Repression of Repulsive Guidance Molecule C during Inflammation Is Independent of Hfe and Involves Tumor Necrosis Factor-α

Abstract

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-␣, 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-␣. 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.

Hepcidin expression in mouse retina and its regulation via lipopolysaccharide/Toll-like receptor-4 pathway independent of Hfe

“…Alternatively, proinflammatory mediators, released in response to LPS in one eye, may travel to the contralateral eye via circulation and elicit their effects. It has been shown that LPS may produce its effects on hepcidin expression in the liver through IL-6 and/or TNF-α in an autocrine manner [35]. Such intermediates may also be released into circulation from the retina of the LPS-injected eye and subsequently elicit their effects on hepcidin expression in the contralateral eye.…”

Friend of GATA suppresses the GATA-induced transcription of hepcidin in hepatocytes through a GATA-regulatory element in the HAMP promoter

“…The first-strand cDNA synthesized (20 ml) was diluted to 120 ml with RNase-free water, 5 ml of which was used as a template in quantitative RT-PCRs. Adult human liver total RNA was purchased from Clontech Laboratories, Inc. Quantification of gene expression was performed by a Rotor Gene 3000 Real-time DNA Detection System (Montreal Biotech, Kirkland, QC, Canada) with QuantiTect SYBRGreen I PCR kits (Qiagen), as described previously (Constante et al 2007). The oligonucleotides used to amplify b-actin, HAMP, GATA-2, GATA-3, GATA-4, GATA-6, FOG-1, and FOG-2 genes are listed in Table 1.…”

Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications

“…10 Most of the murine models display a mild anemia and hypoferremia after injection of inflammatory stimuli, but the hypoferremia normalizes within 24 to 72 hours. 18 Here, we report a rat model in which arthritis was induced on intraperitoneal administration of peptidoglycan-polysaccharidefragments (PG-APS). Arthritic rats develop a long-lasting anemia 19 with the features of ACD.…”

“…10 Most of the murine models display a mild anemia and hypoferremia after injection of inflammatory stimuli, but the hypoferremia normalizes within 24 to 72 hours. 18 Submitted December 19, 2008; accepted March 3, 2009. Prepublished online as Blood First Edition paper, March 17, 2009; DOI 10.1182 DOI 10.…”