Attenuation of very late antigen-5-mediated adhesion of bone marrow-derived mast cells to fibronectin by peptides with inverted hydropathy to EF-hands

Academic Article

Abstract

  • Release of allergic mediators from mast cells is enhanced by very late Ag (VLA)-5-mediated interaction of these cells with fibronectin. In this report, we show that VLA-5-mediated adhesion of bone marrow-derived mast cells to fibronectin can be induced by two different pathways: first, FcεRI clustering, which depends on calmodulin activation and extracellular Ca2+, and, second, by Mn2+ stimulation, which is independent of calmodulin activation and antagonized by Ca2+. Previous studies have shown the presence of several cation-binding domains in VLA-5 that are homologous to the calcium-binding EF-hands of calmodulin. To show a role for EF-hands of different proteins in VLA-5-mediated adhesion, we used calcium-like peptides (CALP), CALP1 and CALP2, designed to bind to EF-hands based on inverted hydropathy. CALP1 and, more potently, CALP2 inhibited FcεRI-induced adhesion to fibronectin via different mechanisms. The target for the effects of CALP1 and 2 on FcεRI-induced adhesion and degranulation was intracellular and likely involved calmodulin. Interestingly only CALP2 was able to inhibit Mn2+-induced calmodulin-independent adhesion by interfering with an extracellular target, which is probably VLA-5. We conclude that CALP1 and 2 can inhibit VLA-5-mediated adhesion of mast cells to fibronectin through binding to EF-hands of multiple proteins, and that these peptides can be used as lead compounds for the development of future therapy against allergy.
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    Digital Object Identifier (doi)

    Author List

  • Houtman R; Broeke RT; Blalock JE; Villain M; Koster AS; Nijkamp FP
  • Start Page

  • 861
  • End Page

  • 867
  • Volume

  • 166
  • Issue

  • 2