RGD- and MLD-disintegrins, jarastatin and EC3, activate integrin-mediated signaling modulating the human neutrophils chemotaxis, apoptosis and IL-8 gene expression
| Autor: | Luis Felipe Ribeiro Pinto, Andréa Mariano-Oliveira, Ana Lucia J. Coelho, Davy C M Rapozo, Marta S. De Freitas, Christina Barja-Fidalgo, Russolina B. Zingali, Cezary Marcinkiewicz, Stefan Niewiarowski |
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| Rok vydání: | 2004 |
| Předmět: |
Cell Extracts
MAPK/ERK pathway Integrins MAP Kinase Signaling System Neutrophils Disintegrins Integrin Active Transport Cell Nucleus Genistein Apoptosis Viper Venoms Biology Antibodies Focal adhesion Phosphatidylinositol 3-Kinases chemistry.chemical_compound Animals Humans Drug Interactions LY294002 RNA Messenger Interleukin 8 Enzyme Inhibitors Cells Cultured PI3K/AKT/mTOR pathway Mitogen-Activated Protein Kinase 1 Cell Membrane Interleukin-8 Chemotaxis Cell Biology Protein-Tyrosine Kinases Peptide Fragments Cell biology Chemotaxis Leukocyte Gene Expression Regulation chemistry Focal Adhesion Kinase 1 Focal Adhesion Protein-Tyrosine Kinases biology.protein |
| Zdroj: | Experimental Cell Research. 292:371-384 |
| ISSN: | 0014-4827 |
| DOI: | 10.1016/j.yexcr.2003.09.013 |
| Popis: | 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-alpha(M) antibody whereas anti-alpha(9)beta(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. |
| Databáze: | OpenAIRE |
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