Prostaglandin E synthases: Understanding their pathophysiological roles through mouse genetic models

Hara, Shuntaro; Kamei, Daisuke; Sasaki, Yuka; Tanemoto, Akemi; Nakatani, Yoshihito; Murakami, Makoto

doi:10.1016/j.biochi.2010.02.007

Cited by 137 publications

(161 citation statements)

References 91 publications

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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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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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“…Balb/c and C57BL6 mice were purchased from Saitama Experimental Animals Supply Co. Ltd. (Saitama, Japan). mPGES-1 KO mice were described previously (Kamei et al, 2004Hara et al, 2010), and were backcrossed at least 10 generations onto Balb/c mice. For experiments using LLC cells, we used mPGES-1 KO mice on a C57BL/6 background.…”

Section: Animalsmentioning

confidence: 99%

“…Thus far, three PGES enzymes have been identified: microsomal PGES (mPGES)-1, mPGES-2 and cytosolic PGES (Murakami and Kudo, 2004;Nakatani, 2007;Hara et al, 2010). Among these PGES enzymes, mPGES-1 is induced by proinflammatory stimuli and downregulated by antiinflammatory glucocorticoids, as in the case of COX-2, and is functionally coupled with COX-2 in marked preference to COX-1 (Jakobsson et al, 1999;Murakami et al, 2000;Mancini et al, 2001;Stichtenoth et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…Among these PGES enzymes, mPGES-1 is induced by proinflammatory stimuli and downregulated by antiinflammatory glucocorticoids, as in the case of COX-2, and is functionally coupled with COX-2 in marked preference to COX-1 (Jakobsson et al, 1999;Murakami et al, 2000;Mancini et al, 2001;Stichtenoth et al, 2001). Induction of mPGES-1 expression and its function have been observed in various diseases and systems in which COX-2-driven PGE 2 has been implicated, such as rheumatoid arthritis, febrile response, reproduction, bone metabolism, cardiovascular function, stroke and Alzheimer's disease (Kamei et al, 2004;Samuelsson et al, 2007;Hara et al, 2010). It has also been reported that mPGES-1 is constitutively expressed in several cancers, most of which also express COX-2 constitutively (Kamei et al, 2003;Golijanin et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Microsomal prostaglandin E synthase-1 is involved in multiple steps of colon carcinogenesis

et al. 2011

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Accumulating evidence indicates that cyclooxygenase (COX)-2-derived prostaglandin (PG) E 2 is involved in the development of various tumors, including colorectal cancer. However, the precise contribution of microsomal PGE synthase (mPGES)-1, a terminal enzyme that acts downstream of COX-2 in the PGE 2 -biosynthetic pathway, to multiple processes of tumor development is not yet fully understood. Here, we show the pro-tumorigenic role of mPGES-1 in chemical carcinogen-induced colon carcinogenesis and intrasplenic tumor transplantation models. Genetic deletion of mPGES-1 significantly reduced both the total number and size of colorectal polyps at 18 weeks after azoxymethane administration with reduced nuclear translocation of b-catenin, altered expression profiles of chemokines/cytokines and increased production of antitumorigenic PGs, prostaglandin D 2 and prostacyclin in tumor tissues. At an early stage (6 weeks), mPGES-1 deficiency significantly reduced the number of aberrant crypt foci, while its transgenic overexpression increased the number. Furthermore, the growth of intrasplenically transplanted tumor cells was suppressed in mPGES-1 knockout (KO) mice. Co-culture of tumor cells with bone marrow-derived macrophages (BM-MUs) isolated from wild-type (WT) mice resulted in the induction of mPGES-1 in BM-MUs and increased the growth of tumor cells in vitro, whereas mPGES-1-null BM-MUs failed to facilitate tumor growth. The adoptive transfer of WT BM-MUs into mPGES-1 KO mice restored the growth of transplanted tumor cells, indicating that mPGES-1 in MUs is important for the growth of adjacent tumor cells. Taken together, our findings suggest that the inhibition of mPGES-1 is an alternative therapeutic target for colorectal and possibly other cancers.

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“…PGE 2 biosynthesis is upregulated by the induction of cyclooxygenase 2 (COX2) and microsomal prostaglandin E synthases 1 and 2 (mPGES1, mPGES2). 5,6 Prostaglandins may affect hepatocyte metabolism directly 7 or they can modulate the regulation of hepatocyte metabolism by hormones 8,9 or cytokines. 10,11 There are conflicting reports about the impact of prostaglandins on hepatic lipid metabolism.…”

Section: Introductionmentioning

confidence: 99%

Stimulation of fat accumulation in hepatocytes by PGE2-dependent repression of hepatic lipolysis, β-oxidation and VLDL-synthesis

Henkel

Frede

Schanze

et al. 2012

Laboratory Investigation

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Hepatic steatosis is recognized as hepatic presentation of the metabolic syndrome. Hyperinsulinaemia, which shifts fatty acid oxidation to de novo lipogenesis and lipid storage in the liver, appears to be a principal elicitor particularly in the early stages of disease development. The impact of PGE 2 , which has previously been shown to attenuate insulin signaling and hence might reduce insulin-dependent lipid accumulation, on insulin-induced steatosis of hepatocytes was studied. The PGE 2 -generating capacity was enhanced in various obese mouse models by the induction of cyclooxygenase 2 and microsomal prostaglandin E-synthases (mPGES1, mPGES2). PGE 2 attenuated the insulin-dependent induction of SREBP-1c and its target genes glucokinase and fatty acid synthase. Nevertheless, PGE 2 enhanced incorporation of glucose into hepatic triglycerides synergistically with insulin. This was most likely due to a combination of a PGE 2 -dependent repression of (1) the key lipolytic enzyme adipose triglyceride lipase, (2) carnitine-palmitoyltransferase 1, a key regulator of mitochondrial b-oxidation, and (3) microsomal transfer protein, as well as (4) apolipoprotein B, key components of the VLDL synthesis. Repression of PGC1a, a common upstream regulator of these genes, was identified as a possible cause. In support of this hypothesis, overexpression of PGC1a completely blunted the PGE 2 -dependent fat accumulation. PGE 2 enhanced lipid accumulation synergistically with insulin, despite attenuating insulin signaling and might thus contribute to the development of hepatic steatosis. Induction of enzymes involved in PGE 2 synthesis in in vivo models of obesity imply a potential role of prostanoids in the development of NAFLD and NASH.

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Prostaglandin E synthases: Understanding their pathophysiological roles through mouse genetic models

Cited by 137 publications

References 91 publications

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

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

Microsomal prostaglandin E synthase-1 is involved in multiple steps of colon carcinogenesis

Stimulation of fat accumulation in hepatocytes by PGE2-dependent repression of hepatic lipolysis, β-oxidation and VLDL-synthesis

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