Thiocyanate-dependent induction of endothelial cell adhesion molecule expression by phagocyte peroxidases: a novel HOSCN-specific oxidant mechanism to amplify inflammation.

Abstract

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-kappaB 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-kappaB, 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.

• Authors: Jian-Guo Wang, Shawn A Mahmud, Julia Nguyen, Arne Slungaard
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 177 Issue 12 Pg. 8714-22 (Dec 15 2006) ISSN: 0022-1767 [Print] United States
• PMID: 17142773 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cell Adhesion Molecules
• Oxidants
• Thiocyanates
• Transcription Factors
• Vascular Cell Adhesion Molecule-1
• Eosinophil Peroxidase
• Peroxidases
• Peroxidase
• thiocyanate

Topics

• Cell Adhesion Molecules (genetics)
• Cells, Cultured
• Endothelium, Vascular (cytology)
• Eosinophil Peroxidase
• Gene Expression Regulation (drug effects)
• Humans
• Inflammation (etiology)
• Neutrophils (enzymology, physiology)
• Oxidants (physiology)
• Peroxidase
• Peroxidases (metabolism, physiology)
• Phagocytes (drug effects, enzymology)
• Thiocyanates (metabolism, pharmacology)
• Transcription Factors (drug effects)
• Umbilical Veins (cytology)
• Vascular Cell Adhesion Molecule-1 (genetics)