Cysteinyl-leukotriene type 1 receptors transduce a critical signal for the up-regulation of eosinophilopoiesis by interleukin-13 and eotaxin in murine bone marrow

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 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.

International Union of Basic and Clinical Pharmacology. LXXXIV: Leukotriene Receptor Nomenclature, Distribution, and Pathophysiological Functions

“…In a recent study, the CysLT 1 R has been associated with cytokine transduction signals for the up-regulation of eosinophilopoiesis by IL-13 and eotaxin in murine bone marrow (Queto et al, 2010). These data support early reports demonstrating the inhibitory action of CysLT 1 R antagonists on eosinophil activation and migration (Virchow et al, 2001;Fregonese et al, 2002;Suzuki et al, 2003;Ueda et al, 2003;Saito et al, 2004;Nagata et al, 2005), as well as on adhesion (Fregonese et al, 2002;Nagata et al, 2002;Kushiya et al, 2006;Meliton et al, 2007;Profita et al, 2008).…”

IL-4 and IL-13 Differentially Regulate TLR-Induced Eosinophil-Basophil Differentiation Of Cord Blood CD34+ Progenitor Cells

“…In these models, IL-13 was found to have an enhancing effect on both migratory responses to stromal-derived factor 1a and on Eo/B differentiation. Our observation that IL-13 did not have an inhibitory effect on Eo/B CFU ( Figure 2D-F) is in line with those of others [20] demonstrating promotion of eosinophilopoiesis. Conversely, there are reports in which IL-4 has an inhibitory role in eosinophilopoiesis of CB-derived progenitor cells [28,29].…”

“…The cytokines IL-4 and IL-13 have been shown to influence hematopoietic progenitor cell chemotaxis [19] and Eo/B CFU [20] in human and murine systems, respectively. In these models, IL-13 was found to have an enhancing effect on both migratory responses to stromal-derived factor 1a and on Eo/B differentiation.…”

“…The expression of IL-4 is increased in the airways of allergic subjects [18] and in the CB of at-risk infants who subsequently develop atopic disease [12,13]. Although these cytokines have recently been shown to influence human CB CD34 + cell chemotaxis [19] and murine bone marrow (BM) Eo/B CFU formation ex vivo [20] it is unclear what effects IL-4 or IL-13 might have on LPS-induced Eo/B CFU formation from human CB CD34 + cells. In this study, we investigated whether the T H 2 cytokines IL-4 and IL-13 influence LPS-induced Eo/B CFU of CB progenitor cells.…”

G-CSF suppresses allergic pulmonary inflammation, downmodulating cytokine, chemokine and eosinophil production

“…Accordingly, bone-marrow and blood eosinophilia, and lung eosinophil infiltration depend on IL-5. Both eotaxin and IL-13 enhance eosinophil production in the presence of IL-5 (Queto et al 2010). Eotaxin and IL-13 also interact with IL-5 to induce lung eosinophilic inflammation and airway hyperreactivity (Townley and Horiba 2003;Effros and Nagaraj 2007).…”