Cysteinyl-leukotriene type 1 receptors transduce a critical signal for the up-regulation of eosinophilopoiesis by interleukin-13 and eotaxin in murine bone marrow.
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 differentiation. Semi-solid or liquid cultures were established from murine bone marrow with GM-CSF or IL-5, respectively, and the effects of IL-13, eotaxin, or CysLT on eosinophil colony formation and on eosinophil differentiation in liquid culture were evaluated, in the absence 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 formation and IL-5-stimulated eosinophil differentiation. Although IL-13 did not induce eotaxin production, its effects were abolished by anti-eotaxin and anti-CCR3 antibodies, 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 transducing cytokine regulatory signals.
Queto
Tulio
T
Department of Pediatrics, Instituto Fernandes Figueira, Rio de Janeiro, Brazil.
Gaspar-Elsas
Maria I
MI
Masid-de-Brito
Daniela
D
Vasconcelos
Zilton F M
ZF
Ferraris
Fausto K
FK
Penido
Carmen
C
Cunha
Fernando Q
FQ
Kanaoka
Yoshihide
Y
Lam
Bing K
BK
Xavier-Elsas
Pedro
P
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D054413:Chemokine CCL11 / Q000378:metabolism*; D004804:Eosinophils / Q000166:cytology* / Q000378:metabolism; D005260:Female; D006410:Hematopoiesis / Q000502:physiology*; D018793:Interleukin-13 / Q000378:metabolism*; D008297:Male; D051379:Mice; D018613:Microscopy, Confocal; D018077:Receptors, Leukotriene / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D015854:Up-Regulation
D054413:Chemokine CCL11; D018793:Interleukin-13; D018077:Receptors, Leukotriene; C083169:leukotriene D4 receptor