Involvement of PGE2 and the cAMP signalling pathway in the up-regulation of COX-2 and mPGES-1 expression in LPS-activated macrophages

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

doi:10.1042/bj20111052

Cited by 97 publications

(74 citation statements)

References 58 publications

(95 reference statements)

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“…How this takes place is currently under study in our laboratory. Previous results from our laboratory indicate that macrophages' autocrine PGE 2 secretion is likely required to maintain gene expression of cytokines, Cox-2, and mPGES-1 (74). This might be equally true for signaling kinases like p110g.…”

Section: Discussionmentioning

confidence: 92%

Cyclooxygenase-2 Deficiency in Macrophages Leads to Defective p110γ PI3K Signaling and Impairs Cell Adhesion and Migration

Díaz-Muñoz

Osma-García

Íñiguez

et al. 2013

The Journal of Immunology

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Cyclooxygenase (Cox)-2 dependent PGs modulate several functions in many pathophysiological processes, including migration of immune cells. In this study, we addressed the role of Cox-2 in macrophage migration by using in vivo and in vitro models. Upon thioglycolate challenge, CD11b+ F4/80+ macrophages showed a diminished ability to migrate to the peritoneal cavity in cox-2−/− mice. In vivo migration of cox-2−/− macrophages from the peritoneal cavity to lymph nodes, as well as cell adhesion to the mesothelium, was reduced in response to LPS. In vitro migration of cox-2−/− macrophages toward MCP-1, RANTES, MIP-1α, or MIP-1β, as well as cell adhesion to ICAM-1 or fibronectin, was impaired. Defects in cell migration were not due to changes in chemokine receptor expression. Remarkably, cox-2−/− macrophages showed a deficiency in focal adhesion formation, with reduced phosphorylation of paxillin (Tyr188). Interestingly, expression of the p110γ catalytic subunit of PI3K was severely reduced in the absence of Cox-2, leading to defective Akt phosphorylation, as well as cdc42 and Rac-1 activation. Our results indicate that the paxillin/p110γ-PI3K/Cdc42/Rac1 axis is defective in cox-2−/− macrophages, which results in impaired cell adhesion and migration.

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Section: Discussionmentioning

confidence: 92%

Cyclooxygenase-2 Deficiency in Macrophages Leads to Defective p110γ PI3K Signaling and Impairs Cell Adhesion and Migration

Díaz-Muñoz

Osma-García

Íñiguez

et al. 2013

The Journal of Immunology

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“…In the present study, several hundreds of genes showed changed expression in the tumor tissues from the EP2-knockout mice compared with tumor tissues from the wild-type mice. A reason for this could be that EP2 signaling in host tissues is involved in several different pathways that are important events in tumor cells associated with tumor progression, including angiogenesis, the upregulation of COX-2, the loss of E-cadherin expression and anti-apoptosis in stem cells (16,22,(25)(26)(27)(28). Prom-1, also known as CD133, and CD44 are well-known markers of cancer stem cells, indicating reduced gene expression in the tumor tissues from the EP2-knockout mice in the present study.…”

Section: Discussionmentioning

confidence: 99%

Host knockout of E-prostanoid 2 receptors reduces tumor growth and causes major alterations of gene expression in prostaglandin E2-producing tumors

et al. 2016

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Abstract. Prostaglandin E 2 (PGE 2 ) is elevated in a variety of malignant tumors and has been shown to affect several hallmarks of cancer. Accordingly, the PGE 2 receptor, E-prostanoid 2 (EP2), has been reported to be associated with patient survival and reduced tumor growth in EP2-knockout mice. Thus, the aim of the present study was to screen for major gene expression alterations in tumor tissue growing in EP2-knockout mice. EP2-knockout mice were bred and implanted with EP2 receptor-expressing and PGE 2 -producing epithelial-like tumors. Tumor tissue and plasma were collected and used for analyses with gene expression microarrays and multiplex enzyme-linked immunosorbent assays. Tumor growth, acute phase reactions/systemic inflammation and the expression of interleukin-6 were reduced in EP2-knockout tumor-bearing mice. Several hundreds of genes displayed major changes of expression in the tumor tissue when grown in EP2-knockout mice. Such gene alterations involved several different cellular functions, including stemness, migration and cell signaling. Besides gene expression, several long non-coding RNAs were downregulated in the tumors from the EP2-knockout mice. Overall, PGE 2 signaling via host EP2 receptors affected a large number of different genes involved in tumor progression based on signaling between host stroma and tumor cells, which caused reduced tumor growth.

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“…5B). On the other hand, COX2 expression was found to be upregulated by directly binding CREB to a COX2 promoter (Diaz-Munoz et al 2012), which indicates that NF-kB may be the downstream molecule of the COX2 pathway and regulate ICAM1 expression only. Thus, selective COX2 inhibitor NS-398 was used and the phosphorylation level of NF-kB was determined.…”

Section: Pka-creb Participated In the Signaling Events Leading To Indmentioning

confidence: 99%

Urocortin increased endothelial ICAM1 by cPLA2-dependent NF-κB and PKA pathways in HUVECs

Wan¹,

Liu²,

Li³

et al. 2014

Journal of Molecular Endocrinology

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Urocortin (Ucn1), a member of the corticotrophin-releasing hormone (CRH) family, has been reported to participate in inflammation. The increased expression of intercellular adhesion molecule 1 (ICAM1) plays important roles in inflammation and immune responses. Our previous results demonstrated that Ucn1 significantly enhanced the expression of ICAM1. However, the underlying mechanisms are still unknown. The purpose of this study is to investigate the detailed mechanisms of Ucn1-induced upregulation of ICAM1. Here, we characterized the mechanisms of Ucn1 usage to regulate ICAM1 expression in human umbilical vein endothelial cells (HUVECs). Our data revealed that Ucn1 increased ICAM1 and cyclooxygenase 2 (COX2) expressions in a time-dependent manner via CRH receptor 2 (CRHR2). In addition, COX2 was involved in ICAM1 upregulation. Furthermore, Ucn1 could increase the expression and phosphorylation of cytosolic phospholipases A2 (cPLA2) in a time-dependent manner via CRHR2 and CRHR1. Moreover, ablation of cPLA2 by the inhibitor pyrrophenone or siRNA attenuated the ICAM1 increase induced by Ucn1. In addition, nuclear factor kB (NF-kB) was activated, indicated by the increase in nuclear p65NF-kB expression and phosphorylation of p65NF-kB, depending on cPLA2 and CRHR2 activation. Pyrrolidinedithiocarbamic acid, an inhibitor of NF-kB, abolished the elevation of ICAM1 but not COX2. Also, Ucn1 increased the production of prostaglandin E 2 (PGE 2 ) which further activated protein kinase A (PKA)-CREB pathways dependent of cPLA2 via CRHR2. Moreover, the increase in NF-kB phosphorylation was not affected by the selective COX2 inhibitor NS-398 or the PKA inhibitor H89. In conclusion, these data indicate that Ucn1 increase the ICAM1 expression via cPLA2-NF-kB and cPLA2-COX2-PGE 2 -PKA-CREB pathways by means of CRHR2.

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Involvement of PGE2 and the cAMP signalling pathway in the up-regulation of COX-2 and mPGES-1 expression in LPS-activated macrophages

Cited by 97 publications

References 58 publications

Cyclooxygenase-2 Deficiency in Macrophages Leads to Defective p110γ PI3K Signaling and Impairs Cell Adhesion and Migration

Cyclooxygenase-2 Deficiency in Macrophages Leads to Defective p110γ PI3K Signaling and Impairs Cell Adhesion and Migration

Host knockout of E-prostanoid 2 receptors reduces tumor growth and causes major alterations of gene expression in prostaglandin E2-producing tumors

Urocortin increased endothelial ICAM1 by cPLA2-dependent NF-κB and PKA pathways in HUVECs

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