Subject: Intracellular Labile Iron In Alcoholic Liver Disease
Author: ironjustice@aol.comDate: 8 Jul
"Intracellular labile iron a priming mechanism for alcoholic liver
disease"
Hepatic macrophage iron aggravates experimental alcoholic
steatohepatitis.
Xiong S, She H, Zhang AS, Wang J, Mkrtchyan H, Dynnyk A, Gordeuk VR,
French SW, Enns CA, Tsukamoto H
Am J Physiol Gastrointest Liver Physiol 2008 Jul 3.
One prime feature of alcoholic liver disease (ALD) is iron
accumulation in hepatic macrophages/Kupffer cells (KC) associated with
enhanced NF-kappaB activation.
Our recent work demonstrates a peroxynitrite-mediated transient rise
in intracellular labile iron (ILI response) as novel signaling for
endotoxin-induced IkappaB kinase (IKK) and NF-kappaB activation in
rodent KC.
The present study investigated the mechanism of KC iron accumulation
and its effects on ILI response in experimental ALD.
We also tested ILI response in human blood monocytes.
Chronic alcohol feeding in rats results in increased expression of
transferrin (Tf) receptor-1 and hemochromatosis gene (HFE), enhanced
iron uptake, an increase in non-heme iron content, and accentuated ILI
response for NF-kappaB activation in KC.
Ex vivo treatment of these KC with an iron chelator abrogates the
increment of iron content, ILI response, and NF-kappaB activation.
The ILI response is evident in macrophages derived from human blood
monocytes by PMA treatment but not in vehicle-treated monocytes, and
this differentiation-associated phenomenon is essential for maximal
TNFalpha release.
PMA-induced macrophages load iron dextran and enhance ILI response and
TNFalpha release.
These effects are reproduced in KC selectively loaded in vivo with
iron dextran in mice and more importantly aggravate experimental ALD.
Our results suggest enhanced iron uptake as a mechanism of KC iron
loading in ALD and demonstrate the ILI response as a function acquired
by differentiated macrophages in man and as a priming mechanism for
ALD.
Key words: IKK, NF-B, labile iron, TNF.
American journal of physiology. Gastrointestinal and liver physiology
[Am J Physiol Gastrointest Liver Physiol]
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