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EVIDENCE FOR A REGULATORY ROLE OFA4 – INTEGRINS IN THE MATURATION OF EOSINOPHILS GENERATED FROM THE BONE MARROW IN THE PRESENCE OF DEXAMETHASONE
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Fundação Oswaldo Cruz. Instituto Fernandes Figueira. Departamento de Pediatria. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Fernandes Figueira. Departamento de Pediatria. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Fernandes Figueira. Departamento de Pediatria. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Prof. Paulo de Góes. Departamento de Imunologia. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Prof. Paulo de Góes. Departamento de Imunologia. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Fernandes Figueira. Departamento de Pediatria. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Fernandes Figueira. Departamento de Pediatria. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Prof. Paulo de Góes. Departamento de Imunologia. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Prof. Paulo de Góes. Departamento de Imunologia. Rio de Janeiro, RJ, Brasil.
Abstract
Background: Although eosinophils co-express multiple integrin receptors, the contributions of integrins to eosinophil development have not been explored. We previously described extensive aggregation and cytological immaturity in eosinophils developing in bone-marrow (BM) cultures exposed to dexamethasone. Here we examined the relationship ofa4 integrins with these effects of dexamethasone. ObjectivesWe evaluated: (a) the effects of exposure to dexamethasone in BM culture on eosinophil expression ofa4 integrin receptors and ligands; (b) the contribution ofa4 integrins to eosinophil aggregation and maturation. Methods: Cultures were established with IL-5 (alone or with dexamethasone) for up to 7 days, and eosinophil production,a4 integrin receptor/ligand expression, aggregation and morphology were evaluated before and after targetinga4 integrin-dependent adhesions. Because prostaglandin E2 (PGE2) modifies the effects of dexamethasone on eosinophilopoiesis, PGE2 effects ona4 integrin expression and function were also evaluated. Results: Dexamethasone increased the yield of eosinophils up to day 7. The frequency of eosinophils expressinga4,b1 andb7 integrin receptors at day 7 was also increased by dexamethasone. Eosinophils also expressed thea4b1 ligand, VCAM-1. Dexamethasone increased the expression ofa4 integrin and VCAM-1 in aggregates containing eosinophils as early as day 3. PGE2, added up to day 3, modified the effects of dexamethasone to suppress the expression ofa4 integrin, decrease aggregation and promote cytological maturation of eosinophils recovered at day 7. Dissociation of immature eosinophils from clusters present at day 3 by reagents targetinga4orb1 integrins or VCAM-1 also induced cytological maturation. The concordant effects of targetinga4 integrins with drugs and antibodies support a relationship betweena4-mediated aggregation and maturational arrest. Conclusions: These observations support a novel role fora4 integrin receptors and ligands in eosinophilopoiesis. In addition, increaseda4 expression following glucocorticoid exposure may contribute to the retention and accumulation of eosinophils in haemopoietic tissue.
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