Papel do domínio desintegrina da ADAM9 na ativação e quimiotaxia de neutrófilos humanos

Abstract

ADAM comprise a family of secreted and transmembrane proteins involved in important physiological process such as cell adhesion and proteolysis. On the other hand, miltiple ADAM play a central role in the formation and progression of various diseases. The increased expression of ADAM9 is correlated with tumor development due to proteolytic activity mediated by metalloprotease domain. Although many studies address the proteolytic activity of members of this family, the role of the disintegrin-like domain remains unknown. The present study aims to investigate the effects of ADAM9D on the activation and chemotaxis of human neutrophils. We used an experimental model in which human neutrophils isolated from peripheral blood were stimulated in vitro to better understand the mechanisms by ADAM9D in the migration process. ADAM9D was able to promote neutrophil recruitment, and make them less responsive to classical chemotactic stimuli such as fMLP, IL-8 and LTB4. This effect seems to depend on expression of α5β1 integrin, αvβ3 and α9β1, since treatment of the cells with blocking antibodies inhibited migration in response to ADAM9D. Addionally, the treatment of neutrophil with a inhibitory G protein (pertussis toxin) or inhibitors of CXCR2 (SB225002 and repertaxina) also inhibited the migratory response. Taken together, our data suggest that ADAM9D induces migration of neutrophils through the PI3K/Akt pathway. In addition, the chemotactic effect seems to depend on the ADAM9D CXCR2 activation, suggesting a possible mechanism of transactivation present in this phenomenon.