hepcidin is most likely the mediator of AI. Hepcidin blocks iron absorption, release of recycled iron from macrophages and mobilization of stored iron from liver. We sought to determine whether hepcidin recapitulates the acute hypoferremia seen in anemia of inflammation and to determine the inflammatory mediators that regulate its expression.
We have shown that IL-6 is necessary for the upregulation of hepcidin in acute sterile inflammation (Nemeth et al, JCI 2004). In this study, we created a model of infectious peritonitis in IL-6 deficient mice and WT controls. We treated primary human hepatocytes with various cytokines to further study the regulation of hepcidin. Finally, we injected hepcidin and inactive peptide into mice to test whether they cause hypoferremia.
Both WT and IL-6 knockouts increased hepcidin significantly and developed anemia but there was no difference between the two groups. In primary hepatocytes, TGFβ-1 induced hepcidin mRNA to a similar degree as IL-6 and the effect could not be blocked by the addition of anti-IL-6 antibody. IL-1 also induced hepcidin but this was IL-6-dependent since the anti-IL-6 antibody blocked the effect. IFN-gamma, BMP, and IL-10 did not affect hepcidin expression. A single IP dose of hepcidin and showed a dose-dependent fall in serum iron from 32±8 μM in control mice to 6.4±1.2 μM in mice injected with 50 μg hepcidin (Spearman R=-0.929, p<0.001). The effect was rapid, with maximal suppression achieved within 1 hour of hepcidin administration and lasting at least 48 hours.
This is the first evidence that hepcidin can directly cause the acute hypoferremia seen in AI. Hepcidin increase in inflammation is mediated by IL-6, but other cytokines, such as TGFβ, may be important during infection.
Targeting hepcidin may help prevent AI without interfering with important inflammatory regulators.
Seth Rivera, None.