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CYSTEINYL LEUKOTRIENES MEDIATE THE ENHANCING EFFECTS OF INDOMETHACIN AND ASPIRIN ON EOSINOPHIL PRODUCTION IN MURINE BONE MARROW CULTURES
Leucotrienos
Medula Óssea
Eosinófilos
Hematopoese
Araquidonato 5-Lipoxigenase
Affilliation
Universidade Federal do Rio de Janeiro. Instituto de Puericultura e Pediatria Martagão Gesteira. Departamento de Imunologia. Rio de Janeiro, RJ, Brasil / Brigham and Women’s Hospital. Division of Rheumatology, Immunology and Allergy. Department of Medicine. Boston, MA, USA.
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.
Brigham and Women’s Hospital. Division of Rheumatology, Immunology and Allergy. Department of Medicine. Boston, MA, USA.
Brigham and Women’s Hospital. Division of Rheumatology, Immunology and Allergy. Department of Medicine. Boston, MA, USA.
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.
Brigham and Women’s Hospital. Division of Rheumatology, Immunology and Allergy. Department of Medicine. Boston, MA, USA.
Brigham and Women’s Hospital. Division of Rheumatology, Immunology and Allergy. Department of Medicine. Boston, MA, USA.
Abstract
Background:Prostaglandin E2(PGE2) suppresses, while indomethacin and aspirin enhance, eosinophil production in murine
liquid bone-marrow cultures. Because cysteinyl leukotrienes (cys-LTs) enhance human eosinophil colony formation, we
investigated whether the effects of indomethacin and aspirin on murine bone-marrow were due to blockade of PGE2
production alone, or involved further promotion of cys-LTs production/signalling.
Experimental approach: BALB/c liquid bone-marrow cultures were established with IL-5, alone or associated with
indomethacin, aspirin, or cys-LTs. The effects of preventing cys-LT production or signalling were assessed.
Key results:Indomethacin and aspirin counteracted the suppression of eosinophil production by exogenous PGE2. LTD4, LTC4
and LTE4 enhanced IL-5-dependent eosinophil production and further counteracted the effect of exogenous PGE2. The
5-lipoxygenase activating protein (FLAP) inhibitor, MK886, a leukotriene synthesis inhibitor, zileuton, the CysLT1receptor
antagonists, MK571 and montelukast, or inactivation of the LTC4synthase gene, abolished effects of indomethacin and aspirin.
MK886 and zileuton were ineffective but MK571 and montelukast were effective, against LTD4. Indomethacin, aspirin and
LTD4failed to enhance eosinophil production in bone-marrow from CysLT1 receptor-deficient mice. Indomethacin, aspirin
and LTD4no longer counteracted the effects of exogenous PGE2in the presence of MK571 and montelukast. MK886, MK571
and montelukast had no effect by themselves, or in association with PGE2.
Conclusions and implications:Dependence on the FLAP/5-lipoxygenase/LTC4 synthase pathway and receptor signalling
shows that cyclo-oxygenase inhibitors act here through endogenous cys-LTs. While PGE2does not act by suppressing cys-LT
production, cys-LTs override PGE2signalling. Eosinophil production is therefore coordinately regulated by both pathways.
DeCS
Asma Induzida por AspirinaLeucotrienos
Medula Óssea
Eosinófilos
Hematopoese
Araquidonato 5-Lipoxigenase
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