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Am J Physiol Gastrointest Liver Physiol 277: G1240-G1250, 1999;
0193-1857/99 $5.00
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Vol. 277, Issue 6, G1240-G1250, December 1999

Iron primes hepatic macrophages for NF-kappa B activation in alcoholic liver injury

Hidekazu Tsukamoto1,2, Min Lin1, Mitsuru Ohata1, Cecilia Giulivi3, Samuel W. French4, and Gary Brittenham5

1 Department of Medicine and Pathology, University of Southern California School of Medicine, Los Angeles 90033; 2 Research Service, Department of Veteran Affairs Medical Center, Sepulveda 91343; 4 Department of Pathology, Harbor-UCLA Medical Center, Torrance, California 90073; 3 Department of Chemistry, University of Minnesota, Duluth, Minnesota 55812; and 5 Departments of Pediatrics and Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032

NF-kappa B activation induced by lipopolysaccharide (LPS) in cultured hepatic macrophages (HM) may be abrogated by pretreatment of cells with a lipophilic iron chelator, 1,2-dimethyl-3-hydroxypyrid-4-one (L1, deferiprone), suggesting a role for iron in this molecular event [M. Lin, M., R. A. Rippe, O. Niemelä, G. Brittenham, and H. Tsukamoto, Am. J. Physiol. 272 (Gastrointest. Liver Physiol. 35): G1355-G1364, 1997]. To ascertain the relevance in vivo of this hypothesis, HM from an experimental model of alcoholic liver injury were examined for the relationship between nuclear factor (NF)-kappa B activation and iron storage. HM showed a significant increase in nonheme iron concentration (+70%), accompanied by enhanced generation of electron paramagnetic resonance-detected radicals (+200%), NF-kappa B activation (+100%), and tumor necrosis factor-alpha (+150%) and macrophage inflammatory protein-1 (+280%) mRNA induction. Treatment of the cells ex vivo with L1 normalized all these parameters. HM content of ferritin protein, ferritin L chain mRNA, and hemeoxygenase-1 mRNA and splenic content of nonheme iron were increased, suggesting enhanced heme turnover as a cause of the increased iron storage and NF-kappa B activation. To test this possibility, increased iron content in HM was reproduced in vitro by phagocytosis of heat-treated red blood cells. Treatment caused a 40% increase in nonheme iron concentration and accentuated LPS-induced NF-kappa B activation twofold. Both effects could be abolished by pretreatment of cells with zinc protoporphyrin, a hemeoxygenase inhibitor. To extend this observation, animals were splenectomized before 9-wk alcohol feeding. Splenectomy resulted in further increments in HM nonheme iron storage (+60%) and NF-kappa B activation (+90%) and mononuclear cell infiltration (+450%), particularly around the iron-loaded HM in alcohol-fed animals. These results support the pivotal role of heme-derived iron in priming HM for NF-kappa B activation and expression of proinflammatory genes in alcoholic liver injury.

Kupffer cells; nuclear factor-kappa B; chemokines; inflammation; erythrophagocytosis


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