Attenuated inflammatory responses in hemochromatosis reveal a role for iron in the regulation of macrophage cytokine translation.

Abstract

Disturbances of iron homeostasis are associated with altered susceptibility to infectious disease, but the underlying molecular mechanisms are poorly understood. To study this phenomenon, we examined innate immunity to oral Salmonella infection in Hfe knockout (Hfe(-/-)) mice, a model of the human inherited disorder of iron metabolism type I hemochromatosis. Salmonella- and LPS-induced inflammatory responses were attenuated in the mutant animals, with less severe enterocolitis observed in vivo and reduced macrophage TNF-alpha and IL-6 secretion measured in vitro. The macrophage iron exporter ferroportin (FPN) was up-regulated in the Hfe(-/-) mice, and correspondingly, intramacrophage iron levels were lowered. Consistent with the functional importance of these changes, the abnormal cytokine production of the mutant macrophages could be reproduced in wild-type cells by iron chelation, and in a macrophage cell line by overexpression of FPN. The results of analyzing specific steps in the biosynthesis of TNF-alpha and IL-6, including intracellular concentrations, posttranslational stability and transcript levels, were consistent with reduced translation of cytokine mRNAs in Hfe(-/-) macrophages. Polyribosome profile analysis confirmed that elevated macrophage FPN expression and low intracellular iron impaired the translation of specific inflammatory cytokine transcripts. Our results provide molecular insight into immune function in type I hemochromatosis and other disorders of iron homeostasis, and reveal a novel role for iron in the regulation of the inflammatory response.

• Authors: Lijian Wang, Erin E Johnson, Hai Ning Shi, W Allan Walker, Marianne Wessling-Resnick, Bobby J Cherayil
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 181 Issue 4 Pg. 2723-31 (Aug 15 2008) ISSN: 1550-6606 [Electronic] United States
• PMID: 18684963 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cation Transport Proteins
• Cytokines
• Hemochromatosis Protein
• Hfe protein, mouse
• Histocompatibility Antigens Class I
• Inflammation Mediators
• Membrane Proteins
• metal transporting protein 1
• Iron

Topics

• Animals
• Cation Transport Proteins (biosynthesis, genetics, physiology)
• Cell Line
• Cytokines (biosynthesis, genetics)
• Enterocolitis (genetics, immunology, pathology)
• Hemochromatosis (immunology, metabolism, pathology)
• Hemochromatosis Protein
• Histocompatibility Antigens Class I (genetics, physiology)
• Immunity, Innate (genetics)
• Inflammation Mediators (metabolism, physiology)
• Iron (metabolism, physiology)
• Macrophages, Peritoneal (immunology, metabolism, pathology)
• Membrane Proteins (deficiency, genetics, physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Protein Biosynthesis (immunology)
• Salmonella Infections, Animal (genetics, immunology, pathology)
• Salmonella typhimurium (immunology)