Prostaglandin D2 Selectively Induces Chemotaxis in T Helper Type 2 Cells, Eosinophils, and Basophils via Seven-Transmembrane Receptor Crth2

Hirai, Hiroyuki; Tanaka, Kohei; Yoshie, Osamu; Ogawa, Kazuyuki; Kenmotsu, Kazumi; Takamori, Yasushi; Ichimasa, Michiko; Sugamura, Kazuo; Nakamura, Masataka; Takano, Shoichi; Nagata, Kazuhiro

doi:10.1084/jem.193.2.255

Cited by 1,000 publications

(957 citation statements)

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“…36: 2401 chemotactic responsiveness to eotaxin and 5-oxo-ETE, while the DP-selective antagonist BWA868c had no effect. Moreover, we found that this PGD 2 effect was specific for eosinophils as compared with neutrophils, since PGD 2 did not alter the responsiveness of neutrophils to 5-oxo-ETE or IL-8, which is in agreement with CRTH2 being expressed in eosinophils and basophils, but not neutrophils [9]. Unexpectedly, PGD 2 even inhibited basophil chemotaxis to 5-oxo-ETE and eotaxin in a ramatroban-sensitive manner, which indicates that the down-stream events following CRTH2 activation in basophils differ fundamentally from eosinophils.…”

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confidence: 85%

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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confidence: 85%

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

et al. 2006

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“…1 PGD2 is principally produced by activated mast cells and, to a lesser extent, by T helper cell 2 (Th2) cells and dendritic cells 2-4 and exerts its effect through D prostanoid 5 and chemoattractant receptor-homologous molecule receptors expressed onTh2 lymphocytes (CRTH2). 6 A number of recent studies have shown that PGD2 is involved in inflammatory reactions. Mast cell-derived PGD2 suppresses IL-12 production by dendritic cells that induce Th2 responses in vivo.…”

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confidence: 99%

“…6 A number of recent studies have shown that PGD2 is involved in inflammatory reactions. Mast cell-derived PGD2 suppresses IL-12 production by dendritic cells that induce Th2 responses in vivo.…”

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confidence: 99%

“…7 PGD2 both activates and induces chemotaxis of Th2 cells, eosinophils, and basophils. 6 A large amount of PGD2 is detected in broncho-alveolar lavage fluid during allergen-induced airway inflammation. 8 Transgenic mice overexpressing human PGD synthase showed exacerbation of ovalbumin (OVA)-induced lung inflammation associated with pronounced eosinophilia and increased Th2 cytokine production.…”

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confidence: 99%

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FcεRI, but Not FcγR, Signals Induce Prostaglandin D2 and E2 Production from Basophils

Ugajin

Satoh

Kanamori

et al. 2011

The American Journal of Pathology

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Prostaglandin (PG) D2 and PGE2 are arachidonic acid metabolites that are generated though an isomerization reaction catalyzed by PG synthases. PGs have been implicated in immunologic reactions in addition to a wide range of physiological functions. It has long been thought that basophils, in contrast to mast cells, do not synthesize PGs, although they do release leukotrienes and platelet-activating factor. Here, we show that basophils function as a source of PGD2 and PGE2. In vitrocultured basophils from mouse bone marrow produced both PGD2 and PGE2 in response to IgE ؉ antigen (Ag), but not to IgG ؉ Ag. Release of PGs was almost completely abrogated in cultured basophils from FcR␥-chain ؊/؊ mice, indicating the involvement of Fc RI. Basophils freshly isolated from bone marrow cells (primary basophils) were also capable of secreting PGD2 and PGE2. Although the amount of PGD2 released from primary basophils was lower than that from mast cells, the capability of primary basophils to generate PGE2 was more potent than that of mast cells. Transcripts and proteins for both hematopoietic-type PGD synthase and PGE synthase were detected in basophils. In addition, human basophils, like mouse basophils, also produced PGD2 through IgE-mediated stimulation. Thus, basophils could be an important source of PGD2/ PGE2 and may contribute to allergic inflammation and immune responses. Prostaglandins, such as PGD2 and PGE2, are cyclooxygenase (COX) metabolites of arachidonic acids. They have a wide range of biological activities, including relaxation and contraction of smooth muscles, and modulation of neuronal activity. 1 PGD2 is principally produced by activated mast cells and, to a lesser extent, by T helper cell 2 (Th2) cells and dendritic cells 2-4 and exerts its effect through D prostanoid 5 and chemoattractant receptor-homologous molecule receptors expressed onTh2 lymphocytes (CRTH2). 6 A number of recent studies have shown that PGD2 is involved in inflammatory reactions. Mast cell-derived PGD2 suppresses IL-12 production by dendritic cells that induce Th2 responses in vivo. 7 PGD2 both activates and induces chemotaxis of Th2 cells, eosinophils, and basophils. 6 A large amount of PGD2 is detected in broncho-alveolar lavage fluid during allergen-induced airway inflammation. 8 Transgenic mice overexpressing human PGD synthase showed exacerbation of ovalbumin (OVA)-induced lung inflammation associated with pronounced eosinophilia and increased Th2 cytokine production. 9 In our previous studies, mice deficient in the CRTH2 gene were characterized by alleviated IgE-mediated cutaneous responses, contact hypersensitivity reactions, 10 and cedar pollen dermatitis. 11 However, PGE2 is produced by a variety of cells, including fibroblasts and macrophages, and exerts its effects via prostaglandin E2 (EP)1, EP2, EP3, and EP4 receptors. 12 PGE2 acts on T cells to enhance production of Th2-type cytokines and to inhibit production of Th1 cytokines in vitro, 13 whereas another study showed that PGE2 facilitates Th1 differentiation via EP...

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“…The DP1 receptor is coupled to G s protein and stimulates adenylyl cyclase, leading to increased levels of cyclic adenosine monophosphate (cAMP; Hata and Breyer 2004). A second type of DP receptor [DP2, also referred to as chemoattractant receptor-homologous molecule expressed on T helper cells (CRTH2)] has also been reported, but it has no significant homology with DP1 and has different biological functions and cellular distribution (Hirai et al 2001;Sawyer et al 2002), and some of its signaling is thought to be independent of PGD 2 levels. Furthermore, it has been documented that its activation decreases cAMP and increases intracellular calcium levels (Bohm et al 2004;Sandig et al 2006).…”

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Prostaglandin D2 DP1 receptor is beneficial in ischemic stroke and in acute exicitotoxicity in young and old mice

Ahmad

Maruyama

et al. 2010

AGE

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The cardiovascular complications reported to be associated with cyclooxygenase inhibitor use have shifted our focus toward prostaglandins and their respective receptors. Prostaglandin D 2 and its DP1 receptor have been implicated in various normal and pathologic conditions, but their role in stroke is still poorly defined. Here, we tested whether DP1 deletion aggravates N-methyl-D-aspartic acid (NMDA)-induced acute toxicity and whether DP1 pharmacologic activation protects mice from acute excitotoxicity and transient cerebral ischemia. Moreover, since the elderly are more vulnerable to stroke-related damage than are younger patients, we tested the susceptibility of aged DP1 knockout (DP1 −/− ) mice to brain damage. We found that intrastriatal injection of 15 nmol NMDA caused significantly larger lesion volumes (27.2±6.4%) in young adult DP1 −/− mice than in their wild-type counterparts. Additionally, intracerebroventricular pretreatment of wild-type mice with 10, 25, and 50 nmol of the DP1-selective agonist BW245C significantly attenuated the NMDA-induced lesion size by 19.5± 5.0%, 39.6±7.7%, and 28.9±7.0%, respectively. The lowest tested dose of BW245C also was able to reduce middle cerebral artery occlusion-induced brain infarction size significantly (21.0±5.7%). Interestingly, the aggravated NMDA-induced brain damage was persistent in older DP1 −/− mice as well. We conclude that the DP1 receptor plays an important role in attenuating brain damage and that selective targeting of this receptor could be considered as an adjunct therapeutic tool to minimize stroke damage.

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Prostaglandin D2 Selectively Induces Chemotaxis in T Helper Type 2 Cells, Eosinophils, and Basophils via Seven-Transmembrane Receptor Crth2

Cited by 1,000 publications

References 26 publications

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

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

FcεRI, but Not FcγR, Signals Induce Prostaglandin D2 and E2 Production from Basophils

Prostaglandin D2 DP1 receptor is beneficial in ischemic stroke and in acute exicitotoxicity in young and old mice

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