HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Repression of repulsive guidance molecule C during inflammation is independent of Hfe and involves tumor necrosis factor-alpha.

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-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.
AuthorsMarco Constante, Dongmei Wang, Valérie-Ann Raymond, Marc Bilodeau, Manuela M Santos
JournalThe American journal of pathology (Am J Pathol) Vol. 170 Issue 2 Pg. 497-504 (Feb 2007) ISSN: 0002-9440 [Print] United States
PMID17255318 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antimicrobial Cationic Peptides
  • GPI-Linked Proteins
  • HAMP protein, human
  • Hamp protein, mouse
  • Hemochromatosis Protein
  • Hepcidins
  • Hfe protein, mouse
  • Histocompatibility Antigens Class I
  • Interleukin-6
  • Lipopolysaccharides
  • Membrane Proteins
  • Muscle Proteins
  • Rgmc protein, mouse
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • Iron
Topics
  • Animals
  • Antimicrobial Cationic Peptides (genetics, metabolism)
  • Down-Regulation (drug effects, genetics)
  • GPI-Linked Proteins
  • Hemochromatosis (genetics, metabolism)
  • Hemochromatosis Protein
  • Hepcidins
  • Histocompatibility Antigens Class I (metabolism)
  • Humans
  • Inflammation (genetics, metabolism)
  • Interleukin-6 (metabolism)
  • Iron (metabolism)
  • Lipopolysaccharides (pharmacology)
  • Membrane Proteins (deficiency, metabolism)
  • Mice
  • Muscle Proteins (biosynthesis)
  • Signal Transduction (drug effects, genetics)
  • Toll-Like Receptor 4 (deficiency, metabolism)
  • Tumor Necrosis Factor-alpha (metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: