Disease relevance of Ptges

• Likewise, inducible microsomal PGES (mPGES-1) is expressed in several types of cancer, although its role in benign polyp formation has not been investigated [1].
• Induction of mPGES-1 in the component of articular tissues of patients with rheumatoid arthritis and osteoarthritis has been demonstrated in vitro [2].
• Furthermore, Helicobacter infection upregulated epithelial PGE2 production, suggesting that the COX-2/mPGES-1 pathway contributes to the Helicobacter-associated gastric tumorigenesis [3].
• Collectively, our present results provide unequivocal evidence that mPGES-1 contributes to the formation of PGE2 involved in pain hypersensitivity and inflammation [4].
• EXPERIMENTAL DESIGN: Immunohistochemistry and immunoblotting were used to evaluate the expression of COX-2 and mPGES-1 in benign and malignant lesions including metastases to lymph nodes [5].
• In the bone fracture model, fracture healing was impaired by the mPGES-1 deficiency, with half of the mice remaining in a non-bone union state even after 21 days; normal fracture healing was restored by adenoviral reintroduction of mPGES-1 [6].

Psychiatry related information on Ptges

• Both wild-type and mPGES-1 mutant mice also showed strongly reduced motor activity following turpentine injection [7].
• The concomitant reduction in food intake and central mPGES-1 gene upregulation led us to test the feeding behavior of mice lacking mPGES-1 during inflammation [8].

High impact information on Ptges

• Our findings identify mPGES-1 as the central switch during immune-induced pyresis and as a target for the treatment of fever and other PGE2-dependent acute phase reactions elicited by the brain [9].
• We studied the febrile response in mice deficient in microsomal prostaglandin E synthase-1 (mPGES-1), an inducible terminal isomerase expressed in cytokine-sensitive brain endothelial cells [9].
• Hyperplastic gastric tumors induced by activated macrophages in COX-2/mPGES-1 transgenic mice [3].
• Stimulation of mPGES-1(-/-) VSMC and macrophages with bacterial LPS increased PGI(2) and thromboxane A(2) to varied extents [10].
• Urinary PGE-M was depressed, whereas urinary 2,3-dinor 6-keto PGF(1alpha), but not 2,3-dinor-TxB(2), was increased in mPGES-1(-/-) LDLR(-/-)s. mPGES-1-derived PGE(2) accelerates atherogenesis in LDLR(-/-) mice [10].

Chemical compound and disease context of Ptges

• To evaluate the role of PGESs in preterm delivery, we used mPGES-1 knockout mice in a lipopolysaccharide (LPS)-induced preterm labor model [11].

Biological context of Ptges

• Thus, COX-2 and mPGES are essential components for delayed PGE(2) biosynthesis, which may be linked to inflammation, fever, osteogenesis, and even cancer [12].
• Here we have used mPGES-1 wild type, heterozygote, and null mice to assess the impact of reduction or absence mPGES-1 protein on the production of PGE2 and other prostaglandins in lipopolysaccharide (LPS)-treated macrophages and mice [13].
• Phase 1 involves transcriptional up-regulation of the couple COX-2 -->mPGES-1 in the liver and lungs [14].
• The high magnitude of up-regulation of mPGES and sPLA2-IIA (1,260 and 130 fold, respectively) and that of down-regulation of 15-PGES (30 fold) during LPS fever makes these enzymes attractive targets for anti-inflammatory therapy [14].
• Both mPGES-1 mRNA and protein were only observed in the subluminal stroma surrounding the implanting blastocyst at the implantation site on day 6 of pregancy , but were not seen in the inter-implantation site on day 6 of pregnancy and on day 6 of pseudopregnancy [15].

Anatomical context of Ptges

• In polyps >1 mm, not only COX-2 but also mPGES was induced in the stromal fibroblasts where COX-1 had already been expressed [1].
• Thioglycollate-elicited peritoneal macrophages with mPGES-1 deficiency were found to lose their ability to produce PGE2 upon LPS stimulation [13].
• Other prostaglandins (thromboxane B2, PGD2, PGF(2alpha), and 6-keto-PGF(1alpha)) were significantly elevated in stomachs of mPGES-1-null mice but not in other tissues [13].
• Cytosolic and microsomal PGE synthases (cPGES and mPGES) were also found, but they occurred diffusely across the cytosol [16].
• Our data suggest that the presence of an active blastocyst is required for mPGES-1 expression at the implantation site [15].

Associations of Ptges with chemical compounds

• In vivo, mPGES-1 deletion abolished the LPS-stimulated production of PGE2 in spleen, kidney, and brain [13].
• Here we report the molecular identification of membrane-bound glutathione (GSH)-dependent prostaglandin (PG) E(2) synthase (mPGES), a terminal enzyme of the cyclooxygenase (COX)-2-mediated PGE(2) biosynthetic pathway [12].
• Unlike primary fibroblasts, immortalized cells were deficient in microsomal PGE synthase (mPGES) but expressed slightly higher levels of cytosolic PGES [17].
• There was a strong cPGES immunostaining in the luminal and glandular epithelium on days 12, 16, 20 and 25 of the menstrual cycle. mPGES immunostaining was strongly detected in the glandular epithelium on days 20 and 25 of the menstrual cycle [18].
• SC-560 treatment neither altered TNFalpha-induced COX-2 or mPGES-1 expression nor did the addition of the calcium ionophore A23187 or arachidonic acid reverse the inhibition by SC-560 [19].

Enzymatic interactions of Ptges

• The membrane fraction containing recombinant mPGES-1 catalyzed the isomerization of PGH2 to PGE2 in the presence of GSH with K(m) values of 130 microM for PGH2 and 37 microM for GSH, a turnover number of 600 min(-1), and a k(cat)/K(m) ratio of 4.6 min(-1) microM(-1) [20].

Regulatory relationships of Ptges

• These results suggest that Egr-1 is a key transcription factor in regulating the inducible expression of mPGES [21].
• In neuron-glial mixed cultures, mPGES-1 was co-induced with cyclooxygenase-2 (COX-2) specifically in microglia, but not in astrocytes, oligodendrocytes or neurons [22].
• We showed that mPGES-1 gene expression was robustly upregulated in these structures after intraperitoneal and intracerebroventricular injections of anorexigenic doses of IL-1beta [8].
• RECENT FINDINGS: Various in vitro and in vivo studies demonstrated that proinflammatory stimuli, such as interleukin-1beta and tumor necrosis factor-alpha upregulate the expression of mPGES-1 at the protein and mRNA level [23].
• In conclusion, mPGES is constitutively expressed along the urogenital tract, where it may have important roles in normal physiology and disease [24].

Other interactions of Ptges

• Examination of mRNA for several terminal prostaglandin synthases did not reveal changes in expression levels associated with mPGES-1 deficiency, indicating that gastric prostaglandin changes may be due to shunting of cyclooxygenase products to other terminal synthases [13].
• The purpose of this study was to elucidate the regulation of mPGES-1 mRNA expression in cardiomyocytes, define the role of JNK enzymes in this process, and characterize the role of mPGES-1 in cardiomyocyte PGE(2) biosynthesis [25].
• The tumor tissues were quantified for the induction of apoptosis, intratumor levels/expressions of prostaglandin E2 (PGE2), 15 deoxy prostaglandin J2 (15-d PGJ2), microsomal prostaglandin E synthase (mPGES) and cytoplasmic phospholipase A2 (cPLA2) [26].
• However, microsomal PGE synthase (mPGES) and lipocalin-type PGD synthase (L-PGDS) were selectively upregulated [27].
• The expression of mPGES was not induced by LPS in mice lacking Toll-like receptor 4 or MyD88 [28].

Analytical, diagnostic and therapeutic context of Ptges

• Animals with a deletion of the Ptges gene, which encodes mPGES-1, or their wild-type littermates were given either a subcutaneous injection of turpentine--a model for aseptic cytokine-induced pyresis--or an intraperitoneal injection of interleukin-1beta [7].
• In addition, reports of mPGES-1-deficient mice clearly suggest the role of mPGES-1 in the process of chronic inflammation such as collagen-induced arthritis and collagen antibody induced arthritis in vivo [2].
• In situ hybridization and immunostaining were used to determine the intrarenal localization of mPGES-1 and cyclooxygenases [29].
• Northern blotting revealed that the mPGES-1 mRNA was expressed intensely in the epididymis and weakly in the lung, spleen, skin, kidney, colon, and brain [30].
• Northern and Western blotting analyses revealed that mPGES-1 was induced together with cyclooxygenase-2 in mouse macrophages after treatment of the cells with lipopolysaccharide [20].

References