A dominant role for chemoattractant receptor‐homologous molecule expressed on T helper type 2 (Th2) cells (CRTH2) in mediating chemotaxis of CRTH2<sup>+</sup> CD4<sup>+</sup> Th2 lymphocytes in response to mast cell supernatants

Gyles, Shân L.; Xue, Luzheng; Townsend, Elizabeth; Wettey, Frank R.; Pettipher, Roy

doi:10.1111/j.1365-2567.2006.02440.x

Cited by 47 publications

(54 citation statements)

References 31 publications

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“…In line with our findings in this murine model, protective activity of PGE 2 is also observed in asthmatics [22]. Inhalation of PGE 2 prevents allergen-induced early and late airway responses after allergen challenge [23][24][25].…”

Section: Discussionsupporting

confidence: 79%

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Dissociation of airway inflammation and hyperresponsiveness by cyclooxygenase inhibition in allergen challenged mice

Swedin¹,

Neimert-Andersson²,

Hjoberg³

et al. 2009

European Respiratory Journal

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The aim of the current study was to define how cyclooxygenase (COX)-activity affects airway hyperresponsiveness (AHR) and inflammation using interventions with COX inhibitors at different time points during allergen challenge and/or prior to measurement of AHR in an eosinophil-driven allergic mouse model. Inflammatory cells were assessed in bronchioalveolar lavage (BAL) and AHR was evaluated as the total lung resistance to methacholine (MCh) challenge.Administration of FR122047 (COX-1 inhibitor) during ovalbumin (OVA) challenge and prior to MCh challenge enhanced AHR without affecting the inflammatory cell response. In contrast, administration of lumiracoxib (COX-2 inhibitor) during the same time period had no effect on AHR but reduced the inflammatory cells in BAL. Nonselective COX inhibition with diclofenac both enhanced the AHR and reduced the inflammatory cells.Administration of diclofenac only during OVA challenge reduced the cells in BAL without any changes in AHR, whereas administration of diclofenac only prior to MCh challenge enhanced AHR but did not affect the cells in BAL.The present study implicates distinct roles of prostanoids generated along the COX-1 and COX-2 pathways and, furthermore, that inflammatory cells in BAL do not change in parallel with AHR. These findings support the fact that AHR and the inflammatory response are distinct and, at least in part, uncoupled events.

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Section: Discussionsupporting

confidence: 79%

“…Local synergy in the tissue between vascular effects of PGE 2 and chemotactic mediators [27,28], or chemoattractant receptor-homologous molecule expressed on T-helper type (Th) 2 cell-mediated effects of PGD 2 [22,29] are two possible explanations but further studies are required to resolve the mechanism.…”

Section: Discussionmentioning

confidence: 99%

Dissociation of airway inflammation and hyperresponsiveness by cyclooxygenase inhibition in allergen challenged mice

Swedin¹,

Neimert-Andersson²,

Hjoberg³

et al. 2009

European Respiratory Journal

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“…IL-2 itself has been reported to be present in asthmatic airways (58) and may prevent the apoptosis of Th2 cells. However, the high levels of PGD 2 produced in a chronic allergic setting combined with its known dominant role in driving other aspects of Th2 cell activation (59,60) suggest that it may contribute to survival signaling in Th2 cells. Further studies are required to define the precise pathophysiological role of PGD 2 in promoting Th2 cell survival.…”

Section: Discussionmentioning

confidence: 99%

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

Xue

Barrow²,

Pettipher³

2009

The Journal of Immunology

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It is now well established that interaction of PGD2 with chemoattractant receptor- homologous molecule expressed on Th2 cells (CRTH2) promotes chemotaxis and proinflammatory cytokine production by Th2 lymphocytes. In this study we show a novel function of CRTH2 in mediating an inhibitory effect of PGD2 on the apoptosis of human Th2 cells induced by cytokine deprivation. This effect was mimicked by the selective CRTH2 agonist 13,14-dihydro-15-keto-PGD2, inhibited by the CRTH2 antagonists ramatroban and TM30089, and not observed in CRTH2-negative T cells. D prostanoid receptor 1 (DP1) or the thromboxane-like prostanoid (TP) receptor did not play a role in mediating the effects of PGD2 on the apoptosis of Th2 cells because neither the DP1 antagonist BW868C nor the TP antagonist SQ29548 had any effect on the antiapoptotic effect of PGD2. Apoptosis of Th2 cells induced by Fas ligation was not suppressed by treatment with PGD2, illustrating that activation of CRTH2 only inhibits apoptosis induced by cytokine deprivation. Treatment with PGD2 induced phosphorylation of Akt and BAD, prevented release of cytochrome c from mitochondria, and suppressed cleavage of caspase-3 and poly(ADP-ribose) polymerase in Th2 cells deprived of IL-2. The PI3K inhibitor LY294002 blocked the effect of PGD2 both on the signaling events and on the apoptotic death of Th2 cells. These data suggest that in addition to promoting the recruitment and activation of Th2 cells, PGD2 may also impede the resolution of allergic inflammation through inhibiting apoptosis of Th2 cells.

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“…High levels of PGD 2 (Murray et al, 1986;Wenzel et al, 1989;Crea et al, 1992) lead to recruitment and activation of Th2 cells and stimulate eosinophil shape change and migration (Pettipher et al, 2007). PGD 2 also promotes increased CD11b expression, which facilitates cell adhesion on the vascular cell wall and movement of eosinophils from the circulation to the site of inflammation (Monneret et al, 2001;Gyles et al, 2006). Interestingly, severe asthmatics have been reported to accumulate a particular subtype of PGD 2 -producing mast cells in the airway submucosa and epithelium resulting in increased sputum levels of PGD 2 relative to other steroid treated asthma patients (Balzar et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Fevipiprant (QAW039), a Slowly Dissociating CRTh2 Antagonist with the Potential for Improved Clinical Efficacy

et al. 2016

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Here we describe the pharmacologic properties of a series of clinically relevant chemoattractant receptor-homologous molecules expressed on T-helper type 2 (CRTh2) receptor antagonists, including fevipiprant (NVP-QAW039 or QAW039), which is currently in development for the treatment of allergic diseases. min 21 and 0.048 minute 21 , respectively. Importantly, the k off of QAW039 (half-life 5 14.4 minutes) was .7-fold slower than the slowest reference compound tested, AZD-1981. In functional studies, QAW039 behaved as an insurmountable antagonist of PGD 2 -stimulated [35 S]-GTPgS activation, and its effects were not fully reversed by increasing concentrations of PGD 2 after an initial 15-minute incubation period. This behavior is consistent with its relatively slow dissociation from the human CRTh2 receptor.In contrast for the other ligands tested this time-dependent effect on maximal stimulation was fully reversed by the 15-minute time point, whereas QAW039's effects persisted for .180 minutes. All CRTh2 antagonists tested inhibited PGD 2 -stimulated human eosinophil shape change, but importantly QAW039 retained its potency in the whole-blood shape-change assay relative to the isolated shape change assay, potentially reflective of its relatively slower off rate from the CRTh2 receptor. QAW039 was also a potent inhibitor of PGD 2 -induced cytokine release in human Th2 cells. Slow CRTh2 antagonist dissociation could provide increased receptor coverage in the face of pathologic PGD 2 concentrations, which may be clinically relevant.

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A dominant role for chemoattractant receptor‐homologous molecule expressed on T helper type 2 (Th2) cells (CRTH2) in mediating chemotaxis of CRTH2⁺ CD4⁺ Th2 lymphocytes in response to mast cell supernatants

Abstract: The major prostanoid produced by mast cells is prostaglandin D 2 (PGD 2 ), which has been detected in high concentrations in the airways of asthmatics challenged with

Cited by 47 publications

References 31 publications

Dissociation of airway inflammation and hyperresponsiveness by cyclooxygenase inhibition in allergen challenged mice

Dissociation of airway inflammation and hyperresponsiveness by cyclooxygenase inhibition in allergen challenged mice

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

Fevipiprant (QAW039), a Slowly Dissociating CRTh2 Antagonist with the Potential for Improved Clinical Efficacy

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A dominant role for chemoattractant receptor‐homologous molecule expressed on T helper type 2 (Th2) cells (CRTH2) in mediating chemotaxis of CRTH2+ CD4+ Th2 lymphocytes in response to mast cell supernatants

Abstract: The major prostanoid produced by mast cells is prostaglandin D 2 (PGD 2 ), which has been detected in high concentrations in the airways of asthmatics challenged with

Cited by 47 publications

References 31 publications

Dissociation of airway inflammation and hyperresponsiveness by cyclooxygenase inhibition in allergen challenged mice

Dissociation of airway inflammation and hyperresponsiveness by cyclooxygenase inhibition in allergen challenged mice

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

Fevipiprant (QAW039), a Slowly Dissociating CRTh2 Antagonist with the Potential for Improved Clinical Efficacy

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Resources

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A dominant role for chemoattractant receptor‐homologous molecule expressed on T helper type 2 (Th2) cells (CRTH2) in mediating chemotaxis of CRTH2⁺ CD4⁺ Th2 lymphocytes in response to mast cell supernatants