Journal
JOURNAL OF LEUKOCYTE BIOLOGY
Volume 97, Issue 5, Pages 951-962Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1189/jlb.3A0914-455R
Keywords
signal transduction; granulocyte; chemotaxis; apoptosis; IL-8
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Funding
- Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ)
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)
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ADAM9 is a member of the ADAM family whose expression positively correlates with tumor progression. Besides the metalloprotease activity, ADAM9D interacts with different integrins, modulating cell-adhesion events. Previous studies pointed to an important role for neutrophils in tumor development, as the inhibition of neutrophil migration or depletion of this immune cell impairs tumor growth. However, our understanding of the molecular mechanisms involved in this process, as well as the main key players acting on neutrophils, is very limited. Here, we investigated the possible modulatory effects of ADAM9D on human neutrophil functions. Our results show that ADAM9D promotes neutrophil activation and chemotaxis in a process that depends on the engagement of alpha v beta 3 and alpha 9 beta 1 integrins and on the activation of PI3K/Akt and MAPK signaling pathway. ADAM9D impairs migration of neutrophils toward fMLP, LTB4, and IL-8 as classic chemo-attractants. This effect is blocked by PTX, a G(i) PCR inhibitor. Furthermore, CXCR2 antagonists RPTX and SB225002 also impaired neutrophil chemotaxis in response to ADAM9D, suggesting a hierarchical cross-talk of integrinswith CXCR2. Our results indicate that ADAM9D activates neutrophil functions and may be implicated in the inflammatory events associated with cancer and other disorders.
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