Attenuated inflammatory responses in hemochromatosis reveal a role for iron in the regulation of macrophage cytokine translation
Authors
Wang, LijianJohnson, Erin E.
Shi, Hai Ning
Walker, W. Allan
Wessling-Resnick, Marianne
Cherayil, Bobby J.
UMass Chan Affiliations
Department of BiochemistryMucosal Immunology Laboratory
Graduate School of Biomedical Sciences
Document Type
Journal ArticlePublication Date
2008-08-08Keywords
Animals; Cation Transport Proteins; Cell Line; Cytokines; Enterocolitis; Hemochromatosis; Histocompatibility Antigens Class I; Immunity, Innate; Inflammation Mediators; Iron; Macrophages, Peritoneal; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Protein Biosynthesis; Salmonella Infections, Animal; Salmonella typhimuriumLife Sciences
Medicine and Health Sciences
Metadata
Show full item recordAbstract
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.Source
J Immunol. 2008 Aug 15;181(4):2723-31.
DOI
10.4049/jimmunol.181.4.2723Permanent Link to this Item
http://hdl.handle.net/20.500.14038/33025PubMed ID
18684963Related Resources
ae974a485f413a2113503eed53cd6c53
10.4049/jimmunol.181.4.2723