Glucocorticoid-Mediated Suppression of the Promoter Activity of the Cyclooxygenase-2 Gene Is Modulated by Expression of Its Receptor in Vascular Endothelial Cells

Inoue, H.; Umesono, Kazuhiko; Nishimori, Takeo; Hirata, Yukio; Tanabe, Tadashi

doi:10.1006/bbrc.1998.9939

Cited by 77 publications

(75 citation statements)

References 29 publications

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“…In addition, we tested whether S1P 2 R can induce the transcription of the COX-2 gene. For this we measured human COX-2 promoter-driven (phPES2-driven) reporter activity in transfected ECs (34). As expected, the promoter activity of phPES2 that contains the 5ʹ-flanking region (-1432/+59) of the human PTGS2 (COX-2) gene was induced 1.83-fold by PMA in mouse hemangioendothelioma (EOMA) cells.…”

Section: Figurementioning

confidence: 83%

Essential role of sphingosine 1–phosphate receptor 2 in pathological angiogenesis of the mouse retina

Skoura

Sánchez²,

Claffey³

et al. 2007

J. Clin. Invest.

193

153

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Sphingosine 1-phosphate (S1P), a multifunctional lipid mediator that signals via the S1P family of G protein-coupled receptors (S1PR), regulates vascular maturation, permeability, and angiogenesis. In this study, we explored the role of S1P 2 receptor (S1P 2 R) in normal vascularization and hypoxia-triggered pathological angiogenesis of the mouse retina. S1P 2 R is strongly induced in ECs during hypoxic stress. When neonatal mice were subjected to ischemia-driven retinopathy, pathologic neovascularization in the vitreous chamber was suppressed in S1p2 -/-mice concomitant with reduction in endothelial gaps and inflammatory cell infiltration. In addition, EC patterning and normal revascularization into the avascular zones of the retina were augmented. Reduced expression of the proinflammatory enzyme cyclooxygenase-2 (COX-2) and increased expression of eNOS were observed in the S1p2 -/-mouse retina. S1P 2 R activation in ECs induced COX-2 expression and suppressed the expression of eNOS. These data identify the S1P 2 R-driven inflammatory process as an important molecular event in pathological retinal angiogenesis. We propose that antagonism of the S1P 2 R may be a novel therapeutic approach for the prevention and/or treatment of pathologic ocular neovascularization. IntroductionSphingosine 1-phosphate (S1P) is a lipid mediator that regulates various biological processes, such as cell proliferation, migration, survival, and differentiation (1). S1P, generated by the phosphorylation of sphingosine by sphingosine kinase 1 and 2 (Sphk1 and Sphk2), is degraded by S1P-specific phosphatases and a lyase (1). It is also a high-affinity ligand for 5 G protein-coupled S1P receptors, S1P 1 R, S1P 2 R, S1P 3 R, S1P 4 R, and S1P 5 R, which regulate distinct intracellular signaling pathways (2, 3). S1P 1 R, S1P 2 R, and S1P 3 R are widely expressed, whereas S1P 4 and S1P 5 expression is prominent in cells of the immune and nervous systems, respectively. S1P 1 receptor couples exclusively to G i signaling pathway, whereas S1P 2 and S1P 3 receptors couple to G i , G q , and G 12/13 pathways. However, S1P 2 activates G 12/13 potently, whereas S1P 3 activates G q preferentially (4, 5). S1P receptors regulate important physiological functions of the vascular system, such as vascular morphogenesis and maturation, cardiac function, vascular permeability, and tumor angiogenesis (6-10). Indeed, S1p1 receptor-null embryos die due to hemorrhage at E12.5-E14.5. We found that the S1P 1 R signaling in ECs promotes the formation of strong N-cadherin-based junctions between endothelial and vascular smooth muscle cells and thus stabilizes the nascent vasculature (11, 12). However, mice that lack either the S1P 2 R or the S1P 3 R are viable and fertile. Interestingly, S1p1/S1p2-double-null embryos showed a more severe phenotype than S1p1-single-null embryos, suggesting that S1P 2 R also regu-

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Section: Figurementioning

confidence: 83%

Essential role of sphingosine 1–phosphate receptor 2 in pathological angiogenesis of the mouse retina

Skoura

Sánchez²,

Claffey³

et al. 2007

J. Clin. Invest.

193

153

View full text Add to dashboard Cite

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“…Transcriptional activation of the Cox-2 gene induced by LPS has been shown to partly depend on NF-IL6 in macrophages. Indeed, NF-IL6 binding sites have been identified in the promoter region of the Cox-2 gene (4,(25)(26)(27)(28). A recent study showed that Cox-2 mRNA induction and promoter activity were defective in NF-IL6-deficient macrophages, and the defect could be rescued by the expression of NF-IL6 (26).…”

Section: Discussionmentioning

confidence: 99%

“…The initial phase of Cox-2 induction depends on NF-IL6, and the second phase requires coordination of NF-IL6 and NF-IL6␤ in activated macrophages (29). NF-B and cAMP response element CRE have also been shown to regulate the expression of the Cox-2 gene (25)(26)(27)(28). From these findings we speculate that the reduced expression of Cox-2 during the early time period is due to the absence of NF-IL6, but enhanced Cox-2 expression in the late period may be due to compensation by other transcription factors.…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide-Dependent Prostaglandin E2 Production Is Regulated by the Glutathione-Dependent Prostaglandin E2 Synthase Gene Induced by the Toll-Like Receptor 4/MyD88/NF-IL6 Pathway

Uematsu

Matsumoto

Takeda

et al. 2002

The Journal of Immunology

284

224

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Macrophages produce a large amount of PGE2 during inflammation. This lipid mediator modulates various immune responses. PGE2 acts on macrophages and inhibits production of cytokines such as TNF-α and IL-12. Membrane-bound glutathione-dependent PGE2 synthase (mPGES) has been shown to be a terminal enzyme of the cyclooxygenase-2-mediated PGE2 biosynthesis. Here we identified mPGES as a molecule that is induced by LPS in macrophages. The expression of mPGES was not induced by LPS in mice lacking Toll-like receptor 4 or MyD88. Furthermore, mice deficient in NF-IL6 showed neither induction of mPGES nor biosynthesis of PGE2 in response to LPS, indicating that mPGES expression in response to LPS is regulated by a Toll-like receptor 4/MyD88/NF-IL6-dependent signaling pathway. We generated mPGES-deficient mice and investigated the role of mPGES in vivo. The mice showed no augmentation of the PGE2 production in response to LPS. However, they were not impaired in the LPS-induced production of inflammatory cytokines and showed normal response to the LPS-induced shock. Thus, mPGES is critically involved in the biosynthesis of PGE2 induced by LPS, but is dispensable for the modulation of inflammatory responses.

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“…To further confirm NF-B in the regulation of COX-2 expression (23), the COX-2 promoter-luciferase construct, Ϫ327/ϩ59 or B site (Ϫ223/Ϫ214) deletion mutant (KBM) (27), was transfected into NCI-H292 cells. As shown in Fig.…”

Section: Effect Of Inhibitors Of Pkc Tyrosine Kinase or Src Kinase mentioning

confidence: 99%

Tyrosine Phosphorylation of I-κB Kinase α/β by Protein Kinase C-Dependent c-Src Activation Is Involved in TNF-α-Induced Cyclooxygenase-2 Expression

Huang

Chen

Inoue

et al. 2003

The Journal of Immunology

Self Cite

117

106

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The signaling pathway involved in TNF-α-induced cyclooxygenase-2 (COX-2) expression was further studied in human NCI-H292 epithelial cells. A protein kinase C (PKC) inhibitor (staurosporine), tyrosine kinase inhibitors (genistein and herbimycin A), or a Src kinase inhibitor (PP2) attenuated TNF-α- or 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced COX-2 promoter activity. TNF-α- or TPA-induced I-κB kinase (IKK) activation was also blocked by these inhibitors, which reversed I-κBα degradation. Activation of c-Src and Lyn kinases, two Src family members, was inhibited by the PKC, tyrosine kinase, or Src kinase inhibitors. The dominant-negative c-Src (KM) mutant inhibited induction of COX-2 promoter activity by TNF-α or TPA. Overexpression of the constitutively active PKCα (PKCα A/E) or wild-type c-Src plasmids induced COX-2 promoter activity, and these effects were inhibited by the dominant-negative c-Src (KM), NF-κB-inducing kinase (NIK) (KA), or IKKβ (KM) mutant. The dominant-negative PKCα (K/R) or c-Src (KM) mutant failed to block induction of COX-2 promoter activity caused by wild-type NIK overexpression. In coimmunoprecipitation experiments, IKKα/β was found to be associated with c-Src and to be phosphorylated on its tyrosine residues after TNF-α or TPA treatment. Two tyrosine residues, Tyr188 and Tyr199, near the activation loop of IKKβ, were identified to be crucial for NF-κB activation. Substitution of these residues with phenylalanines attenuated COX-2 promoter activity and c-Src-dependent phosphorylation of IKKβ induced by TNF-α or TPA. These data suggest that, in addition to activating NIK, TNF-α also activates PKC-dependent c-Src. These two pathways cross-link between c-Src and NIK and converge at IKKα/β, and go on to activate NF-κB, via serine phosphorylation and degradation of IκB-α, and, finally, to initiate COX-2 expression.

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Glucocorticoid-Mediated Suppression of the Promoter Activity of the Cyclooxygenase-2 Gene Is Modulated by Expression of Its Receptor in Vascular Endothelial Cells

Cited by 77 publications

References 29 publications

Essential role of sphingosine 1–phosphate receptor 2 in pathological angiogenesis of the mouse retina

Essential role of sphingosine 1–phosphate receptor 2 in pathological angiogenesis of the mouse retina

Lipopolysaccharide-Dependent Prostaglandin E2 Production Is Regulated by the Glutathione-Dependent Prostaglandin E2 Synthase Gene Induced by the Toll-Like Receptor 4/MyD88/NF-IL6 Pathway

Tyrosine Phosphorylation of I-κB Kinase α/β by Protein Kinase C-Dependent c-Src Activation Is Involved in TNF-α-Induced Cyclooxygenase-2 Expression

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