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https://www.arca.fiocruz.br/handle/icict/9546
CYSTEINYL-LEUKOTRIENE TYPE 1 RECEPTORS TRANSDUCE A CRITICAL SIGNAL FOR THE UP-REGULATION OF EOSINOPHILOPOIESIS BY INTERLEUKIN-13 AND EOTAXIN IN MURINE BONE MARROW
Author
Affilliation
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.
Fundação Oswaldo Cruz. Instituto Fernandes Figueira. Departamento de Pediatria. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos. Rio de Janeiro, RJ, Brasil.
Universidade de São Paulo. Faculdade de Medicina de Ribeirão Preto. Departamento de Farmacologia. Ribeirão Preto, SP, Brasil.
Brigham and Women’s Hospital. Department of Medicine. Division of Rheumatology. Boston, Massachusetts, USA.
Brigham and Women’s Hospital. Department of Medicine. Division of Rheumatology. Boston, Massachusetts, USA.
Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Professor 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.
Fundação Oswaldo Cruz. Instituto Fernandes Figueira. Departamento de Pediatria. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos. Rio de Janeiro, RJ, Brasil.
Universidade de São Paulo. Faculdade de Medicina de Ribeirão Preto. Departamento de Farmacologia. Ribeirão Preto, SP, Brasil.
Brigham and Women’s Hospital. Department of Medicine. Division of Rheumatology. Boston, Massachusetts, USA.
Brigham and Women’s Hospital. Department of Medicine. Division of Rheumatology. Boston, Massachusetts, USA.
Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Professor Paulo de Góes. Departamento de Imunologia. Rio de Janeiro, RJ, Brasil.
Abstract
IL-13 and eotaxin play important, inter-related roles in asthma models. In the lungs, CysLT, produced by the 5-LO-LTC4S pathway, mediate some local responses to IL-13 and eotaxin; in bone marrow, CysLT enhance IL-5-dependent eosinophil differentiation. We examined the effects of IL-13 and eotaxin on eosinophil differenti-ation. Semi-solid or liquid cultures were established from murine bone marrow with GM-CSF or IL-5, re-spectively, and the effects of IL-13, eotaxin, or CysLT on eosinophil colony formation and on eosinophil differ-entiation in liquid culture were evaluated, in the ab-sence or presence of: a) the 5-LO inhibitor zileuton, the FLAP inhibitor MK886, or the CysLT1R antagonists, montelukast and MK571; b) mutations that inactivate 5-LO, LTC4S, or CysLT1R; and c) neutralizing mAb against eotaxin and its CCR3 receptor. Both cytokines enhanced GM-CSF-dependent eosinophil colony forma-tion and IL-5-stimulated eosinophil differentiation. Al-though IL-13 did not induce eotaxin production, its ef-fects were abolished by anti-eotaxin and anti-CCR3 an-tibodies, suggesting up-regulation by IL-13 of responses to endogenous eotaxin. Anti-CCR3 blocked eotaxin completely. The effects of both cytokines were prevented by zileuton, MK886, montelukast, and MK571, as well as by inactivation of the genes coding for 5-LO, LTC4S, and CysLT1R. In the absence of either cytokine, these treatments or mutations had no effect. These findings provide evidence for: a) a novel role of eotaxin and IL-13 in regulating eosinophilopoiesis; and b) a role for CysLTRs in bone marrow cells in transduc-ing cytokine regulatory signals.
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