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B activation in
alcoholic liver injury
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-
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)-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-B activation (+100%), and tumor necrosis
factor-
(+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-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-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-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-B activation
and expression of proinflammatory genes in alcoholic liver injury.
Kupffer cells; nuclear factor-B; chemokines; inflammation; erythrophagocytosis
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