Indomethacin Causes Prostaglandin D2-like and Eotaxin-like Selective Responses in Eosinophils and Basophils

Stubbs, Victoria; Schratl, Petra; Hartnell, Adele; Williams, Timothy J.; Peskar, Bernhard A.; Heinemann, Ákos; Sabroe, Ian

doi:10.1074/jbc.m201803200

Cited by 74 publications

(96 citation statements)

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“…To determine how exposure of eosinophils to a chemoattractant alters their responsiveness to a second chemoattractant, we mixed purified eosinophils with a first chemoattractant, applied them to the top wells of a microBoyden chamber and allowed them to migrate towards a second chemoattractant in the bottom wells. The concentrations of eotaxin (3 nM), 5-oxo-ETE (10 nM) and PGD 2 (30 nM) in the bottom wells were selected from previous experiments, because they were approximately equieffective and gave 25-35% of the maximal chemotactic response [10,24,27]. When present in the top wells, PGD 2 concentration-dependently augmented the migration of eosinophils toward eotaxin (Fig.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2006

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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...

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Section: Resultsmentioning

confidence: 99%

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

et al. 2006

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“…Eosinophil, basophil, and neutrophil shape change was assayed as described in previous work (17,18). Stimulation of these leukocytes by chemoattractant and chemokinetic agonists results in changes in the cell shape that increase the scattering of light when illuminated in a flow cytometer (Fig.…”

Section: Leukocyte Shape Change Assaymentioning

confidence: 99%

“…1). To investigate basophil shape change, PBMC were stained with anti-HLA-DR (FITC) and anti-CD123 (PE; 1/100 dilution of each Ab) for 6 min, and basophils were identified as CD123 pos /HLA-DR neg cells (17)(18)(19). Samples were immediately analyzed on a FACSort flow cytometer (BD Biosciences), and data were displayed as the percent increase in forward scatter compared with samples treated with buffer or vehicle alone.…”

Section: Leukocyte Shape Change Assaymentioning

confidence: 99%

“…Preparations of polymorphonuclear leukocytes (containing eosinophils and neutrophils) and PBMC (including basophils, monocytes, and lymphocytes) were prepared by Histopaque gradients as previously described (17,18). In some experiments eosinophils were further purified from granulocyte populations by negative magnetic selection using an Ab mixture from StemCell Technologies (Vancouver, Canada), (18).…”

Section: Preparation Of Human Leukocytesmentioning

confidence: 99%

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Δ12-Prostaglandin J2, a Plasma Metabolite of Prostaglandin D2, Causes Eosinophil Mobilization from the Bone Marrow and Primes Eosinophils for Chemotaxis

Heinemann

Schuligoi

Sabroe

et al. 2003

The Journal of Immunology

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PGD2, a major mast cell mediator, is a potent eosinophil chemoattractant and is thought to be involved in eosinophil recruitment to sites of allergic inflammation. In plasma, PGD2 is rapidly transformed into its major metabolite Δ12-PGJ2, the effect of which on eosinophil migration has not yet been characterized. In this study we found that Δ12-PGJ2 was a highly effective chemoattractant and inducer of respiratory burst in human eosinophils, with the same efficacy as PGD2, PGJ2, or 15-deoxy-Δ12,14-PGJ2. Moreover, pretreatment of eosinophils with Δ12-PGJ2 markedly enhanced the chemotactic response to eotaxin, and in this respect Δ12-PGJ2 was more effective than PGD2. Δ12-PGJ2-induced facilitation of eosinophil migration toward eotaxin was not altered by specific inhibitors of intracellular signaling pathways relevant to the chemotactic response, phosphatidylinositol 3-kinase (LY-294002), mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (U-0126), or p38 mitogen-activated protein kinase (SB-202190). Desensitization studies using calcium flux suggested that Δ12-PGJ2 signaled through the same receptor, CRTH2, as PGD2. Finally, Δ12-PGJ2 was able to mobilize mature eosinophils from the bone marrow of the guinea pig isolated perfused hind limb. Given that Δ12-PGJ2 is present in the systemic circulation at relevant levels, a role for this PGD2 metabolite in eosinophil release from the bone marrow and in driving eosinophil recruitment to sites of inflammation appears conceivable.

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“…Leukocytes from citrated whole blood were separated into a polymorphonuclear (PMN) cell population (containing eosinophils and neutrophils) and a PBMC population (containing basophils, monocytes, and lymphocytes) by dextran sedimentation and centrifugation on Histopaque 1077 as described previously (19,20,30,31). For chemotaxis experiments, basophils and eosinophils were further purified from PBMC or PMN preparations, respectively, by negative magnetic selection using Ab mixtures from StemCell Technologies, according to the manufacturer's protocol.…”

Section: Preparation Of Human Leukocytesmentioning

confidence: 99%

Identification of Selective Basophil Chemoattractants in Human Nasal Polyps as Insulin-Like Growth Factor-1 and Insulin-Like Growth Factor-2

Hartnell

Heinemann

Conroy

et al. 2004

The Journal of Immunology

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In a search for novel leukocyte chemoattractants at sites of allergic inflammation, we found basophil-selective chemoattractant activity in extracts of human nasal polyps. The extracts were fractionated by reverse phase HPLC, and the resulting fractions were tested for leukocyte-stimulating activity using sensitive shape change assays. The basophil-selective activity detected was not depleted by a poxvirus CC-chemokine-binding protein affinity column. This activity was further purified by HPLC, and proteins in the bioactive fractions were analyzed by tandem electrospray mass spectrometry. Insulin-like growth factor-2 (IGF-2) was identified in these HPLC fractions, and the basophil-stimulating activity was inhibited by an anti-IGF-2-neutralizing Ab. Recombinant IGF-2 induced a substantial shape change response in basophils, but not eosinophils, neutrophils, or monocytes. IGF-2 stimulated chemokinesis of basophils, but not eosinophils or neutrophils, and synergized with eotaxin-1/CCL11 in basophil chemotaxis. IGF-2 also caused up-regulation of basophil CD11b expression and inhibited apoptosis, but did not stimulate degranulation or Ca2+ flux. Recombinant IGF-1 exhibited similar basophil-selective effects as IGF-2, and both growth factors were detected in nasal polyp extracts by ELISA. This is the first demonstration of chemokinetic factors that increase the motility of basophils, but do not act on other granulocytes or monocytes. IGF-1 and IGF-2 could play a role in the selective recruitment of basophils in vivo.

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Indomethacin Causes Prostaglandin D2-like and Eotaxin-like Selective Responses in Eosinophils and Basophils

Cited by 74 publications

References 59 publications

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

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

Δ12-Prostaglandin J2, a Plasma Metabolite of Prostaglandin D2, Causes Eosinophil Mobilization from the Bone Marrow and Primes Eosinophils for Chemotaxis

Identification of Selective Basophil Chemoattractants in Human Nasal Polyps as Insulin-Like Growth Factor-1 and Insulin-Like Growth Factor-2

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