Cellular Prostaglandin E2 Production by Membrane-bound Prostaglandin E Synthase-2 via Both Cyclooxygenases-1 and -2

Murakami, Makoto; Nakashima, Karin; Kamei, Daisuke; Masuda, Shiro; Ishikawa, Yukio; Ishii, Toshiharu; Ohmiya, Yoshihiro; Watanabe, Kikuko; Kudo, Ichiro

doi:10.1074/jbc.m305108200

Cited by 313 publications

(340 citation statements)

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“…In contrast, no major changes in COX-1 expression were noted in either cell type. PGE 2 is the major prostaglandin generated in the skin and is produced by the action of the microsomal PGE 2 synthases, mPGES-1 and mPGES-2 (Murakami et al, 2003). We found that mRNA expression of these enzymes increased 4-6-fold in both undifferentiated and differentiated keratinocytes following exposure to UVB (Fig 6).…”

Section: Effects Of Uvb On Expression Of Coxs Prostaglandin Synthasmentioning

confidence: 69%

UVB light upregulates prostaglandin synthases and prostaglandin receptors in mouse keratinocytes

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Gray

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: Effects Of Uvb On Expression Of Coxs Prostaglandin Synthasmentioning

confidence: 69%

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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“…35 PGES1 is involved in the COX-2-mediated PGE2-biosynthetic pathway 35 ; mPGES2 is abundant in brain, heart, skeletal muscle, kidney, and liver 37 ; cPGES is distributed ubiquitously in the cytosol of various cells 36 ; and COX-1 contributes to PGE2 generation by PGES2 and cPGES. 36,39,40 We immunohistochemically confirmed the presence of mPGES1 in primary basophils, but we were unable to assess the protein expression of the other PGES enzymes, because antibodies against mPGES2 and cPGES were not available in our laboratory. Nevertheless, transcripts encoding mPGES1, mPGES2, and cPGES were all detected in BMBAs.…”

Section: Discussionmentioning

confidence: 96%

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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“…Microsomal PGES-1 is induced by proinflammatory agents and is down-regulated by glucocorticoids in various cells (3,5,6). In contrast to the inducible mPGES-1, another mPGES (mPGES-2) is constitutively expressed in many cells without any further induction during inflammation (7). In addition, a cytosolic protein possessing PGES activity (cPGES) has been characterized and found to be constitutively expressed in various cells (8).…”

mentioning

confidence: 99%

“…It has been demonstrated that mPGES-1 functionally uses PGH 2 generated by COX-2 (5,6), but some evidence also exists for a role of COX-1 (9). Recently, it has been shown that synoviocytes isolated from patients with RA coexpress both mPGES-1 and COX-2 and generate high amounts of PGE 2 after treatment with proinflammatory cytokines (10); mPGES-1 expression has also been detected in RA synovial lining cells (7).…”

mentioning

confidence: 99%

Expression of microsomal prostaglandin E synthase 1 in rheumatoid arthritis synovium

Westman¹,

Korotkova²,

Klint³

et al. 2004

Arthritis & Rheumatism

109

102

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Objective. Microsomal prostaglandin E synthase 1 (mPGES-1) catalyzes the formation of PGE 2 from cyclooxygenase-derived PGH 2 . Microsomal PGES-1 is induced by proinflammatory cytokines and is strongly linked to conditions that result in high PGE 2 biosynthesis. PGE 2 contributes to the pathogenesis of rheumatoid arthritis (RA), acting as a mediator of inflammation and promoting bone destruction. Induction of mPGES-1 in rheumatoid synoviocytes by proinflammatory cytokines has been demonstrated in vitro, indicating an important role in RA pathogenesis. Recent studies using mPGES-1-deficient mice demonstrated the importance of this gene in chronic inflammation. The aim of this study was to investigate the expression and localization of mPGES-1 in synovial biopsy specimens obtained from patients with RA.Methods. Synovial tissue samples from 24 patients with RA were obtained, and immunohistologic analysis was performed using polyclonal antibodies against mPGES-1. Double immunofluorescence staining was performed with antibodies to CD3, CD19, CD20, CD68, CD163, and prolyl 4-hydroxylase.Results. Intracellular mPGES-1 staining was observed in synovial membranes from all of the RA patients studied. Specifically, strong expression of mPGES-1 was detected in synovial lining cells. In sublining mononuclear and fibroblast-like cells, the extent of mPGES-1 staining was less than that in the synovial lining cells. In some patients, positive staining was observed in endothelial cells. With the double immunofluorescence technique, mPGES-1 production was detected in synovial macrophages and fibroblasts, while mPGES-1 expression was not observed in lymphocytes.Conclusion. The demonstration of mPGES-1 expression in synovial tissues from patients with RA suggests a role for mPGES-1 in the RA disease process. Microsomal PGES-1 might be a potential new target for treatment strategies to control PGE 2 synthesis in patients with RA, without the systemic side effects associated with cyclooxygenase inhibitors.

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Cellular Prostaglandin E2 Production by Membrane-bound Prostaglandin E Synthase-2 via Both Cyclooxygenases-1 and -2

Cited by 313 publications

References 65 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

Expression of microsomal prostaglandin E synthase 1 in rheumatoid arthritis synovium

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