RGD- and MLD-disintegrins, jarastatin and EC3, activate integrin-mediated signaling modulating the human neutrophils chemotaxis, apoptosis and IL-8 gene expression

• Published in: Experimental cell research 2004-01, Vol.292 (2), p.371-384
• Main Authors: Coelho, Ana Lucia J, De Freitas, Marta S, Mariano-Oliveira, Andrea, Rapozo, Davy Carlos M, Pinto, Luis Felipe R, Niewiarowski, Stefan, Zingali, Russolina B, Marcinkiewicz, Cezary, Barja-Fidalgo, Christina
• Format: Article
• Language: English
• Subjects: Active Transport, Cell Nucleus - drug effects; Active Transport, Cell Nucleus - physiology; Animals; Antibodies - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Cell Extracts; Cell Membrane - drug effects; Cell Membrane - metabolism; Cells, Cultured; Chemotaxis; Chemotaxis, Leukocyte - drug effects; Chemotaxis, Leukocyte - physiology; Disintegrins; Disintegrins - antagonists & inhibitors; Disintegrins - pharmacology; Drug Interactions - physiology; Enzyme Inhibitors - pharmacology; Focal Adhesion Kinase 1; Focal Adhesion Protein-Tyrosine Kinases; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Humans; IL-8 gene expression; Integrin signal transduction; Integrins - drug effects; Integrins - metabolism; Interleukin-8 - genetics; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Mitogen-Activated Protein Kinase 1 - drug effects; Mitogen-Activated Protein Kinase 1 - metabolism; Neutrophils; Neutrophils - drug effects; Neutrophils - metabolism; Peptide Fragments - pharmacology; Phosphatidylinositol 3-Kinases - drug effects; Phosphatidylinositol 3-Kinases - metabolism; Protein-Tyrosine Kinases - drug effects; Protein-Tyrosine Kinases - metabolism; RNA, Messenger - drug effects; RNA, Messenger - metabolism; Viper Venoms - pharmacology
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2003.09.013

The effects of jarastatin (JT), a monomeric RGD-disintegrin, were compared with those of the heterodimeric MLD-disintegrin, EC3, on human neutrophil activation and functions. Both disintegrins inhibited neutrophil chemotaxis induced by fMet-Leu-Phe and were also potent chemotactic agents. These effects were accompanied by an increase in actin polymerization, and both were inhibited by genistein, a tyrosine kinase inhibitor. While JT, but not other RGD-disintegrins, inhibited EC3-induced chemotaxis, EC3 was not able to inhibit JT effect. The chemotactic effect of JT was blocked by anti-α M antibody whereas anti-α 9β 1 inhibited EC3 effect. Both JT and EC3 induced focal adhesion kinase (FAK) and phosphoinositide 3-kinase (PI3K) activation. Accordingly, LY294002, a PI3K inhibitor, impaired their chemotactic effect on neutrophils. JT induced Erk-2 translocation to nucleus and a delay of the spontaneous apoptosis of neutrophils in vitro. In contrast, EC3 inhibited Erk-2 activation and had a proapoptotic effect. These effects were reverted by PD98059, an MEK 1/2 inhibitor and blocked by z-VAD-FMK, a caspase inhibitor. In addition, JT, but not EC3, increased the IL-8 mRNA levels in neutrophils. The data indicate that JT and EC3 directly activate an integrin-coupled signaling and modulate the MAPK pathway in different ways, leading the neutrophils to express different functional response.