Novel Function of CRTH2 in Preventing Apoptosis of Human Th2 Cells through Activation of the Phosphatidylinositol 3-Kinase Pathway

Xue, Luzheng; Barrow, Anna; Pettipher, Roy

doi:10.4049/jimmunol.0804090

Cited by 72 publications

(48 citation statements)

References 61 publications

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“…In recent years, increasing evidence suggests that through its action on CRTH2, PGD 2 elicits many proinflammatory responses in leukocytes, including chemotaxis of eosinophils, basophils, and Th2 cells (10,11), cytokine production by Th2 cells (12,13), and proinflammatory protein expression by eosinophils and Th2 cells (12,14). Our recent studies also demonstrated that activation of CRTH2 suppresses Th2 cell apoptosis (15), a process that is likely to impede the resolution of allergic inflammation. Allergic responses mediated by IgE, mast cells, Th2 cells, and eosinophils are dramatically reduced in mice in which CRTH2 is genetically ablated or by small molecule CRTH2 antagonists (16)(17)(18)(19)).…”

mentioning

confidence: 87%

Leukotriene E4 Activates Human Th2 Cells for Exaggerated Proinflammatory Cytokine Production in Response to Prostaglandin D2

Xue

Barrow

Fleming

et al. 2012

The Journal of Immunology

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PGD2 exerts a number of pro-inflammatory responses through a high affinity interaction with chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) and has been detected at high concentrations at sites of allergic inflammation. Since cysteinyl leukotrienes (cysLTs) are also produced during the allergic response we investigated the possibility that cysLTs may modulate the response of human Th2 cells to PGD2. PGD2 induced concentration-dependent Th2 cytokine production in the absence of TCR stimulation. Leukotrienes D4 (LTD4) and E4 (LTE4) also stimulated the cytokine production but were much less active than PGD2. However, when combined with PGD2, cysLTs caused a greater than additive enhancement of the response, with LTE4 being most effective in activating Th2 cells. LTE4 enhanced calcium mobilisation in response to PGD2 in Th2 cells without affecting endogenous PGD2 production or CRTH2 receptor expression. The effect of LTE4 was inhibited by montelukast but not by the P2Y12 antagonistmethylthioadenosine 5′-monophosphate. The enhancing effect was also evident with endogenous cysLTs produced from immunologically activated mast cells since inhibition of cysLT action by montelukast or cysLT sythesis by MK886, an inhibitor of 5-LO-activating protein, reduced the response of Th2 cells to the levels produced by PGD2 alone. These findings reveal that cysLTs, in particular LTE4, have a significant pro-inflammatory impact on T cells and demonstrate their effects on Th2 cells are mediated by a montelukast-sensitive receptor.

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mentioning

confidence: 87%

Leukotriene E4 Activates Human Th2 Cells for Exaggerated Proinflammatory Cytokine Production in Response to Prostaglandin D2

Xue

Barrow

Fleming

et al. 2012

The Journal of Immunology

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“…Apoptosis of Th2 cells was measured after the withdrawal of IL-2 treatment as described previously (Xue et al, 2009). The cells were treated with PGD 2 (100 nM) in the presence and absence of various concentrations of OC000459 (1-1000 nM) for 16 h. Cells were then harvested and transferred to annexin-binding buffer, followed by incubation with phycoerythrin-annexin V/PI at room temperature for 15 min according to the manufacturer's (Invitrogen) instructions.…”

Section: Crth2mentioning

confidence: 99%

Pharmacologic Profile of OC000459, a Potent, Selective, and Orally Active D Prostanoid Receptor 2 Antagonist That Inhibits Mast Cell-Dependent Activation of T Helper 2 Lymphocytes and Eosinophils

Pettipher¹,

Vinall²,

Xue³

et al. 2011

J Pharmacol Exp Ther

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D prostanoid receptor 2 (DP 2 ) [also known as chemoattractant receptor-homologous molecule expressed on T helper 2 (Th2) cells (CRTH2)] is selectively expressed by Th2 lymphocytes, eosinophils, and basophils and mediates recruitment and activation of these cell types in response to prostaglandin D 2 (PGD 2 ). (5-Fluoro-2-methyl-3-quinolin-2-ylmethylindo-1-yl)-acetic acid (OC000459) is an indole-acetic acid derivative that potently displaces [ 3 H]PGD 2 from human recombinant DP 2 (K i ϭ 0.013 M), rat recombinant DP 2 (K i ϭ 0.003 M), and human native DP 2 (Th2 cell membranes; K i ϭ 0.004 M) but does not interfere with the ligand binding properties or functional activities of other prostanoid receptors (prostaglandin E 1-4 receptors, D prostanoid receptor 1, thromboxane receptor, prostacyclin receptor, and prostaglandin F receptor). OC000459 inhibited chemotaxis (IC 50 ϭ 0.028 M) of human Th2 lymphocytes and cytokine production (IC 50 ϭ 0.019 M) by human Th2 lymphocytes. OC000459 competitively antagonized eosinophil shape change responses induced by PGD 2 in both isolated human leukocytes (pK B ϭ 7.9) and human whole blood (pK B ϭ 7.5) but did not inhibit responses to eotaxin, 5-oxo-eicosatetraenoic acid, or complement component C5a. OC000459 also inhibited the activation of Th2 cells and eosinophils in response to supernatants from IgE/anti-IgE-activated human mast cells. OC000459 had no significant inhibitory activity on a battery of 69 receptors and 19 enzymes including cyclooxygenase 1 (COX1) and COX2. OC000459 was found to be orally bioavailable in rats and effective in inhibiting blood eosinophilia induced by 13,14-dihydro-15-keto-PGD 2 (DK-PGD 2 ) in this species (ED 50 ϭ 0.04 mg/kg p.o.) and airway eosinophilia in response to an aerosol of DK-PGD 2 in guinea pigs (ED 50 ϭ 0.01 mg/kg p.o.). These data indicate that OC000459 is a potent, selective, and orally active DP 2 antagonist that retains activity in human whole blood and inhibits mast cell-dependent activation of both human Th2 lymphocytes and eosinophils.

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“…CRTH2 is coupled to Gi-type G proteins. Previous studies reported that CRTH2 agonism activates PI3K, which then suppresses IL-2-induced apoptosis in Th2 cells (39). Other groups showed that the constitutive activation of PI3K, by creating a deficiency in the PTEN gene, inhibits the expression of proinflammatory cytokines, including TNF-a and IL-6, in macrophages (40).…”

Section: Discussionmentioning

confidence: 99%

A Deficiency in the Prostaglandin D2 Receptor CRTH2 Exacerbates Adjuvant-Induced Joint Inflammation

Tsubosaka

Nakamura

Hirai³

et al. 2014

The Journal of Immunology

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Although the cyclooxygenase metabolites PGs are known to be involved in the progression of arthritis, the role of PGD2 remains unclear. In this study, we evaluated the contribution of signaling mediated through a PGD2 receptor, chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), in the progression of adjuvant-induced joint inflammation. Injection of CFA into the ankle joint stimulated PGD2 production and induced paw swelling in both CRTH2-naive (WT) and CRTH2−/− mice. CRTH2−/− mice presented more severe arthritic manifestations than did WT mice. Through bone marrow transplantation experiments between WT and CRTH2−/− mice, we showed that CRTH2 deficiency in bone marrow–derived immune cells is involved in disease progression. Morphological studies showed that CRTH2 deficiency accelerated the infiltration of macrophages into the inflamed paw. Consistent with this finding, we observed that treatment with the macrophage inactivator GdCl3 or the macrophage-depleting agent liposomal clodronate improved arthritis symptoms in CRTH2−/− mice. Adoptive transfer of CRTH2−/− macrophages exacerbated joint inflammation in WT mice. In addition, CRTH2 deficiency accelerated, whereas CRTH2 agonism inhibited, the expression of a macrophage-activating cytokine (GM-CSF) and a chemokine receptor (CXCR2) in CFA-treated peritoneal macrophages. Together, these observations demonstrate that PGD2–CRTH2 signaling plays a protective role in joint inflammation by attenuating the infiltration of macrophages.

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Novel Function of CRTH2 in Preventing Apoptosis of Human Th2 Cells through Activation of the Phosphatidylinositol 3-Kinase Pathway

Cited by 72 publications

References 61 publications

Leukotriene E4 Activates Human Th2 Cells for Exaggerated Proinflammatory Cytokine Production in Response to Prostaglandin D2

Leukotriene E4 Activates Human Th2 Cells for Exaggerated Proinflammatory Cytokine Production in Response to Prostaglandin D2

Pharmacologic Profile of OC000459, a Potent, Selective, and Orally Active D Prostanoid Receptor 2 Antagonist That Inhibits Mast Cell-Dependent Activation of T Helper 2 Lymphocytes and Eosinophils

A Deficiency in the Prostaglandin D2 Receptor CRTH2 Exacerbates Adjuvant-Induced Joint Inflammation

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