Functional Coupling of Cyclooxygenase 1 and 2 to Discrete Prostanoid Synthases in Liver Macrophages

Dieter, Peter; Scheibe, Roland; Jakobsson, Per‐Johan; Watanabe, Kikuko; Kolada, Angelika; Kamionka, Sabine

doi:10.1006/bbrc.2000.3496

Cited by 47 publications

(33 citation statements)

References 19 publications

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“…21,35 Regarding the functional coupling observed between COX-2 and TXAS, although TXA 2 production was originally linked to COX-1 activity, it can vary in heterologous systems expressing both COX isoenzymes. In fact, preferential coupling of TXAS to COX-2 has been reported in macrophages, 36 cancer cells, 37 and even healthy brain and kidney. 38 A previous study 13 reported a lack of PGE 2 and PGI 2 synthesis in resting HUVECs, associated with the lack of basal COX-2 expression in these cells.…”

Section: Discussionmentioning

confidence: 99%

COX-2 Limits Prostanoid Production in Activated HUVECs and Is a Source of PGH ₂ for Transcellular Metabolism to PGE ₂ by Tumor Cells

Salvado

Alfranca

Escolano

et al. 2009

ATVB

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Objective-Inducible expression of cyclooxygenase-2 (COX-2) and terminal prostaglandin synthases (tPGS) has been mainly analyzed in tumor, stromal, and inflammatory cells, and little is known about the regulation of prostanoid biosynthesis by endothelial cells. Here we characterize the profile of prostanoids produced by activated HUVECs and analyze the expression and activities of tPGS. Methods and Results-Enzyme immunoassays indicated increased endothelial prostanoid production after proangiogenic stimulation, but without parallel upregulation of tPGS. Endothelial prostanoid production instead depended on the induction of COX-2 and was abolished by COX-2 silencing or pharmacological inhibition. COX-2 is functionally coupled to prostacyclin and thromboxane synthases in HUVECs, but these cells show no detectable PGE 2 synthase (PGES) activity. Endothelial PGE 2 production is partly mediated by nonenzymatic decomposition of COX-2-derived PGH 2 , but endothelialproduced PGH 2 can also be metabolized enzymatically by microsomal PGES-1 in cocultured tumor cells. Conclusions-Our findings identify a novel transcellular metabolism of PGE 2 between the endothelial and tumor compartments. Given the role of PGE 2 as a mediator of COX-2 proangiogenic effects, transcellular metabolism of endothelial-derived PGH 2 is a potential target for treatment of pathological angiogenesis. Key Words: angiogenesis Ⅲ endothelium Ⅲ cyclooxygenases Ⅲ prostanoids Ⅲ transcellular metabolism N umerous studies indicate that enzymes involved in the metabolism of AA and its products might contribute to tumor-induced angiogenesis. 1,2 Cyclooxygenase-2 (COX-2), which converts AA into the prostanoid precursor PGH 2 , is induced by the proangiogenic factor VEGF, released by tumor cells. Moreover, proinflammatory cytokines such as IL-1␤ and TNF␣, potent COX-2 inducers, also have proangiogenic activity. 3 COX-2 expression is elevated in tumors, and genetic inactivation or pharmacological inhibition of COX-2 reduces tumor-induced neovascularization. 4 COX-2-associated angiogenesis is thought to be mediated by derived prostanoids, such as PGE 2 , PGI 2 , and TXA 2. Strong evidence exists for a link between PGE 2 and tumor angiogenesis; and of the PGES enzymes (cPGES, mPGES-1, mPGES-2), inducible mPGES-1 appears to be critical for tumor angiogenesis. 5 Moreover, in vivo models of TXAS or PGIS overexpression indicate proangiogenic effects for TXA 2 and antiantiogenic effects for PGI 2 . 6 Despite the evidence linking prostanoids to tumor angiogenesis, their mechanism of action is poorly understood. In particular, very little is known about the possible contribution made by the regulation of endothelial terminal prostanoid synthases. PGH 2 release by endothelium has been shown in vivo and ex vivo 7,8 ; however, whether PGH 2 is transformed into final prostanoids in endothelial cells spontaneously or enzymatically is unknown.We investigated the regulation of terminal prostaglandin synthases by VEGF and IL-1␤. Our results indicate that although endothelial cel...

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Section: Discussionmentioning

confidence: 99%

COX-2 Limits Prostanoid Production in Activated HUVECs and Is a Source of PGH ₂ for Transcellular Metabolism to PGE ₂ by Tumor Cells

Salvado

Alfranca

Escolano

et al. 2009

ATVB

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“…Both macrophages and fibroblasts are chronically activated in RA and play an important role in initiating and driving the disease. In vitro, macrophages have been shown to coexpress inducible COX-2 and mPGES-1 and to produce substantial amounts of PGE 2 in response to inflammatory stimuli (6,9). The observed expression of mPGES-1 in RA synovial tissue macrophages is logical, based on the known properties of these cells in the setting of inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…Cytosolic PGES is not generally induced by proinflammatory stimuli except in the brain, where a minor increase has been reported (8). 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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“…The constitutive expression of mPGES-1 has been described in urogenital organs (Guan et al, 2001;Lazarus et al, 2002b;Fuson et al, 2003), gastric mucosa, spleen, resident peritoneal macrophages (Boulet et al, 2004), and liver Kupffer cells (Dieter et al, 2000). Thus, in these cells and organs mPGES-1 might have physiological roles.…”

Section: A Constitutive Expression Of Membrane Prostaglandin E Synthmentioning

confidence: 99%

Membrane Prostaglandin E Synthase-1: A Novel Therapeutic Target

2007

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Functional Coupling of Cyclooxygenase 1 and 2 to Discrete Prostanoid Synthases in Liver Macrophages

Cited by 47 publications

References 19 publications

COX-2 Limits Prostanoid Production in Activated HUVECs and Is a Source of PGH ₂ for Transcellular Metabolism to PGE ₂ by Tumor Cells

COX-2 Limits Prostanoid Production in Activated HUVECs and Is a Source of PGH ₂ for Transcellular Metabolism to PGE ₂ by Tumor Cells

Expression of microsomal prostaglandin E synthase 1 in rheumatoid arthritis synovium

Membrane Prostaglandin E Synthase-1: A Novel Therapeutic Target

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Functional Coupling of Cyclooxygenase 1 and 2 to Discrete Prostanoid Synthases in Liver Macrophages

Cited by 47 publications

References 19 publications

COX-2 Limits Prostanoid Production in Activated HUVECs and Is a Source of PGH 2 for Transcellular Metabolism to PGE 2 by Tumor Cells

COX-2 Limits Prostanoid Production in Activated HUVECs and Is a Source of PGH 2 for Transcellular Metabolism to PGE 2 by Tumor Cells

Expression of microsomal prostaglandin E synthase 1 in rheumatoid arthritis synovium

Membrane Prostaglandin E Synthase-1: A Novel Therapeutic Target

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COX-2 Limits Prostanoid Production in Activated HUVECs and Is a Source of PGH ₂ for Transcellular Metabolism to PGE ₂ by Tumor Cells

COX-2 Limits Prostanoid Production in Activated HUVECs and Is a Source of PGH ₂ for Transcellular Metabolism to PGE ₂ by Tumor Cells