Prostaglandin D2 Plays an Essential Role in Chronic Allergic Inflammation of the Skin via CRTH2 Receptor

Satoh, Takahiro; Moroi, Rie; Aritake, Kosuke; Urade, Yoshihiro; Kanai, Yasumasa; Sumi, Koji; Yokozeki, Hiroo; Hirai, Hiroyuki; Nagata, Kazuhiro; Hara, Toshifumi; Utsuyama, Masanori; Hirokawa, Katsuíku; Sugamura, Kazuo; Nishioka, Kiyoshi; Nakamura, Masataka

doi:10.4049/jimmunol.177.4.2621

Cited by 184 publications

(185 citation statements)

References 36 publications

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“…These data are generally consistent with the results of our metabolism studies. PGD 2 and its receptors, DP and CRTH2, are known to be involved in chronic allergic skin inflammation (Angeli et al, 2004;Satoh et al, 2006). The marked increases in PGFS and PGIS that we noted in response to UVB also suggest that eicosanoids produced by these enzymes may be important mediators of cutaneous inflammation (Muller et al, 2000;Takahashi et al, 2002).…”

Section: Discussionmentioning

confidence: 62%

UVB light upregulates prostaglandin synthases and prostaglandin receptors in mouse keratinocytes

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Shakarjian

et al. 2008

Toxicology and Applied Pharmacology

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Prostaglandins belong to a class of cyclic lipid-derived mediators synthesized from arachidonic acid via COX-1, COX-2 and various prostaglandin synthases. Members of this family include prostaglandins such as PGE 2 , PGF 2α , PGD 2 and PGI 2 (prostacyclin) as well as thromboxane. In the present studies we analyzed the effects of UVB on prostaglandin production and prostaglandin synthase expression in primary cultures of undifferentiated and calcium-differentiated mouse keratinocytes. Both cell types were found to constitutively synthesize PGE 2 , PGD 2 and the PGD 2 metabolite PGJ 2 . Twenty-four hr after treatment with UVB (25 mJ/cm 2 ), production of PGE 2 and PGJ 2 increased, while PGD 2 production decreased. This was associated with increased expression of COX-2 mRNA and protein. UVB (2.5 -25 mJ/cm 2 ) also caused marked increases in mRNA expression for the prostanoid synthases PGDS, mPGES-1, mPGES-2, PGFS and PGIS, as well as expression of receptors for PGE 2 (EP1 and EP2), PGD 2 (DP and CRTH2) and prostacyclin (IP). UVB was more effective in inducing COX-2 and DP in differentiated cells and EP1 and IP in undifferentiated cells. UVB readily activated keratinocyte PI-3-kinase (PI3K)/Akt, JNK and p38 MAP signaling pathways which are known to regulate COX-2 expression. While inhibition of PI3K suppressed UVB-induced mPGES-1 and CRTH2 expression, JNK inhibition suppressed mPGES-1, PGIS, EP2 and CRTH2, and p38 kinase inhibition only suppressed EP1 and EP2. These data indicate that UVB modulates expression of prostaglandin synthases and receptors by distinct mechanisms. Moreover, both the capacity of keratinocytes to generate prostaglandins and their ability to respond to these lipid mediators are stimulated by exposure to UVB.

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Section: Discussionmentioning

confidence: 62%

UVB light upregulates prostaglandin synthases and prostaglandin receptors in mouse keratinocytes

Black

Gray

Shakarjian

et al. 2008

Toxicology and Applied Pharmacology

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“…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.…”

mentioning

confidence: 99%

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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“…SPF/VAF male CRTH2-deficient (BALB/c) mice (31) were bred in the Keio University Animal Research Facility. All animals were housed at the facility in bioBubble barrier units under positive pressure.…”

Section: Animalsmentioning

confidence: 99%

“…CRTH2, another PGD 2 receptor identified as a molecule preferentially expressed on Th2 lymphocytes, eosinophils, and basophils, transduces the chemokinetic activity of PGD 2 on eosinophils (26,27). We and others have recently shown that CRTH2 agonists administered into the trachea led to translocation of eosinophils from the bloodstream into the airway (28 -30), and that CRTH2-deficient mice exhibited decreased infiltration of eosinophils and other inflammatory cells during chronic allergic skin inflammation (31).…”

mentioning

confidence: 99%

Cyclooxygenase-2/Prostaglandin D2/CRTH2 Pathway Mediates Double-Stranded RNA-Induced Enhancement of Allergic Airway Inflammation

Shiraishi

Asano

Niimi

et al. 2008

The Journal of Immunology

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Respiratory RNA viruses responsible for the common cold often worsen airway inflammation and bronchial responsiveness, two characteristic features of human asthma. We studied the effects of dsRNA, a nucleotide synthesized during viral replication, on airway inflammation and bronchial hyperresponsiveness in murine models of asthma. Intratracheal instillation of poly I:C, a synthetic dsRNA, increased the airway eosinophilia and enhanced bronchial hyperresponsiveness to methacholine in OVA-sensitized, exposed rats. These changes were associated with induction of cyclooxygenase-2 (COX-2) expression and COX-2-dependent PGD2 synthesis in the lungs, particularly in alveolar macrophages. The direct intratracheal instillation of PGD2 enhanced the eosinophilic inflammation in OVA-exposed animals, whereas pretreatment with a dual antagonist against the PGD2 receptor-(CRTH2) and the thromboxane A2 receptor, but not with a thromboxane A2 receptor-specific antagonist, nearly completely eliminated the dsRNA-induced worsening of airway inflammation and bronchial hyperresponsiveness. CRTH2-deficient mice had the same degree of allergen-induced airway eosinophilia as wild-type mice, but they did not exhibit a dsRNA-induced increase in eosinophil accumulation. Our data demonstrate that COX-2-dependent production of PGD2 followed by eosinophil recruitment into the airways via a CRTH2 receptor are the major pathogenetic factors responsible for the dsRNA-induced enhancement of airway inflammation and responsiveness.

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Prostaglandin D2 Plays an Essential Role in Chronic Allergic Inflammation of the Skin via CRTH2 Receptor

Cited by 184 publications

References 36 publications

UVB light upregulates prostaglandin synthases and prostaglandin receptors in mouse keratinocytes

UVB light upregulates prostaglandin synthases and prostaglandin receptors in mouse keratinocytes

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

Cyclooxygenase-2/Prostaglandin D2/CRTH2 Pathway Mediates Double-Stranded RNA-Induced Enhancement of Allergic Airway Inflammation

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