IL-6 and Anemia of Inflammation.

BACKGROUND: Anemia of inflammation (AI, anemia of chronic disease) is an iron-restricted anemia caused by hepcidin limiting the supply of iron for erythropoiesis. We had previously shown that IL-6 was necessary for the induction of hepcidin and the development of hypoferremia during acute inflammation in vivo (Nemeth E et al, JCI, 2004). In vitro, IL-1 (Lee P et al, PNAS, 2005) and TGF-β (unpublished data) can also stimulate hepcidin production in primary murine hepatocytes in an IL-6 independent fashion. METHODS: We sought to determine whether IL-6 was necessary for the development of AI using a model of chronic peritonitis in IL-6 deficient mice and wild type (WT) controls. RESULTS: IL-6 deficient mice developed anemia of similar severity as their WT counterparts. WT mice developed microcytic anemia consistent with inflammation-induced iron restriction. In contrast, the inflamed IL-6 deficient mice developed mild macrocytosis indicating markedly different erythrocyte iron metabolism. Hepcidin mRNA increased in WT mice but not IL-6 deficient mice in response to inflammation. CONCLUSION: IL-6 is the principal regulator of hepcidin during acute and chronic inflammation. However, anemia still occurs in the absence of IL-6. The difference in mean corpuscular volume implies that the mechanism of anemia in IL-6 deficient mice is likely different than in WT mice.