Coordinated up-regulation of cyclooxygenase-2 and microsomal prostaglandin E synthase 1 transcription by nuclear factor kappa B and early growth response-1 in macrophages

Díaz-Muñoz, Manuel D.; Osma-García, Inés C.; Cacheiro-Llaguno, Cristina; Fresno, Manuel; Íñiguez, Miguel A.

doi:10.1016/j.cellsig.2010.05.011

Cited by 69 publications

(68 citation statements)

References 44 publications

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“…In addition, here we report that the expression of the mPges-1 gene after LPS was up-regulated through the MyD88 pathway, like Cox-2. Therefore, LPS induces the coordinated expression of COX-2 and mPGES-1, which appeared to be functionally coupled and accounts for the high production and release of PGE 2 in astrocytes, in a manner similar to the responses described in macrophages (34).…”

Section: Discussionmentioning

confidence: 93%

Induction of COX-2 Enzyme and Down-regulation of COX-1 Expression by Lipopolysaccharide (LPS) Control Prostaglandin E2 Production in Astrocytes

Font-Nieves¹,

Sans-Fons

Gorina

et al. 2012

Journal of Biological Chemistry

176

111

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Background:The relative contribution of COX-2 and COX-1 to prostanoid formation under neuroinflammation is complex. Results: LPS induced COX-2 and mPGES1 but down-regulated COX-1 and TS in astroglia. These effects accounted for the high production of PGE 2 . Conclusion: PGE 2 after LPS results from the coordinated COX-2 up-regulation and COX-1 down-regulation in astrocytes. Significance: Changes in COX-2 and COX-1 expression mediate astroglial PGE 2 generation in neuroinflammation.

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Section: Discussionmentioning

confidence: 93%

Induction of COX-2 Enzyme and Down-regulation of COX-1 Expression by Lipopolysaccharide (LPS) Control Prostaglandin E2 Production in Astrocytes

Font-Nieves¹,

Sans-Fons

Gorina

et al. 2012

Journal of Biological Chemistry

176

111

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“…Egr-1, NFkB, AP-1 and c/EBP response elements (Dı´az-Mun˜oz et al, 2010). The detailed analysis of the mPGES-1 promoter (from-1100 to þ 30), performed by transfecting tumor cells with mPGES-1 promoter constructs of different length, revealed a consistent enhancement of the EGF-driven mPGES-1 transcription, enabling also to identify the minimal sequence, containing solely the Egr-1 binding sequence, capable of eliciting a response.…”

Section: Mpges-1 Modulates Egfr-mediated Malignancy S Donnini Et Almentioning

confidence: 99%

“…Among the wide repertoire of pro-inflammatory stimuli known to induce mPGES-1 gene (phorbol 12-myristate 13-acetate (PMA), IL-1b, TNFa or lipopolysaccharide (LPS)), recently some of us described the involvement of NFkB in both Egr-1 and mPGES-1 expression in macrophages exposed to LPS (Dı´az-Mun˜oz et al, 2010). Indeed, in HT-29 tumor cells, inhibition of NF-kB activity by an IKK inhibitor prevented the EGF-induced mPGES-1 overexpression (data not shown), suggesting that also in tumor cells the mPGES-1 transcription could be controlled by several transcription factors, whose action might be exerted in cell and context-dependent manner (Naraba et al, 2002;Cheng et al, 2004;Lin and Karin, 2007;Deckmann et al, 2010;Dı´az-Mun˜oz et al, 2010). Inhibition of NF-kB activity precludes from distinguishing from its transcriptional effect on mPGES-1 by direct binding of mPGES-1 promoter or indirectly, by altering Egr-1 expression (Dı´az-Mun˜oz et al, 2010).…”

Section: Mpges-1 Modulates Egfr-mediated Malignancy S Donnini Et Almentioning

confidence: 99%

“…Luciferase activity Cells were transiently transfected with luciferase constructs containing different deletions of the murine promoter of mPGES-1 cloned in the pxP2-LUC plasmid: mPGES-1-1100 (À1100 to þ 30) mPGES-1-895 (À895 to þ 30), mPGES-1-483 (À483 to þ 30) and mPGES-1-154 (À154 to þ 30), or with a construct containing two Egr-1 consensus binding sites insert upstream of a prolactin minimal promoter (Egr-1-Pro36LUC) (Dı´az-Mun˜oz et al, 2010;Crosby et al, 1991).…”

Section: Real-time Pcrmentioning

confidence: 99%

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EGFR signaling upregulates expression of microsomal prostaglandin E synthase-1 in cancer cells leading to enhanced tumorigenicity

et al. 2011

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In this report we describe the contribution of prostaglandin E 2 (PGE 2 ) derived from the inducible microsomal PGE-synthase type-1 (mPGES-1) to the epidermal growth factor receptor (EGFR) oncogenic drive in tumor epithelial cells and in tumor-bearing mice. EGFR stimulation upregulated expression of mPGES-1 in HT-29, A431 and A549 cancer cells. Egr-1, a transcription factor induced by EGF, mediated this response. The Egr-1 rise provoked the overexpression of mPGES-1 messenger and protein, and enhanced PGE 2 formation. These changes were suppressed either by silencing Egr-1, or by upstream blockade of EGFR or ERK1/2 signals. Further, in a clonogenic assay on tumor cells, EGF induced a florid tumorigenic phenotype, which regressed when mPGES-1 was silenced or knocked down. EGF-induced mPGES-1 overexpression in epithelial cell reduced E-cadherin expression, whereas enhancing that of vimentin, suggesting an incipient mesenchymal phenotype. Additionally, inhibiting the EGFR in mice bearing the A431 tumor, the mPGES-1 expression and the tumor growth, exhibited a parallel decline. In conclusion, these findings provide novel evidence that a tight cooperation between the EGF/EGFR and mPGES-1 leads to a significant tumorigenic gain in epithelial cells, and provide clues for controlling the vicious association.

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“…Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible enzyme (Ek et al, 2001;Jakobsson et al, 1999), with low constitutive levels in most tissues (Jakobsson et al, 1999) and is often co-expressed and functionally coupled with COX-2 Samuelsson et al, 2007;Thoren and Jakobsson, 2000). Being inducible enzymes, the COX-2 and mPGES-1 genes have complex promoter regions with binding motifs for several transcription factors like NF-kB (Crofford et al, 1997;Diaz-Munoz et al, 2010) and early growth response-1 (Egr-1) (Diaz-Munoz et al, 2010). Cytosolic prostaglandin E synthase, the second enzyme to be discovered, is constitutively expressed and functionally coupled with cPLA2 and COX-1 .…”

Section: Pge2 Biosynthesismentioning

confidence: 99%

Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

Vasilache¹

2015

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The immune-to-brain signaling is a critical survival factor when the body is confronted by pathogens, and in particular by microorganisms. During infections, the ability of the immune system to engage the central nervous system (CNS) in the management of the inflammatory response is just as important as its ability to mount a specific immune response against the pathogen, since the CNS can provide a systemic negative feed-back to the immune activation by release of stress hormones and also can prioritize the usage of the energy resources by the vital organs. Prostaglandin E2 (PGE2) and pro-inflammatory cytokines were among the first mediators to be identified to participate in the immune-to-brain signaling, a process that is clinically recognized by the development of manifestations of common illness such as fever, anorexia, decreased social interactions, lethargy, sleepiness, and hyperalgesia.In this thesis the contribution of PGE2 to the immune-to-brain signaling was further characterized at the blood-brain-barrier (BBB) and in the anterior preoptic area (POA) of the hypothalamus (i.e. the thermoregulatory region or, in sickness, the fever generating region).BBB is the major interface region between peripheral circulating cytokines and the neuronal parenchyma and a critical source of PGE2. Using chimeric mice lacking the inducible enzyme for PGE2 synthesis, microsomal PGE synthase-1 (mPGES-1), in either hematopoietic or nonhematopoietic cells, we demonstrate in paper I that brain endothelial cells are the critical source of PGE2 in BBB during peripheral inflammation. For the demonstration of the mPGES-1 expression in the BBB cells we developed in paper I a method for enzymatic dissociation of these cells, followed by fluorescence activated cell sorting (FACS). Using the same method, we show in paper II that the BBB response to immune stimuli is towards an increased production of PGE2 in endothelial cells and an increased sensitivity of these cells for proinflammatory cytokines. These changes are supported by decreased PGE2 degradation and decreased synthesis of other prostanoids in perivascular macrophages, which hence respond in concordance with the endothelial cells in enhancing PGE2 signaling.Once released in the neuronal tissue, PGE2 has been shown to be critical for the fever response by acting on the type 3 PGE2 receptors (EP3) within POA. By laser capture microdissection (LCM) we extracted the EP3 receptor expressing region in POA, defined by in situ hybridization histochemistry, from mouse brain sections. We demonstrate in paper III that the predominant subtypes of the EP3 receptor in POA are EP3α and EP3γ. In paper IV we further analyze the effect of PGE2 on the LCM dissected EP-rich POA using gene expression microarrays. We demonstrate that PGE2 has a limited effect on the gene expression changes within POA, suggesting that the neuronal activity is modulated by PGE2 in a transcriptionindependent manner and that the profound gene expression changes that are seen in the CNS during inflammation ...

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Coordinated up-regulation of cyclooxygenase-2 and microsomal prostaglandin E synthase 1 transcription by nuclear factor kappa B and early growth response-1 in macrophages

Cited by 69 publications

References 44 publications

Induction of COX-2 Enzyme and Down-regulation of COX-1 Expression by Lipopolysaccharide (LPS) Control Prostaglandin E2 Production in Astrocytes

Induction of COX-2 Enzyme and Down-regulation of COX-1 Expression by Lipopolysaccharide (LPS) Control Prostaglandin E2 Production in Astrocytes

EGFR signaling upregulates expression of microsomal prostaglandin E synthase-1 in cancer cells leading to enhanced tumorigenicity

Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

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