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Published online before print August 11, 2003
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0103028

Received for publication January 17, 2003.

Accepted for publication July 18, 2003.

Article

Eosinophil peroxidase catalyzes JNK-mediated membrane blebbing in a Rho kinase-dependent manner

Brian McElhinney *, Matthew E. Poynter *, Punya Shrivastava *, Stanley L. Hazen {dagger},{ddagger}, and Yvonne M. W. Janssen-Heininger *,§@

*Department of Pathology, University of Vermont, Burlington; Departments of {dagger}Cell Biology and {ddagger}Cardiology and the Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic Foundation, Ohio; and §Department of Pulmonology, Maastricht University, The Netherlands

@ To whom correspondence should be addressed. E-mail: yvonne.janssen{at}uvm.edu.


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Abstract

Eosinophilic influx is characteristic of numerous inflammatory conditions. Eosinophil peroxidase (EPO) is a major enzyme present in eosinophils and upon degranulation, becomes released into the airways of asthmatics. As a result of its cationic nature and its ability to catalyze the formation of highly toxic oxidants, EPO has significant potential to induce cellular injury. The focus of the present study was to determine the cell-signaling events important in EPO-induced death of lung epithelial cells. In the presence of hydrogen peroxide and nitrite (NO2-; hereafter called EPO with substrates), EPO catalyzes the formation of nitrogen dioxide. EPO with substrates induced rapid and sustained activation of c-Jun-NH2-terminal kinase (JNK) and led to cell death, as was evidenced by enhanced mitochondrial depolarization, cytochrome c release, cleavage of caspases 9 and 3, poly-adenosine 5`-diphosphate ribosylation of proteins, the formation of single-stranded DNA, and membrane permeability. Moreover, EPO with substrates caused Rho-associated coiled coil-containing kinase-1-dependent dynamic membrane blebbing. Inhibition of JNK activity in cells expressing a dominant-negative JNK-1 construct (JNK-APF) prevented mitochondrial membrane depolarization and substantially decreased the number of cells blebbing compared with vector controls. The cellular responses to EPO with substrates were independent of whether NO2-, bromide-, or thiocyanide- was used as substrates. Our findings demonstrate that catalytically active EPO is capable of causing significant damage to lung epithelial cells in vitro and that this involves the activation of JNK.

Key Words: nitrotyrosine • asthma • epithelium • ROCK • cationic protein




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