Iron-mediated H2O2 production as a mechanism for cell type-specific inhibition of tumor necrosis factor alpha-induced but not interleukin-1beta-induced IkappaB kinase complex/nuclear factor-kappaB activation.
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 IkappaB kinase complex (IKK)/NF-kappaB 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 TNFalpha 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-kappaB activation by IL-1beta. l-Mimosine caused cell cycle arrest at G(1)-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 H(2)O(2). Addition of FeSO(4) restored IKK activation by TNFalpha as did ectopic expression of catalase or pretreatment of cells with N-aceltyl-l-cysteine, indicating a role for intracellular H(2)O(2) as a mediator of inhibition. Cleavage and degradation of TNF pathway components TNFR1, RIP, and Hsp90 were observed in l-mimosine and H(2)O(2) treated cells indicating a putative mechanism for selective inhibition of TNF but not IL-1beta-induced IKK activation.
Panopoulos
Andreas
A
Department of Molecular Microbiology and Immunology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine at USC, Los Angeles, California 90033, USA.
Harraz
Maged
M
Engelhardt
John F
JF
Zandi
Ebrahim
E
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D002374:Catalase / Q000378:metabolism; D002453:Cell Cycle; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D002469:Cell Separation; D002478:Cells, Cultured; D004789:Enzyme Activation; D005434:Flow Cytometry; D016193:G1 Phase; D018922:HL-60 Cells; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism* / Q000494:pharmacology*; D051550:I-kappa B Kinase; D007249:Inflammation; D007375:Interleukin-1 / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D019169:Jurkat Cells; D051379:Mice; D008898:Mimosine / Q000494:pharmacology; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D041681:NIH 3T3 Cells; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D016196:S Phase; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D020298:U937 Cells; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D018841:HSP90 Heat-Shock Proteins; D007375:Interleukin-1; D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D008898:Mimosine; D006861:Hydrogen Peroxide; D007501:Iron; D002374:Catalase; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; D048055:Mitogen-Activated Protein Kinase 8; D048051:p38 Mitogen-Activated Protein Kinases; D000111:Acetylcysteine