Hepatic macrophage iron aggravates experimental alcoholic steatohepatitis.
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) as novel signaling for endotoxin-induced 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 nonheme 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 TNF-alpha release. PMA-induced macrophages load iron dextran and enhance ILI response and TNF-alpha 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 humans and as a priming mechanism for ALD.
Xiong
Shigang
S
Department of Pathology, Keck School of Medicine, University of Southern California, 1333 San Pablo St., MMR 402, Los Angeles, CA 90033-9141, USA.
She
Hongyun
H
Zhang
An-Sheng
AS
Wang
Jiaohong
J
Mkrtchyan
Hasmik
H
Dynnyk
Alla
A
Gordeuk
Victor R
VR
French
Samuel W
SW
Enns
Caroline A
CA
Tsukamoto
Hidekazu
H
D000818:Animals; D027682:Cation Transport Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000431:Ethanol; D005235:Fatty Liver, Alcoholic / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D007505:Iron-Dextran Complex; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011990:Receptors, Transferrin / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000098742:Ferroportin
D027682:Cation Transport Proteins; C484232:HFE protein, rat; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D007502:Iron Chelating Agents; D008565:Membrane Proteins; D016328:NF-kappa B; D011990:Receptors, Transferrin; D014409:Tumor Necrosis Factor-alpha; D000098742:Ferroportin; D000431:Ethanol; D007505:Iron-Dextran Complex; D007501:Iron