In Chronic Inflammation, There Exists an IL-6 Independent Pathway for the Induction of Hepcidin.

Abstract

The iron regulatory hormone hepcidin is presumed to be the mediator of anemia of inflammation (AI). Patients with hepatic adenomas producing large amounts of hepcidin had severe AI that resolved when the tumors were resected (Weinstein et al, 2002). Patients with disorders associated with AI and mice with acute inflammation also have increased hepcidin. However, hepcidin deficient mice do not develop hypoferremia in response to acute inflammation (Nicolas et al, 2002). We previously showed that IL-6 was necessary for the inflammatory induction of hepcidin and the development of hypoferremia in an acute turpentine model of inflammation (Nemeth et al, 2004). In order to determine whether IL-6 was necessary for the development of AI, we induced chronic peritoneal S. epidermidis abscesses in IL-6 deficient mice (19 with abscesses, 12 controls) and wild type mice with the same genetic background (16 with abscesses, 10 controls). In contrast to our previous results, both IL-6 deficient and wild type mice had a significant rise in hepcidin-1 expression (27.6 vs. 10.9-fold, respectively) but there was no difference between the groups (p=0.939 by 2-way ANOVA). Both IL-6 deficient and control mice demonstrated a similar small but significant fall in hematocrit (49% to 44% vs. 46% to 42%, p=0.538 by 2-way ANOVA) in response to the abscesses. IL-6 is not necessary for the induction of hepcidin or the development of AI in a physiological model of infection. Experiments are underway to define which other inflammatory mediators induce hepcidin.