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This Article Full Text Full Text (PDF) All Versions of this Article: 295/3/G512    most recent ajpgi.90327.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Xiong, S. Articles by Tsukamoto, H. Search for Related Content PubMed PubMed Citation Articles by Xiong, S. Articles by Tsukamoto, H.

LIVER AND BILIARY TRACT

Hepatic macrophage iron aggravates experimental alcoholic steatohepatitis

¹Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California; ²Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon; ³Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California; ⁴Center for Sickle Cell Disease, Howard University, Washington, DC; and ⁵Department of Pathology, Harbor-UCLA Medical Center, Torrance, California

Submitted 6 May 2008 ; accepted in final form 1 July 2008

One prime feature of alcoholic liver disease (ALD) is iron accumulation in hepatic macrophages/Kupffer cells (KC) associated with enhanced NF-B activation. Our recent work demonstrates a peroxynitrite-mediated transient rise in intracellular labile iron (ILI) as novel signaling for endotoxin-induced IKK and NF-B 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-B activation in KC. Ex vivo treatment of these KC with an iron chelator abrogates the increment of iron content, ILI response, and NF-B 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- release. PMA-induced macrophages load iron dextran and enhance ILI response and TNF- 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.

IKK; NF-B; labile iron; TNF-; transferrin receptor-1; HFE