Essential Roles of PKA, iNOS, CD95/CD95L, and Terminal Caspases in Suppression of Eosinopoiesis by PGE2 and Other cAMP-Elevating Agents

Author:

de Luca Bianca1,Xavier-Elsas Pedro2,Barradas Mônica2,Luz Ricardo A.2,Queto Túlio1,Jones Carla2,Arruda Maria Augusta3,Cunha Thiago Mattar4,Cunha Fernando Queiroz4,Gaspar-Elsas Maria Ignez1

Affiliation:

1. Department of Pediatrics, Instituto Nacional de Saúde da Mulher, da Criança e do Adolescente Fernandes Figueira, FIOCRUZ, Avenue Rui Barbosa 716, 22250-020 Rio de Janeiro, RJ, Brazil

2. Department of Immunology, Instituto de Microbiologia Professor Paulo de Góes, Universidade Federal do Rio de Janeiro, CCS, Bloco I, Room I-2-066, 22205-020, Rio de Janeiro, Brazil

3. Farmanguinhos, FIOCRUZ, Avenue Comandante Guaranys No. 447, Jacarepaguá, 22775-903 Rio de Janeiro, RJ, Brazil

4. Department of Pharmacology, Faculdade de Medicina da USP, Avenue Bandeirantes 3900, Monte Alegre, 14049-900 Ribeirão Preto, SP, Brazil

Abstract

Up- and downregulation of eosinopoiesis control pulmonary eosinophilia in human asthma. In mice, eosinopoiesis is suppressed in vitro by prostaglandin E2 (PGE2) and in vivo by diethylcarbamazine, through a proapoptotic mechanism sequentially requiring inducible NO synthase (iNOS) and the ligand for death receptor CD95 (CD95L). We examined the roles of iNOS, cAMP-mediated signaling, caspases, and CD95L/CD95 in suppression of eosinopoiesis by PGE2 and other agents signaling through cAMP. Bone-marrow collected from BALB/c mice, or from iNOS-, CD95-, or CD95L-deficient mutants (and wild-type controls), was cultured with interleukin-5 (IL-5), alone or associated with PGE2, cAMP-inducing/mimetic agents, caspase inhibitor zVAD-fmk, iNOS inhibitor aminoguanidine, or combinations thereof, and eosinopoiesis was evaluated at various times. PGE2, added up to 24 hours of culture, dose-dependently suppressed eosinopoiesis, by inducing apoptosis. This effect was (a) paralleled by induction of iNOS in eosinophils; (b) duplicated by sodium nitroprusside, isoproterenol, and cAMP-inducing/mimetic agents; (c) prevented by protein kinase A inhibition. NO was produced through iNOS by dibutyryl-cAMP-stimulated bone-marrow. Overall, PGE2 and isoproterenol shared a requirement for four effector elements (iNOS, CD95L, CD95, and terminal caspases), which together define a pathway targeted by several soluble up- and downmodulators of eosinopoiesis, including drugs, mediators of inflammation, and cytokines.

Funder

CNPq

Publisher

Hindawi Limited

Subject

General Environmental Science,General Biochemistry, Genetics and Molecular Biology,General Medicine

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