Signaling Role of Intracellular Iron in NF-κB Activation

Shigang Xiong; Hongyun She; Heigo Takeuchi; Bora Han; John F. Engelhardt; C.H. Barton; Ebrahim Zandi; Cecilia Giulivi; Hidekazu Tsukamoto

doi:10.1074/jbc.M210905200

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Signaling Role of Intracellular Iron in NF-κB Activation

Journal article

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Peer reviewed

Signaling Role of Intracellular Iron in NF-κB Activation

Shigang Xiong, Hongyun She, Heigo Takeuchi, Bora Han, John F. Engelhardt, C.H. Barton, Ebrahim Zandi, Cecilia Giulivi and Hidekazu Tsukamoto

The Journal of biological chemistry, Vol.278(20), pp.17646-17654

05/2003

DOI: 10.1074/jbc.M210905200

PMID: 12637578

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Abstract

Iron chelators inhibit endotoxin-induced NF-κB activation in hepatic macrophages (HMs), suggesting a role for the intracellular chelatable pool of iron in NF-κB activation. The present study tested this hypothesis. Analysis of Fe59-loaded HMs stimulated with lipopolysaccharide (LPS), revealed a previously unreported, transient rise in intracellular low molecular weight (LMW)·Fe59 complex ([LMW·Fe]i) at ≤2 min returning to the basal level within 15 min. The [LMW·Fe]i response preceded IκB kinase (IKK) (≥15 min) and NF-κB (≥30 min) activation. Iron chelators (1,2-dimethyl-3-hydroxy-pyridin-4-one and N,N′-bis-2-hydroxybenzylethylenediamine-N,N′-diacetic acid) abrogated the [LMW·Fe]i response and IKK and NF-κB activation. The [LMW·Fe]i response was also observed in tumor necrosis factor α (TNFα)-stimulated HMs and RAW264.7 cells treated with LPS and interferon-γ but not in primary rat hepatocytes or myofibroblastic cells exposed to LPS or TNFα. Both [LMW·Fe]i response and IKK activation in LPS-stimulated HMs were inhibited by diphenylene iodonium (nonspecific inhibitor for flavin-containing oxidases), L-N6(1-iminoethyl)lysine (selective iNOS inhibitor), and adenoviral-mediated expression of a dominant negative mutant of Rac1 or Cu,Zn-superoxide dismutase, suggesting the role of .NO and O2.- in mediating the iron signaling. In fact, this inhibition was recapitulated by a cell-permeable scavenger of ONOO-, 5,10,15,20-tetrakis (4-sulfonatophenyl)porphyrinato iron (III) chloride. Conversely, ONOO- alone induced both [LMW·Fe]i response and IKK activation. Finally, direct addition of ferrous iron to cultured HMs activated IKK and NF-κB. These results support a novel signaling role for [LMW·Fe]i in IKK activation, which appears to be induced by ONOO- and selectively operative in macrophages.

Details

Title: Subtitle: Signaling Role of Intracellular Iron in NF-κB Activation
Creators: Shigang Xiong - University of Southern California
Hongyun She - University of Southern California
Heigo Takeuchi - University of Southern California
Bora Han
John F. Engelhardt - University of Iowa
C.H. Barton - University of Southampton
Ebrahim Zandi - University of Southern California
Cecilia Giulivi - University of Minnesota, Duluth
Hidekazu Tsukamoto - University of Southern California
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.278(20), pp.17646-17654
DOI: 10.1074/jbc.M210905200
PMID: 12637578
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Language: English
Date published: 05/2003
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Radiation Oncology; Internal Medicine
Record Identifier: 9984284457602771

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