Interaction of disintegrins with human neutrophils induces cytoskeleton reorganization, focal adhesion kinase activation, and extracellular-regulated kinase-2 nuclear translocation, interfering with the chemotactic function.

Abstract

SPECIFIC AIMSDisintegrins have often been described as passive blockers of integrins, inhibiting integrin-related functions like tumor cell metastasis, angiogenesis, and platelet aggregation. This report shows that jarastatin (JT) and two other RGD-monomeric disintegrins—kistrin (KR) and flavoridin (FL)—modulate human neutrophil (PMN) chemotaxis and chemokinesis by interfering with the activation of integrin-mediated signaling pathways.PRINCIPAL FINDINGS1. Disintegrins inhibited PMN chemotaxis in vitro and induced alterations in actin network dynamicsIncubation of PMN with JT, KR, or FL (0.1–10 μM) inhibited the chemotactic effect induced by N-formyl-methionyl-leucyl-phenylalanine peptide (fMLP; 0.1 μM) in Boyden chamber. Chemotaxis of PMN in vitro was partially reduced (10 μM=50%) by JT and completely inhibited by KR or FL (1 μM). In another set of experiments, PMN were allowed to migrate toward different concentrations of disintegrins (0.01–10 μM) placed into the bottom wells of the chamber. JT (10 μM),...