Evidence for a regulatory role of alpha 4-integrins in the maturation of eosinophils generated from the bone marrow in the presence of dexamethasone.
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 of alpha 4 integrins with these effects of dexamethasone.


OBJECTIVE
We evaluated: (a) the effects of exposure to dexamethasone in BM culture on eosinophil expression of alpha 4 integrin receptors and ligands; (b) the contribution of alpha 4 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, alpha 4 integrin receptor/ligand expression, aggregation and morphology were evaluated before and after targeting alpha 4 integrin-dependent adhesions. Because prostaglandin E2 (PGE2) modifies the effects of dexamethasone on eosinophilopoiesis, PGE2 effects on alpha 4 integrin expression and function were also evaluated.


RESULTS
Dexamethasone increased the yield of eosinophils up to day 7. The frequency of eosinophils expressing alpha 4, beta1 and beta 7 integrin receptors at day 7 was also increased by dexamethasone. Eosinophils also expressed the alpha 4 beta 1 ligand, VCAM-1. Dexamethasone increased the expression of alpha 4 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 of alpha 4 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 targeting alpha 4 or beta1 integrins or VCAM-1 also induced cytological maturation. The concordant effects of targeting alpha 4 integrins with drugs and antibodies support a relationship between alpha 4-mediated aggregation and maturational arrest.


CONCLUSIONS
These observations support a novel role for alpha 4 integrin receptors and ligands in eosinophilopoiesis. In addition, increased alpha 4 expression following glucocorticoid exposure may contribute to the retention and accumulation of eosinophils in haemopoietic tissue.
Gaspar-Elsas
M I
MI
Department of Paediatrics, Instituto Fernandes Figueira, Rio de Janeiro, Brazil.
Queto
T
T
Vasconcelos
Z
Z
Jones
C P
CP
Lannes-Vieira
J
J
Xavier-Elsas
P
P
D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000276:immunology; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D039441:Integrin alpha4 / Q000187:drug effects / Q000276:immunology*; D039041:Integrin alpha4beta1 / Q000096:biosynthesis / Q000187:drug effects; D015848:Interleukin-5 / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000187:drug effects; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000187:drug effects
D039041:Integrin alpha4beta1; D015848:Interleukin-5; D008024:Ligands; D011971:Receptors, Immunologic; D019010:Vascular Cell Adhesion Molecule-1; D039441:Integrin alpha4; D003907:Dexamethasone