Role of Prostaglandin D2 and Its Receptors in the Pathophysiology of Asthma

Oguma, Tsuyoshi; Asano, Koichiro; Ishizaka, Akitoshi

doi:10.2332/allergolint.08-rai-0033

Cited by 56 publications

(48 citation statements)

References 48 publications

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“…While these data strongly suggest the presence of an endogenous suppressive COX metabolite whose removal unmasks allergic inflammation, its precise identity remains uncertain. COX metabolites include five major bioactive prostanoids – prostaglandin E 2 (PGE 2 ), prostacyclin, PGD 2 , PGF 2α , and thromboxane A 2 – and all of these have been implicated in various aspects of asthma pathogenesis 6–10 .…”

Section: Introductionmentioning

confidence: 99%

Prostaglandin E2 suppresses allergic sensitization and lung inflammation by targeting the E prostanoid 2 receptor on T cells

Zasłona¹,

Okunishi²,

Bourdonnay³

et al. 2014

Journal of Allergy and Clinical Immunology

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Background Endogenous prostanoids have been suggested to modulate sensitization during experimental allergic asthma, but the specific role of prostaglandin E2 (PGE2) or of specific E prostanoid (EP) receptors is not known. Objective Here we tested the role of EP2 signaling in allergic asthma. Methods Wild type (WT) and EP2−/− mice were subjected to ovalbumin sensitization and acute airway challenge. The PGE2 analog misoprostol was administered during sensitization in both genotypes. In vitro culture of splenocytes and of flow-sorted dendritic cells and T cells defined the mechanism by which EP2 exerted its protective effect. Adoptive transfer of WT and EP2−/− CD4 T cells was used to validate the importance of EP2 expression on T cells. Results As compared to WT mice, EP2−/− mice had exaggerated airway inflammation in this model. Splenocytes and lung lymph node cells from sensitized EP2−/− mice produced more IL-13 than did WT cells, suggesting increased sensitization. In WT but not EP2−/− mice, subcutaneous administration of a stable PGE2 analog during sensitization inhibited allergic inflammation. PGE2 decreased cytokine production and inhibited STAT6 phosphorylation by CD3/CD28-stimulated CD4pos T cells. Co-culture of flow cytometry-sorted splenic CD4pos T cells and CD11cpos dendritic cells from WT or EP2−/− mice suggested that the increased IL-13 production in EP2−/− mice was due to the lack of EP2 specifically on T cells. Adoptive transfer of CD4pos EP2−/− T cells caused greater cytokine production in the lungs of WT mice than did transfer of WT CD4pos T cells. Conclusion We conclude that the PGE2-EP2 axis is an important endogenous brake on allergic airway inflammation, primarily targets T cells, and its agonism represents a potential novel therapeutic approach to asthma.

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Section: Introductionmentioning

confidence: 99%

Prostaglandin E2 suppresses allergic sensitization and lung inflammation by targeting the E prostanoid 2 receptor on T cells

Zasłona¹,

Okunishi²,

Bourdonnay³

et al. 2014

Journal of Allergy and Clinical Immunology

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“…Binding of PGD 2 to DP results in inhibition of platelet aggregation and causes bronchodilation and vasodilation (11). The activation of DP also inhibits apoptosis of eosinophils and migration and degranulation of basophils (18).…”

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confidence: 99%

ANKRD13C Acts as a Molecular Chaperone for G Protein-coupled Receptors

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Roy

Iorio-Morin

et al. 2010

Journal of Biological Chemistry

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Although the mechanisms that regulate folding and maturation of newly synthesized G protein-coupled receptors are crucial for their function, they remain poorly characterized. By yeast two-hybrid screening, we have isolated ANKRD13C, a protein of unknown function, as an interacting partner for the DP receptor for prostaglandin D 2 . In the present study we report the characterization of this novel protein as a regulator of DP biogenesis and trafficking in the biosynthetic pathway. Colocalization by confocal microscopy with an endoplasmic reticulum (ER) marker, subcellular fractionation experiments, and demonstration of the interaction between ANKRD13C and the cytoplasmic C terminus of DP suggest that ANKRD13C is a protein associated with the cytosolic side of ER membranes. Co-expression of ANKRD13C with DP initially increased receptor protein levels, whereas siRNAmediated knockdown of endogenous ANKRD13C decreased them. Pulse-chase experiments indicated that ANKRD13C can promote the biogenesis of DP by inhibiting the degradation of newly synthesized receptors. However, a prolonged interaction between ANKRD13C and DP resulted in ER retention of misfolded/unassembled forms of the receptor and to their proteasome-mediated degradation. ANKRD13C also regulated the expression of other GPCRs tested (CRTH2, thromboxane A 2 (TP␣), and ␤2-adrenergic receptor), whereas it did not affect the expression of green fluorescent protein, GRK2 (G proteincoupled receptor kinase 2), and VSVG (vesicular stomatitis virus glycoprotein), showing specificity toward G proteincoupled receptors. Altogether, these results suggest that ANKRD13C acts as a molecular chaperone for G proteincoupled receptors, regulating their biogenesis and exit from the ER.As the largest family of membrane receptors, G proteincoupled receptors (GPCRs) 4 mediate physiological responses to a vast array of cellular mediators such as hormones, neurotransmitters, lipids, nucleotides, peptides, ions, and photons. To be fully functional, GPCRs need to be delivered to the plasma membrane in a ligand-responsive and signaling-competent form. The synthesis and maturation of these receptors require a complex combination of processes that include protein folding, posttranslational modifications, and transport through distinct cellular compartments of the secretory pathway (1). In recent years, GPCRs were found to interact with many proteins besides G proteins, and such interactions were shown to play important roles in receptor biogenesis and trafficking. For example, the Drosophila cyclophilin protein ninaA (neither inactivation nor afterpotential A) and its mammalian homolog, RanBP2 (Ran-binding protein 2), associate with rhodopsin and opsins, respectively. They have been characterized as chaperones that can facilitate receptor folding and are essential for efficient localization of opsins at the cell surface (2-4). The receptor-activity-modifying proteins represent another example of GPCR-interacting proteins implicated in the trafficking and functionality of receptors....

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“…[3][4][5] These mediators are devastating to the asthmatic lung causing, for example, bronchoconstriction. 6,7 In comparison with healthy individuals, the mast cell numbers are increased in the airway smooth muscle 8 and alveolar parenchyma 9 of asthmatics. As a consequence, a high number of mast cells can be activated during allergen exposure, and the symptoms can be severe.…”

Section: Introductionmentioning

confidence: 99%