Iron-mediated H2O2 Production as a Mechanism for Cell Type-specific Inhibition of Tumor Necrosis Factor α-Induced but Not Interleukin-1β-induced IκB Kinase Complex/Nuclear Factor-κB Activation

Andreas Panopoulos; Maged Harraz; John F. Engelhardt; Ebrahim Zandi

doi:10.1074/jbc.M409524200

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Iron-mediated H2O2 Production as a Mechanism for Cell Type-specific Inhibition of Tumor Necrosis Factor α-Induced but Not Interleukin-1β-induced IκB Kinase Complex/Nuclear Factor-κB Activation

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Iron-mediated H2O2 Production as a Mechanism for Cell Type-specific Inhibition of Tumor Necrosis Factor α-Induced but Not Interleukin-1β-induced IκB Kinase Complex/Nuclear Factor-κB Activation

Andreas Panopoulos, Maged Harraz, John F. Engelhardt and Ebrahim Zandi

The Journal of biological chemistry, Vol.280(4), pp.2912-2923

01/28/2005

DOI: 10.1074/jbc.M409524200

PMID: 15550384

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Abstract

Coordinated and specific regulation of tumor necrosis factor (TNF) and interleukin (IL)-1 signaling pathways and how and whether they are modified by different agents are key events for proper immune responses. The IκB kinase complex (IKK)/NF-κB and JNK/AP-1 pathways are central mediators of TNF and IL-1 during inflammatory responses. Here we show that l-mimosine, a toxic non-protein amino acid that has been shown to reduce serum TNFα levels and affect inflammatory responses, specifically inhibits TNF-induced IKK but not JNK in a cell type-specific manner. l-Mimosine did not affect IKK and NF-κB activation by IL-1β. l-Mimosine caused cell cycle arrest at G1-S phase, but inhibition of IKK was found to be independent of cell cycle arrest. Treatment of cells with l-mimosine resulted in production of H2O2. Addition of FeSO4 restored IKK activation by TNFα as did ectopic expression of catalase or pretreatment of cells with N-aceltyl-l-cysteine, indicating a role for intracellular H2O2 as a mediator of inhibition. Cleavage and degradation of TNF pathway components TNFR1, RIP, and Hsp90 were observed in l-mimosine and H2O2 treated cells indicating a putative mechanism for selective inhibition of TNF but not IL-1β-induced IKK activation.

Details

Title: Subtitle: Iron-mediated H2O2 Production as a Mechanism for Cell Type-specific Inhibition of Tumor Necrosis Factor α-Induced but Not Interleukin-1β-induced IκB Kinase Complex/Nuclear Factor-κB Activation
Creators: Andreas Panopoulos - University of Southern California
Maged Harraz - University of Iowa
John F. Engelhardt - University of Iowa
Ebrahim Zandi - University of Southern California
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.280(4), pp.2912-2923
DOI: 10.1074/jbc.M409524200
PMID: 15550384
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: Elsevier Inc
Language: English
Date published: 01/28/2005
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Radiation Oncology; Internal Medicine
Record Identifier: 9984284353302771

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