The principal eosinophil peroxidase product, HOSCN, is a uniquely potent phagocyte oxidant inducer of endothelial cell tissue factor activity: a potential mechanism for thrombosis in eosinophilic inflammatory states.
In vivo, bromide (Br(-)), nitrite (NO(2)(-)), and thiocyanate (SCN(-)) compete for oxidation by eosinophil peroxidase (EPO) and H(2)O(2), yielding, respectively, HOBr, NO(2)., and HOSCN. We have recently shown that SCN(-) is the strongly preferred substrate for EPO in vivo and that HOSCN, in contrast with other EPO-generated oxidants and HOCl, is a relatively weak, cell-permeant, sulfhydryl (SH)-reactive oxidant. We here show that HOSCN is a uniquely potent (up to 100-fold) phagocyte oxidant inducer of tissue factor (TF) activity in human umbilical vein endothelial cells (HUVECs). This induction is attributable to transcriptional up-regulation of TF gene expression dependent upon both activation of the p65/c-Rel TF-kappaB transcription factor and activity of the ERK1/2 kinase pathway upstream of Egr-1 and was markedly further enhanced in the presence of wortmannin, an inhibitor of the PI3 kinase/Akt pathway. HOSCN also markedly activates the proinflammatory p65/p50 NF-kappaB pathway. Based on these findings we hypothesize that HOSCN generated by adherent and infiltrating eosinophils may provoke the development of a prothrombotic and proinflammatory endothelial/endocardial phenotype that promotes the pronounced thrombotic diathesis characteristic of the hypereosinophilic syndrome.
Wang
Jian-Guo
JG
Hematology, Oncology, and Transplantation Section, Department of Medicine, and the Vascular Biology Center, University of Minnesota, Minneapolis, USA.
Mahmud
Shawn A
SA
Thompson
Jacob A
JA
Geng
Jian-Guo
JG
Key
Nigel S
NS
Slungaard
Arne
A
D051766:Early Growth Response Protein 1 / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D047209:Eosinophil Peroxidase / Q000378:metabolism; D004804:Eosinophils / Q000201:enzymology; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010586:Phagocytes / Q000166:cytology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013861:Thiocyanates / Q000494:pharmacology*; D013925:Thromboplastin / Q000378:metabolism*; D013927:Thrombosis / Q000276:immunology* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism; D015854:Up-Regulation
D051766:Early Growth Response Protein 1; D008070:Lipopolysaccharides; D016328:NF-kappa B; D016877:Oxidants; D013861:Thiocyanates; D018808:Transcription Factor AP-1; D051996:Transcription Factor RelA; D013925:Thromboplastin; D047209:Eosinophil Peroxidase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3