title: Myeloperoxidase deficiency induces MIP-2 production via ERK activation in zymosan-stimulated mouse neutrophils.
abstract: Myeloperoxidase (MPO), a major constituent of neutrophils, catalyzes the production of hypochlorous acid (HOCl) from hydrogen peroxide (H2O2) and chloride anion. We have previously reported that MPO-deficient (MPO(-/-)) neutrophils produce greater amount of macrophage inflammatory protein-2 (MIP-2) in vitro than do wild type when stimulated with zymosan. In this study, we investigated the molecular mechanisms governing the up-regulation of MIP-2 production in the mutant neutrophils. Interestingly, we found that zymosan-induced production of MIP-2 was blocked by pre-treatment with U0126, an inhibitor of mitogen-activated protein kinase/extracellular-signal-regulated kinase (ERK), and with BAY11-7082, an inhibitor of nuclear factor (NF)-κB. Western blot analysis indicated that U0126 also inhibited the phosphorylation of p65 subunit of NF-κB (p65), indicating that MIP-2 was produced via the ERK/NF-κB pathway. Intriguingly, we found that ERK1/2, p65, and alpha subunit of inhibitor of κB (IκBα) in the MPO(-/-) neutrophils were phosphorylated more strongly than in the wild type when stimulated with zymosan. Exogenous H2O2 treatment in addition to zymosan stimulation enhanced the phosphorylation of ERK1/2 without affecting the zymosan-induced MIP-2 production. In contrast, exogenous HOCl inhibited the production of MIP-2 as well as IκBα phosphorylation without affecting ERK activity. The zymosan-induced production of MIP-2 in the wild-type neutrophils was enhanced by pre-treatment of the MPO inhibitor 4-aminobenzoic acid hydrazide. Collectively, these results strongly suggest that both lack of HOCl and accumulation of H2O2 due to MPO deficiency contribute to the up-regulation of MIP-2 production in mouse neutrophils stimulated with zymosan.
authors: Graduate School of Nanobioscience, Yokohama City University, Kanazawa, Yokohama, Japan.
authors: N
authors: N
authors: Tateno
authors: N
authors: N
authors: Matsumoto
authors: T
authors: T
authors: Motowaki
authors: K
authors: K
authors: Suzuki
authors: Y
authors: Y
authors: Aratani
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D054426:Chemokine CXCL2 / Q000096:biosynthesis* / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000378:metabolism; D006997:Hypochlorous Acid / Q000378:metabolism; D051379:Mice; D009154:Mutation; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects*; D009570:Nitriles / Q000494:pharmacology; D009195:Peroxidase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013450:Sulfones / Q000494:pharmacology; D015054:Zymosan / Q000008:administration & dosage
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D002070:Butadienes; D054426:Chemokine CXCL2; D016328:NF-kappa B; D009570:Nitriles; D013450:Sulfones; C113580:U 0126; D006997:Hypochlorous Acid; D015054:Zymosan; D006861:Hydrogen Peroxide; D009195:Peroxidase; D048049:Extracellular Signal-Regulated MAP Kinases