- Open Access
Signaling role of iron in NF-kappa B activation in hepatic macrophages
© Xiong et al; licensee BioMed Central Ltd 2004
- Published: 14 January 2004
Iron is both essential and toxic for cells and impaired iron homeostasis has been shown to cause or potentiate various forms of liver injury. Research in our laboratory suggests that iron also plays a pivotal role in intracellular signaling for NF-kappa B activation in hepatic macrophages (HM). Our results showed: 1) HM from alcohol-fed rats had a increase in the nonheme iron content accompanied by NF-kappa B activation; 2) iron chelation normalized nonheme iron concentration and blocked enhanced NF-kappa B activation and TNF-alpha expression in these cells; 3) LPS-induced NF-kappa B activation was also blocked by iron chelator; 4) iron directly induced TNF-alpha expression via IKK and NF-kappa B activation in normal HM. We propose that iron acts as an independent proinflammatory molecule via induction of the intracellular signaling for NF-kappa B activation in HM and primes the liver for chronic inflammation and injury.
- Hepatic Macrophage
- Status Dependent Manner
- Radical Generate System
- Chronic Liver Inflammation
- Nonheme Iron Concentration
Our earlier study showed that hepatic macrophages (HM) from rats fed ethanol and high fat diet had a significant 70% increase in the nonheme iron content as compared to controls . This study also suggested enhanced heme turnover as a cause of the increased iron storage in HM. To test this notion, an increase in HM iron content was recapitulated in vitro by phagocytosis of heat-treated autologous red blood cells. To extend this observation to the whole animal situation, the effects of splenectomy on alcohol-fed animals were also examined. The most intriguing and critical finding from these cellular or animal model experimentations, was that activation of NF-kappa B was tightly correlated with the increased non-heme iron content in HM, suggesting the priming role of iron in NF-kappa B activation and proinflammatory cytokine expression by HM in alcoholic liver disease.
Our studies to date strongly suggest the causal link between iron and activation of NF-kappa B in HM in both normal and alcohol-fed rats. These findings raise a question as to how iron signals to activate NF-kappa B. Since NF-kappa B is a redox sensitive transcription factor and ROS are implicated in its activation [3, 4], it is reasonable to speculate that iron stimulates ROS production in HM and in turn ROS activates NF-kappa B. Conversely, stimulation of HM with an agonist such as LPS, induces ROS generation and ROS may initiate intracellular signaling that is dependent on a chelatable pool of iron. Nitric oxide (NO) is known to cause mobilization of intracellular iron  and to inhibit enzymes with catalytically active iron-sulfur groups . Superoxide anion can also release iron from ferritin . Indeed, our preliminary results demonstrate that a selective inhibitor of iNOS and Cu/Zn SOD overexpression abolish a LPS-mediated transient rise in the intracellular level of chelatable iron and NF-kappa B activation (unpublished observation). We propose that iron acts as a proinflammatory effector molecule via selective induction of the intracellular signaling for NF-kappa B activation and that dysregulation of this signaling mechanism may prime HM for chronic liver inflammation and injury.
- Tsukamoto H, Lin M, Ohata M, Giulivi C, French SW, Brittenham G: Iron primes hepatic macrophages for NF-kappa B activation in alcoholic liver injury. Am J Physiol. 1999, 277: G1240-G1250.PubMedGoogle Scholar
- Shi X, Dong Z, Huang C, Ma W, Liu K, Ye J, Chen F, Leonard SS, Ding M, Castranova V, Vallyathan V: The role of hydroxyl radical as a messenger in the activation of nuclear transcription factor NF-kappa B. Mol Cell Biochem. 1999, 194: 63-70. 10.1023/A:1006904904514.View ArticlePubMedGoogle Scholar
- Anderson MT, Staal FJ, Gitler C, Herzenberg LA, Herzenberg LA: Separation of oxidant-initiated and redox-regulated steps in the NF-kappa B signal transduction pathway. Proc Natl Acad Sci. 1994, 91: 11527-11531. 10.1073/pnas.91.24.11527.PubMed CentralView ArticlePubMedGoogle Scholar
- Schreck R, Baeuerle PA: Assessing oxygen radicals as mediators in activation of inducible eukaryotic transcription factor NF-kappa B. Methods Enzymol. 1994, 234: 151-163.View ArticlePubMedGoogle Scholar
- Drapier JC, Hirling H, Wietzerbin J, Kaldy P, Kuhn LC: Biosynthesis of nitric oxide activates iron regulatory factor in macrophages. EMBO J. 1993, 12: 3643-3649.PubMed CentralPubMedGoogle Scholar
- Drapier JC, Hibbs JB: Differentiation of murine macrophages to express nonspecific cytotoxicity for tumor cells results in L-arginine-dependent inhibition of mitochondrial iron-sulfur enzymes in the macrophage effector cells. J Immunol. 1988, 140: 2829-2838.PubMedGoogle Scholar
- Cairo G, Tacchini L, Pogliaghi G, Anzon E, Tomasi A, Bernelli-Zazzera A: Induction of ferritin synthesis by oxidative stress. Transcriptional and post-transcriptional regulation by expansion of the "free" iron pool. J Biol Chem. 1995, 270: 700-703. 10.1074/jbc.270.2.700.View ArticlePubMedGoogle Scholar
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