PMID:19809161

Citation	Wang, L, Harrington, L, Trebicka, E, Shi, HN, Kagan, JC, Hong, CC, Lin, HY, Babitt, JL and Cherayil, BJ (2009) Selective modulation of TLR4-activated inflammatory responses by altered iron homeostasis in mice. J. Clin. Invest. 119:3322-8
Abstract	Mice deficient in the hemochromatosis gene, Hfe, have attenuated inflammatory responses to Salmonella infection associated with decreased macrophage TNF-alpha and IL-6 biosynthesis after exposure to LPS. In this study, we show that the abnormal cytokine production is related to impaired TLR4 signaling. Despite their abnormal response to LPS, Hfe KO macrophages produced amounts of TNF-alpha similar to those in WT cells after TLR2 stimulation. Consistent with this finding, LPS-induced activation of Mal/MyD88-dependent events was normal in the mutant macrophages. However, LPS-induced IFN-beta expression, a TRAM/TRIF-dependent response activated by TLR4, was reduced by Hfe deficiency. This reduction could be replicated in WT macrophages with the use of iron chelators. In contrast, TLR3-activated expression of IFN-beta, a TRIF-dependent response, was normal in Hfe KO macrophages and was unaffected by iron chelation. Our data suggest that low intracellular iron selectively impairs signaling via the TLR4/TRAM/TRIF pathway proximal to TRIF and results in reduced LPS-induced cytokine expression. Furthermore, by mimicking the altered iron metabolism associated with Hfe deficiency, we found that 3 different inhibitors of hepcidin attenuated Salmonella-induced and noninfectious enterocolitis. Thus, manipulation of iron homeostasis could represent a new therapeutic approach to controlling inflammation.
Links	PubMed PMC2769199 Online version:10.1172/JCI39939
Keywords	Animals; Enterocolitis/genetics; Enterocolitis/immunology; Gene Expression Regulation/drug effects; Hemochromatosis/genetics; Homeostasis/immunology; Immunity, Innate/genetics; Inflammation/immunology; Iron/immunology; Lipopolysaccharides/pharmacology; Macrophages/immunology; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Differentiation Factor 88/immunology; Salmonella Infections/genetics; Salmonella Infections/immunology; Signal Transduction; Toll-Like Receptor 4/immunology
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:HFE		GO:0006955: immune response	ECO:0000314:		P		Figure 1. Peritoneal macrophages from WT and Hfe KO mice were stimulated with LPS. Supernatants were collected and analyzed by ELISA for TNF-α. Observations on TNF-α expression support the notion that the abnormal TLR4-activated cytokine response of the Hfe KO macrophages is caused by the low intracellular iron in these cells rather than being a cell-autonomous consequence of Hfe deficiency.	complete

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