Am J Physiol Cell Physiol AJP: Heart and Circulatory Physiology
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Am J Physiol Cell Physiol (December 3, 2003). doi:10.1152/ajpcell.00296.2003
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Submitted on July 11, 2003
Accepted on November 12, 2003

Modulation of Bone Marrow Derived Neutrophil Signaling by H2O2: Disparate Effects on Kinases, NF-{kappa}B, and Cytokine Expression

Derek Strassheim1*, Karim Asehnoune2, Jong-Sung Park1, Jae-Yeol Kim1, Qianbin He1, Donald Richter1, Sanchayita Mitra1, John Arcaroli1, Katherine Kuhn1, and Edward Abraham1

1 Medicine, Division of Pulmonary Science & Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO, USA
2 Service d'Anesthesie-Reanimation et Unite Propre de Recherche de l' Enseignement, Hospital de Bicetre, Le Kremlin Bicetre, France; Medicine, Division of Pulmonary Science & Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO, USA

* To whom correspondence should be addressed. E-mail: derek.strassheim{at}uchsc.edu.

Reactive oxygen species (ROS), including hydrogen peroxide (H2O2), are generated in increased amounts in pathologic biologic 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 nuclear factor-{kappa}B (NF-{kappa}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, PAK. Stimulating the bone marrow derived neutrophils with (H2O2) did not affect nuclear translocation of NF-{kappa}B. However, production and secretion of the pro-inflammatory cytokine, tumor necrosis factor {alpha} (TNF{alpha}), in lipopolysaccharide (LPS)-stimulated neutrophils was inhibited by (H2O2). Exposure of LPS or TNF{alpha} stimulated neutrophils to (H2O2) decreased nuclear translocation of NF-{kappa}B. LPS induced activation of the transcriptional factor AP-1 was also inhibited by (H2O2). This inhibition of nuclear accumulation of NF-{kappa}B by (H2O2) was not caused by an impaired capacity of LPS to stimulate the I{kappa}B kinase (IKK) pathway or to direct oxidative effects on NF-{kappa}B, but rather reflected diminished degradation of I{kappa}B-{alpha}. These results indicate that oxidative stress, despite being able to selectively activate intracellular kinases in bone marrow derived neutrophils, also inhibits NF-{kappa}B activation, and associated TNF{alpha} expression. Such inhibitory effects on neutrophil activation may limit tissue damage produced by oxidative stress.




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