EurekaMag.com logo
+ Site Statistics
References:
53,869,633
Abstracts:
29,686,251
+ Search Articles
+ Subscribe to Site Feeds
EurekaMag Most Shared ContentMost Shared
EurekaMag PDF Full Text ContentPDF Full Text
+ PDF Full Text
Request PDF Full TextRequest PDF Full Text
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter
Follow on LinkedInFollow on LinkedIn

+ Translate

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



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



American Journal of Physiology 277(6): G1240-G1250



NF-kappaB 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)-kappaB 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-kappaB 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-kappaB 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-kappaB 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-kappaB 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-kappaB activation and expression of proinflammatory genes in alcoholic liver injury.

(PDF emailed within 1 workday: $29.90)

Accession: 010885308

Download citation: RISBibTeXText

PMID: 10600822



Related references

Iron primes hepatic macrophages for NF-kB activation in alcoholic liver injury. American Journal of Physiology 277(6): 240-G1250, 1999

Iron primes hepatic macrophages for NF-κB activation in alcoholic liver injury. American Journal of Physiology. Gastrointestinal and Liver Physiology 277(6): G1240-G1250, 2018

IL-1 receptor like 1 protects against alcoholic liver injury by limiting NF-κB activation in hepatic macrophages. Journal of Hepatology, 2017

Chronic ethanol-mediated decrease in cAMP primes macrophages to enhanced LPS-inducible NF-kappaB activity and TNF expression: relevance to alcoholic liver disease. American Journal of Physiology. Gastrointestinal and Liver Physiology 291(4): G681-G688, 2006

Iron dependent NF-kappaB activation by hepatic macrophages. Hepatology 28(4 PART 2): 440A, 1998

NF-kappaB activation and modulation in hepatic macrophages during cholestatic injury. Journal of Surgical Research 72(2): 129-134, 1997

Nf-kappab activation is associated with free radical generation and endotoxemia and precedes pathological liver injury in experimental alcoholic liver disease. Cytokine 16(1): 36-39, 2001

Iron-dependent activation of NF-kappaB in Kupffer cells: a priming mechanism for alcoholic liver disease. Alcohol 30(2): 107-113, 2003

Relationships among serum iron status markers, chemical and histochemical liver iron content in 117 patients with alcoholic and non-alcoholic hepatic disease. Hepato-Gastroenterology 41(1): 20-24, 1994

The let-7/Lin28 axis regulates activation of hepatic stellate cells in alcoholic liver injury. Journal of Biological Chemistry 292(27): 11336-11347, 2017

Mechanisms of hepatic toxicity. II. Alcoholic liver injury involves activation of Kupffer cells by endotoxin. American Journal of Physiology 275(4): 05-G611, 1998

Activation of farnesoid X receptor attenuates hepatic injury in a murine model of alcoholic liver disease. Biochemical and Biophysical Research Communications 443(1): 68-73, 2014

Mechanism of hepatic toxicity: II. Alcoholic liver injury involves activation of Kupffer cells by endotoxin. American Journal of Physiology 275(4 PART 1): G605-G611, 1998

Chronic ethanol-mediated decrease in cAMP primes macrophages to enhanced LPS-inducible NF-B-K activity and TNF expression: relevance to alcoholic liver disease. American Journal of Physiology Gastrointestinal and Liver Physiology 291(4): G681-G688, 2006

Immunologic activation of hepatic macrophages in septic rats: a possible mechanism of sepsis-associated liver injury. Journal of Laboratory and Clinical Medicine 123(3): 430-436, 1994