Selective modulation of TLR4-activated inflammatory responses
by altered iron homeostasis in mice
Research Article
Published in Volume 119, Issue 11 (November 2,2009)
J. Clin. Invest. 119(11): 3322-3328 (2009).
Lijian Wang1,2, Lynne Harrington1, Estela Trebicka1,
Hai Ning Shi1,3, Jonathan C. Kagan4, Charles C. Hong5,
Herbert Y. Lin6, Jodie L. Babitt6 and Bobby J. Cherayil1,3

1Mucosal Immunology Laboratory, Massachusetts General Hospital,
Charlestown, Massachusetts, USA.
2Department of Nutrition, Harvard School of Public Health,
Boston, Massachusetts, USA.
3Department of Pediatrics, Harvard Medical School,
Boston, Massachusetts, USA.
4Department of Gastroenterology, Children’s Hospital Boston,
Boston, Massachusetts, USA.
5Division of Cardiovascular Medicine, Vanderbilt University Medical
Center,
Nashville, Tennessee, USA.
6Program in Membrane Biology,
Division of Nephrology and Center for Systems Biology,
Massachusetts General Hospital, Boston, Massachusetts, USA.

Address correspondence to:
Bobby J. Cherayil, Mucosal Immunology Laboratory,
Massachusetts General Hospital,
Building 114, 16th Street, Charlestown, Massachusetts 02129, USA.
Phone: (617) 726-4170; Fax: (617) 726-4172;
E-mail: chera...@helix.mgh.harvard.edu.

First published October 5, 2009
Received for publication May 21, 2009, and
accepted in revised form August 19, 2009.

Mice deficient in the hemochromatosis gene, Hfe, have attenuated
inflammatory responses to Salmonella infection associated with
decreased macrophage TNF-α 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-α 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-β 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-β, 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.

J. Clin. Invest. 119(11): 3322-3328 (2009). doi:10.1172/JCI39939.
Copyright © 2009, American Society for Clinical Investigation

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Tom

Jesus Was A Vegetarian!
http://tinyurl.com/2r2nkh

Man Is A Herbivore!
http://tinyurl.com/a3cc3

DEAD PEOPLE WALKING
http://tinyurl.com/zk9fk

Interpretation, in normal people who get an infection reducingthe normal
iron levels might help.

Note, the infection follows being normal and prior to less then normal
iron levels.  Once infection is past, iron levels will be allowed to
return to normal and normal control of iron levels resume.

Conclusion, normal people with normal iron control and levels get
infections too.  The iron did not cause the infection.

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