Antagonism of the prostaglandin D2 receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation

Uller, Lena; Mathiesen, Jesper Mosolff; Alenmyr, Lisa; Korsgren, Magnus; Ulven, Trond; Högberg, Thomas; Andersson, Gunnar; Persson, C. G. A.; Kostenis, Evi

doi:10.1186/1465-9921-8-16

Cited by 130 publications

(99 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, targeting this prostanoid using a CRTH2 antagonist in mouse and guinea pig models of asthma inhibits airway inflammation and mucus production [6,11]. The current study confirms the role of PGD 2 in allergic airway inflammation in humans.…”

Section: Discussionsupporting

confidence: 69%

“…CRTH2 (chemoattractant receptor expressed on Th2 cells) is a G-proteincoupled receptor expressed by Th2 lymphocytes, eosinophils and basophils that mediates chemotaxis and activation of these cells in response to PGD 2 [4]. CRTH2 antagonists inhibit the activation and chemotaxis of lymphocytes, eosinophils and basophils in vitro [2,5], and reduce airway inflammation in animal models of allergic inflammation [6]. These data suggest that inhibition of CRTH2 can suppress allergic inflammation in asthma.…”

mentioning

confidence: 94%

See 1 more Smart Citation

Inhibition of the asthmatic allergen challenge response by the CRTH2 antagonist OC000459

et al. 2012

View full text Add to dashboard Cite

CRTH2 (chemoattractant receptor expressed on T-helper (Th) type 2 cells) is a Gprotein-coupled receptor expressed by Th2 lymphocytes and eosinophils that mediates prostaglandin (PG)D 2 -driven chemotaxis. We studied the efficacy of the oral CRTH2 antagonist OC000459 in steroid-naïve asthmatic patients.A randomised, double-blind, placebo-controlled, two-way crossover study of 16 days' treatment with OC000459 (200 mg twice daily) on the late (LAR) and early (EAR) asthmatic responses to bronchial allergen challenge was conducted, with 16 subjects completing the study.There was a 25.4% (95% CI 5.1-45.6%) reduction in the LAR area under the curve (AUC) for change in forced expiratory volume in 1 s with OC000459 compared with placebo (p50.018) but no effect on the EAR. Sputum eosinophil counts at 1 day post-allergen challenge were lower after OC000459 treatment (p50.002). PGD 2 -induced blood eosinophil shape change ex vivo was assessed at day 7 (n57). The AUC of eosinophil shift for OC000459 was lower than placebo; the mean difference was -33.6% (95% CI -66.8--0.4%; p50.048).OC000459 treatment inhibited LAR and post-allergen increase in sputum eosinophils. This CRTH2 antagonist appears to inhibit allergic inflammation in asthma.

show abstract

Section: Discussionsupporting

confidence: 69%

mentioning

confidence: 94%

Inhibition of the asthmatic allergen challenge response by the CRTH2 antagonist OC000459

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Initial studies with CRTH2 knockout mice (13) suggested that CRTH2 might constrain Th2 cytokine production and promote Th1 cytokine production, but this is likely to be due to CRTH2 expression by Th1 cells in mice and the particular immunization procedures used. More recent studies with selective CRTH2 antagonists and genetically deficient mice have highlighted an important role for CRTH2 in promoting the accumulation of lymphocytes and eosinophils (14,15) and the production of Th2 cytokines (16) and IgE (14,16) at sites of allergic inflammation. The PI3K and calcineurin pathways are involved in mediating the responses of Th2 cells to CRTH2 activation (17).…”

Section: Novel Function Of Crth2 In Preventing Apoptosis Of Human Th2mentioning

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

View full text Add to dashboard Cite

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.

show abstract

“…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)). Antagonism of CRTH2 is currently being considered as a potentially useful approach for the treatment of allergic diseases, including asthma, rhinitis, and atopic dermatitis (20).…”

mentioning

confidence: 99%

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

View full text Add to dashboard Cite

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.

show abstract

Antagonism of the prostaglandin D2 receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation

Cited by 130 publications

References 53 publications

Inhibition of the asthmatic allergen challenge response by the CRTH2 antagonist OC000459

Inhibition of the asthmatic allergen challenge response by the CRTH2 antagonist OC000459

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

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

Contact Info

Product

Resources

About