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RECEPTORS AND SIGNAL TRANSDUCTION

Modulation of bone marrow-derived neutrophil signaling by H₂O₂: disparate effects on kinases, NF-B, and cytokine expression

¹Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262; and ²Service d'Anesthesie-Réanimation et Unité Propre de Recherche de l'Enseignement Superieur-Equipe d'Accueil (UPRES-EA 392), Hopital de Bicêtre, Le Kremlin Bicêtre, France 94275

Submitted 11 July 2003 ; accepted in final form 12 November 2003

Reactive oxygen species (ROS), including hydrogen peroxide (H₂O₂), are generated in increased amounts in pathological, biological processes and can play a role in signal transduction. Neutrophils often accumulate in acute inflammatory reactions, at sites where elevated concentrations of ROS are present. ROS have been demonstrated to participate in the activation of intracellular signaling pathways, including those involved in modulating nuclear accumulation and transcriptional activity of NF-B. However, the role of ROS in affecting such events in neutrophils has not been examined. Using exposure of murine bone marrow neutrophils to H₂O₂ as a model of oxidative stress, we found both strong and persistent activation of ERK1/2, p38, JNK, and PKB, but not the p21-activated kinase. Stimulating the bone marrow-derived neutrophils with H₂O₂ did not affect nuclear translocation of NF-B. However, production and secretion of the proinflammatory cytokine TNF- in LPS-stimulated neutrophils were inhibited by H₂O₂. Exposure of LPS- or TNF--stimulated neutrophils to H₂O₂ decreased nuclear translocation of NF-B. LPS-induced activation of the transcriptional factor AP-1 was also inhibited by H₂O₂. This inhibition of nuclear accumulation of NF-B by H₂O₂ was not caused by an impaired capacity of LPS to stimulate the IKK pathway or to direct oxidative effects on NF-B but rather reflected diminished degradation of IB-. These results indicate that oxidative stress, despite being able to selectively activate intracellular kinases in bone marrow-derived neutrophils, also inhibits NF-B activation and associated TNF- expression. Such inhibitory effects on neutrophil activation may limit tissue damage produced by oxidative stress.

oxidative stress; reactive oxygen species; tumor necrosis factor-

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