Genetic iron overload, or hemochromatosis, can be caused by mutations in HFE, 
hemojuvelin, and hepcidin genes. Hepcidin, a negative regulator of intestinal 
iron absorption, is found to be inappropriately low in both patients and in 
animal models, indicating that proper control of basal hepcidin levels requires 
both hemojuvelin and HFE. In mice, repulsive guidance molecule c (Rgmc, the 
hemojuvelin mouse ortholog) and hepcidin levels are transcriptionally regulated 
during inflammation. Here, we report that basal Rgmc levels in Hfe-deficient 
mice are normal and that these mice retain the ability to suppress Rgmc 
expression after lipopolysaccharide (LPS) challenge. Thus, Rgmc regulation by 
LPS is Hfe-independent. The response of Rgmc to LPS involves signaling through 
toll-like receptor 4 (Tlr4), because Tlr4-deficient mice do not show altered 
Rgmc expression after LPS administration. We further show that tumor necrosis 
factor-alpha, but not interleukin-6, is sufficient to cause Rgmc down-regulation 
by LPS. These results contrast with previous data demonstrating that hepcidin 
levels are directly regulated by interleukin-6 but not by tumor necrosis 
factor-alpha. The regulation of iron-related genes by different cytokines may 
allow for time-dependent control of iron metabolism changes during inflammation 
and may be relevant to chronic inflammation, infections, and cancer settings, 
leading to the development of anemia of chronic disease.