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Blood, 1 December 2005, Vol. 106, No. 12, pp. 3970-3978.
Prepublished online as a Blood First Edition Paper on August 11, 2005; DOI 10.1182/blood-2005-03-1292.
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PHAGOCYTES
Mechanism and effect of thrombospondin-4 polymorphisms on neutrophil function
Elzbieta Pluskota,
Olga I. Stenina,
Irene Krukovets,
Dorota Szpak,
Eric J. Topol, and
Edward F. Plow
From the Joseph Jacobs Center for Thrombosis and Vascular Biology, Cleveland Clinic Foundation, OH.
High-throughput genomic technology identified an association between a single nucleotide polymorphism (SNP), a proline (P387) rather than the predominant alanine (A387) at position 387 in thrombospondin-4 (TSP-4) and premature myocardial infarction. The inflammatory hypothesis of atherosclerosis invokes a prominent role of leukocytes and cytokines in pathogenesis. As the expression of TSP-4 by vascular cells permits its exposure to circulating leukocytes, the interactions of human neutrophils (polymorphonuclear leukocytes [PMNs]) with both TSP-4 variants were investigated. Phorbol 12-myristate 13-acetate (PMA)–stimulated PMNs adhered and migrated well and equally on the TSP-4 variants. Integrin  M 2 was identified as the TSP-4 receptor mediating these responses, and the 3 epidermal growth factor (EGF)–like domains of TSP-4 harboring the SNPs interacted with the MI-domain. Despite the similarity in these responses, the P387 variant induced more robust tyrosine phosphorylation of the stress-related mitogen-activated protein kinases (MAPKs): p38MAPK and c-Jun NH2-terminal kinase (JNK), as well as signal transducer and activator of transcription-1 (STAT1) and heat shock protein 27 (HSP27) than the A387 variant. Additionally, cells adherent to P387 TSP-4 variant released 4-fold more H2O2 and secreted 2-fold more interleukin 8 (IL-8) as compared with the A387. H2O2 release and p38MAPK activation were totally inhibited by blockade of M2. Thus, M2 plays a central role in proinflammatory activities of TSP-4 (P387) and may contribute to the prothrombotic phenotype associated with this variant.
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