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

Hidekazu Tsukamoto, Min Lin, Mitsuru Ohata, Cecilia R Giulivi, Samuel W. French, Gary Brittenham

Research output: Contribution to journalArticle

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Abstract

NF-κB 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. Niemela, 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)-κB 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-κB activation (+100%), and tumor necrosis factor-α (+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-κB 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-κB 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-κB 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-κB activation and expression of proinflammatory genes in alcoholic liver injury.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume277
Issue number6 40-6
StatePublished - Dec 1999
Externally publishedYes

Fingerprint

Iron
Macrophages
Liver
Wounds and Injuries
Heme
Messenger RNA
Lipopolysaccharides
Alcohols
Apoferritins
Macrophage Inflammatory Proteins
Heme Oxygenase-1
Electron Spin Resonance Spectroscopy
Splenectomy
Ferritins
Chelating Agents
Phagocytosis
Theoretical Models
Tumor Necrosis Factor-alpha
Hot Temperature
Erythrocytes

Keywords

  • Chemokines
  • Erythrophagocytosis
  • Inflammation
  • Kupffer cells
  • Nuclear factor- κB

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology
  • Physiology (medical)

Cite this

Iron primes hepatic macrophages for NF-κB activation in alcoholic liver injury. / Tsukamoto, Hidekazu; Lin, Min; Ohata, Mitsuru; Giulivi, Cecilia R; French, Samuel W.; Brittenham, Gary.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 277, No. 6 40-6, 12.1999.

Research output: Contribution to journalArticle

Tsukamoto, Hidekazu ; Lin, Min ; Ohata, Mitsuru ; Giulivi, Cecilia R ; French, Samuel W. ; Brittenham, Gary. / Iron primes hepatic macrophages for NF-κB activation in alcoholic liver injury. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 1999 ; Vol. 277, No. 6 40-6.
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abstract = "NF-κB 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. Niemela, 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)-κB 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-κB activation (+100{\%}), and tumor necrosis factor-α (+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-κB 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-κB 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-κB 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-κB activation and expression of proinflammatory genes in alcoholic liver injury.",
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