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Mechanism and effect of thrombospondin-4 polymorphisms on neutrophil function

Academic Article
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Overview

authors

  • Pluskota, E.
  • Stenina, O. I.
  • Krukovets, I.
  • Szpak, D.
  • Topol, Eric
  • Plow, E. F.

publication date

  • December 2005

journal

  • Blood  Journal

abstract

  • 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 alpha(M)beta2 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 alpha(M)I-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 alpha(M)beta2. Thus, alpha(M)beta2 plays a central role in proinflammatory activities of TSP-4 (P387) and may contribute to the prothrombotic phenotype associated with this variant.

subject areas

  • Cell Adhesion
  • Cell Line
  • Cell Movement
  • Cytokines
  • Humans
  • Hydrogen Peroxide
  • Macrophage-1 Antigen
  • Neutrophils
  • Phosphorylation
  • Polymorphism, Single Nucleotide
  • Signal Transduction
  • Thrombospondins
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Identity

PubMed Central ID

  • PMC1895095

International Standard Serial Number (ISSN)

  • 0006-4971

Digital Object Identifier (DOI)

  • 10.1182/blood-2005-03-1292

PubMed ID

  • 16099885
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Additional Document Info

start page

  • 3970

end page

  • 3978

volume

  • 106

issue

  • 12

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