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* Mucosal Immunology Laboratory, Massachusetts General Hospital, Charlestown, MA 02129;
Department of Pediatrics, Harvard Medical School,
Department of Nutrition, and
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115
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-
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- 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by a pilot feasibility project grant from the Harvard Clinical Nutrition Research Center (to B.J.C.), by an unrestricted educational grant from Wyeth Nutrition (to L.W.), and by Grants R21AI06461 (to B.J.C.) and R01ES014638 and R01DK064750 (to M.W.-R.) from the National Institutes of Health.
2 Address correspondence and reprint requests to Dr. Bobby J. Cherayil, Mucosal Immunology Laboratory, Massachusetts General Hospital, Building 114, 16th Street, Charlestown, MA 02129. E-mail address: cherayil{at}helix.mgh.harvard.edu
3 Abbreviations used in this paper: FPN, ferroportin; SIH, salicylaldehyde isonicotinoyl hydrazone.
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