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Thiocyanate-Dependent Induction of Endothelial Cell Adhesion Molecule Expression by Phagocyte Peroxidases: A Novel HOSCN-Specific Oxidant Mechanism to Amplify Inflammation¹

University of Minnesota, Department of Medicine, Hematology, Oncology and Transplantation Division and The Vascular Biology Center, Minneapolis, MN 55455

Both eosinophil peroxidase (EPO) and neutrophil myeloperoxidase (MPO) preferentially oxidize SCN^– to generate HOSCN, a weak, sulfhydryl-reactive oxidant, as a major physiologic product. We here show that HOSCN is a uniquely potent phagocyte oxidant inducer of E-selectin, ICAM-1, and VCAM-1 expression in HUVEC as detected by Western blot and flow cytometry. EMSA and inhibitor studies show that HOSCN up-regulation of these adhesion molecules is transcriptionally mediated through a mechanism that is dependent upon activation of the NF-B p65/p50 transcription factor and constitutively suppressed by PI3K-Akt pathway activity. HUVEC monolayers exposed to HOSCN bind 8-fold more neutrophils and 3- to 4-fold more Aml14.3D10 cells (a differentiated cell line model of mature eosinophils) than control monolayers. Blocking Ab studies confirm the involvement of E-selectin and ICAM-1 but not VCAM-1 in neutrophil adhesion and of all three in Aml14.3D10 adhesion. Intraperitoneal injection of HOSCN evoked an 8-fold increase in neutrophil peritoneal extravasation. In addition to NF-B, HOSCN also activates the potentially proinflammatory transcription factors Stat4, CDP, GRE, CBF, Ets-1/PEA3, and TFIID, a pattern easily distinguishable from that induced by LPS. These results suggest that phagocyte peroxidases function to amplify inflammation through a novel, HOSCN-specific oxidant mechanism.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant NIH HL-070937.

² Address correspondence and reprint requests to Dr. Arne Slungaard, Mayo Mail Code 480, 420 Delaware Street Southeast, Minneapolis, MN 55455. E-mail address: slung001{at}umn.edu

³ Abbreviations used in this paper: MPO, myeloperoxidase; EO, eosinophil; EPO, eosinophil peroxidase.

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