Hierarchy of eosinophil chemoattractants: role of p38 mitogen‐activated protein kinase

Abstract

Several chemoattractants can regulate the recruitment of eosinophils to sites of inflammation, but the hierarchy among them is unknown. We observed here that eosinophil chemotaxis towards eotaxin or 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) was amplified up to sixfold in the presence of prostaglandin (PG) D 2 . This effect was only seen in eosinophils, and not in neutrophils or basophils. Pretreatment with the chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2) antagonist ramatroban prevented the PGD 2 enhancement of eosinophil migrations. In contrast, eotaxin or 5-oxo-ETE inhibited the migration of eosinophils towards PGD 2 . 5-oxo-ETE enhanced the chemotaxis to eotaxin, while eotaxin had no effect on 5-oxo-ETE-induced migration. 5-oxo-ETE induced the phosphorylation of p38 mitogenactivated protein kinase, and inhibition of p38 mitogen-activated protein kinase by SB-202190 converted the effect of 5-oxo-ETE on the chemotaxis to PGD 2 from inhibition to enhancement. The presence of blood or plasma markedly decreased the sensitivity of eosinophils to eotaxin or 5-oxo-ETE, while responses to PGD 2 were unaltered. In conclusion, PGD 2 might be an initial chemoattractant, since it maintains its potency in the circulation and augments the responsiveness of eosinophils to other chemoattractants. In contrast, eotaxin seems to be an end-point chemoattractant, since it has reduced efficacy in blood and is capable of down-modulating eosinophil responsiveness to other chemoattractants. IntroductionAccumulation of eosinophils at sites of allergic reactions, such as eczema or asthma, is associated with tissue injury and lung dysfunction [1]. It has been shown recently that asthmatic patients that received treatment based on eosinophil counts in sputum had significantly fewer severe asthma exacerbations than patients treated according to standard management therapy [2]. Moreover, genetically modified mice lacking eosinophils are protected against allergen-induced lung injury and asthma [3,4].Although several chemoattractants can mediate eosinophil recruitment, none of them could be identified so far as a predominating factor governing eosinophil infiltration, suggesting a co-operative action of multiple chemoattractants in disease. Among these are the CC-chemokines, such as eotaxin, RANTES, or MCP-4 acting through the chemokine receptor CCR3 [5,6]. Prostaglandin (PG) D 2 , a major mast cell mediator released during the allergic response [7] might be of particular importance, since PGD 2 is capable of inducing the chemotaxis of eosinophils, basophils and Th2-type * These authors contributed equally to this study. T cells via a novel receptor, chemoattractant receptorhomologous molecule expressed on TH2 cells (CRTH2) [8,9]. Besides chemotaxis, we have shown that activation of CRTH2 also causes eosinophil respiratory burst and the release of eosinophils from the bone marrow [10]. In vivo, PGD 2 can induce pulmonary eosinophilia [11], and a significant contribution of PGD 2 to the late phase allergi...

Prostaglandin E2 Inhibits Eosinophil Trafficking through E-Prostanoid 2 Receptors

“…Furthermore, we described that the MAPK pathway determines the hierarchy of eosinophil chemoattractants (11). In that study we observed that pretreatment of eosinophils with the chemoattractants eotaxin or 5-oxo-6,8,11,14-eicosatetraenoic acid inhibited the subsequent migration of the eosinophils toward PGD 2 and that inhibition of p38 MAPK prevented this inhibitory effect and even converted it to enhancement of eosinophil migration.…”

“…Immunoreactive PGE 2 in the supernatants of overnight-cultured monocytes was determined as described previously (34) using [5,6,8,11,12,14, H(N)]PGE 2 as tracer and synthetic PGE 2 as standard. Charcoal was used to separate the free and Ab-bound fractions.…”

“…PI3K and p38 MAPK are known to take part in the regulation of eosinophil responses to chemoattractants (11,30). To this end, eosinophils were pretreated with the respective vehicle, the p38 MAPK inhibitor SB-202190 (2 M) or the PI3K inhibitor LY-294002 (20 M) at 37°C for 20 min and then mixed with PGE 2 (10 -100 nM).…”

Interaction of eosinophils with endothelial cells is modulated by prostaglandin EP4 receptors

“…Polymorphonuclear leukocytes (PMNLs, containing eosinophils and neutrophils) were isolated by dextran sedimentation of erythrocytes then by centrifugation on Histopaque gradients as described previously [51,52]. Eosinophils were purified from polymorphonuclear leukocyte using negative magnetic selection with an Ab cocktail (CD2, CD14, CD16, CD19, CD56, and glycophorin A) and colloidal magnetic particles from StemCell Technologies (Vancouver, Canada) [53]. All separation steps were performed at room temperature.…”

Anti-Allergic Inflammatory Effects of Hepatocyte Growth Factor

“…Further, HGF also suppressed the PGD 2 -induced activation of ERK1/2 and p38, which may be a key regulator of eosinophil migration by PGD 2 (fig. 2) [45]. HGF had no effect on the expression of CCR3 and CRTH2, which is a receptor of PGD 2 in eosinophils.…”