Prostaglandin E2 Induces Matrix Metalloproteinase 9 Expression in Dendritic Cells through Two Independent Signaling Pathways Leading to Activator Protein 1 (AP-1) Activation

Yen, Jui‐Hung; Kocieda, Virginia; Jing, Huie; Ganea, Doina

doi:10.1074/jbc.m111.252932

Cited by 75 publications

(65 citation statements)

References 45 publications

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“…Interestingly enough, it has been recently reported that PGE2 induces MMP-9 expression in dendritic cells and that PGE2-induced MMP-9 is required for dendritic cells migration in vivo and in vitro (58). All together, these findings indicate the existence of a close bidirectional association between some MMPs and PTGS2.…”

Section: Discussionsupporting

confidence: 49%

Matrix Metalloproteinase-19 Is a Key Regulator of Lung Fibrosis in Mice and Humans

Kovkarova-Naumovski²,

Jara³

et al. 2012

Am J Respir Crit Care Med

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Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by epithelial phenotypic changes and fibroblast activation. Based on the temporal heterogeneity of IPF, we hypothesized that hyperplastic alveolar epithelial cells regulate the fibrotic response. Objectives: To identify novel mediators of fibrosis comparing the transcriptional signature of hyperplastic epithelial cells and conserved epithelial cells in the same lung. Methods: Laser capture microscope and microarrays analysis were used to identify differentially expressed genes in IPF lungs. Bleomycininduced lung fibrosis was evaluated in Mmp19-deficient and wild-type (WT) mice. The role of matrix metalloproteinase (MMP)-19 was additionally studied by transfecting the human MMP19 in alveolar epithelial cells. Measurements and Main Results: Laser capture microscope followed by microarray analysis revealed a novel mediator, MMP-19, in hyperplastic epithelial cells adjacent to fibrotic regions. Mmp19 2/2 mice showed a significantly increased lung fibrotic response to bleomycin compared with WT mice. A549 epithelial cells transfected with human MMP19 stimulated wound healing and cell migration, whereas silencing MMP19 had the opposite effect. Gene expression microarray of transfected A549 cells showed that PTGS2 (prostaglandin-endoperoxide synthase 2) was one of the highly induced genes. PTGS2 was overexpressed in IPF lungs and colocalized with MMP-19 in hyperplastic epithelial cells. In WT mice, PTGS2 was significantly increased in bronchoalveolar lavage and lung tissues after bleomycin-induced fibrosis, but not in Mmp19 2/2 mice. Inhibition of Mmp-19 by siRNA resulted in inhibition of Ptgs2 at mRNA and protein levels. Conclusions: Up-regulation of MMP19 induced by lung injury may play a protective role in the development of fibrosis through the induction of PTGS2.

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Section: Discussionsupporting

confidence: 49%

Matrix Metalloproteinase-19 Is a Key Regulator of Lung Fibrosis in Mice and Humans

Kovkarova-Naumovski²,

Jara³

et al. 2012

Am J Respir Crit Care Med

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“…COX2 and EP4 have the ability to increase intracellular cAMP levels (28,29), and given their ablated expression upon the loss of virulence, we compared cAMP levels of virulent and attenuated macrophages. Upon attenuation, the amount of intracellular cAMP decreases by almost 50% and can be restored by the addition of TGF-␤2 ( Fig.…”

Section: Expression Of Cox2 Ep4mentioning

confidence: 99%

Transforming Growth Factor β2 Promotes Transcription of COX2 and EP4 , Leading to a Prostaglandin E ₂ -Driven Autostimulatory Loop That Enhances Virulence of Theileria annulata-Transformed Macrophages

et al. 2015

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Transforming growth factor beta (TGF-␤) is a pleiotropic cytokine known to regulate cell growth, differentiation, and motility and is a potent modulator of immune function. TGF-␤ consequently plays a central role in carcinogenesis, and a dampened TGF-␤2 response by Theileria annulata-infected monocytes/macrophages underpins disease resistance to tropical theileriosis. Here, we show that concomitant with the loss of TGF-␤2 production, there is ablated expression of COX2 and EP4, which leads to a drop in cyclic AMP (cAMP) levels and, consequently, reduced activation of protein kinase A (PKA) and EPAC. This ablated phenotype can be rescued in attenuated macrophages by the addition of exogenous TGF-␤2, which reactivates the expression of COX2 and EP4 while repressing that of protein kinase inhibitor gamma (PKIG) to the levels in virulent macrophages. TGF-␤2 therefore promotes the adhesion and invasiveness of virulent macrophages by modulating COX2, EP4, and PKIG transcription to initiate a prostaglandin E 2 (PGE2)-driven autostimulatory loop that augments PKA and EPAC activities. A virulence phenotype stemming from the double activation of PKA and EPAC is the induction of a CREB-mediated transcriptional program and the upregulation of JAM-L-and integrin 4␣␤1-mediated adhesion of Theileria-infected macrophages.T heileria annulata is a tick-borne apicomplexan parasite and the causative agent of the cattle disease tropical theileriosis, which is of major economic importance in countries in Northern Africa and Asia. T. annulata transforms B cells and monocytes/macrophages, and infected leukocytes display many characteristics of cancer cells, such as heightened migratory and invasive capacities (1, 2). However, and importantly, the tumor-like phenotype is reversed upon drug-induced parasite death (3). Moreover, virulent macrophages can be attenuated by multiple in vitro passages, and upon attenuation, they lose both adhesion and invasiveness (4). The similarities in tumor hyperinvasiveness between Theileria-transformed leukocytes and human leukemias argue that studying Theileria-induced transformation can give insights into generally applicable mechanisms involved in tumor virulence.Transforming growth factor beta (TGF-␤) is a pleiotropic cytokine involved in numerous critical processes such as cell proliferation, differentiation, and survival or apoptosis. In normal cells and cells in early stages of cancer, TGF-␤ acts as a tumor suppressor and inhibits cell growth, while in late stages of cancer, it plays a contrasting role, acting as a tumor promoter enhancing metastasis and invasion. TGF-␤2 is strongly expressed in highly aggressive and malignant tumors (5). We have demonstrated that following infection, Theileria-transformed Holstein-Friesian (HF) (Bos taurus) macrophages produce more TGF-␤2 than do infected Sahiwal (Bos indicus) macrophages, and augmented TGF-␤2 output underpins the greater invasive capacity of infected HF macrophages. Moreover, attenuated Ode HF macrophages used as a live vaccine against tropical ...

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“…Moreover, PGE 2 is able to induce MMP-9 expression in dendritic cells. 52 After cerebral ischemia, HMGB1 can upregulate MMP-9 expression/activity in neurons and astrocytes, signaling neighboring cells to increase blood-brain barrier permeability and recruit immune cells. 53 We recently reported that HMGB1 inhibition decreases MMP-9 activity, thereby decreasing ICH-induced early brain injury.…”

mentioning

confidence: 99%

Cerebroprotection by the neuronal PGE₂ receptor EP2 after intracerebral hemorrhage in middle-aged mice

Han

et al. 2016

J Cereb Blood Flow Metab

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Inflammatory responses mediated by prostaglandins such as PGE 2 may contribute to secondary brain injury after intracerebral hemorrhage (ICH). However, the cell-specific signaling by PGE 2 receptor EP2 differs depending on whether the neuropathic insult is acute or chronic. Using genetic and pharmacologic approaches, we investigated the role of EP2 receptor in two mouse models of ICH induced by intrastriatal injection of collagenase or autologous arterial whole blood. We used middle-aged male mice to enhance the clinical relevance of the study. EP2 receptor was expressed in neurons but not in astrocytes or microglia after collagenase-induced ICH. Brain injury after collagenase-induced ICH was associated with enhanced cellular and molecular inflammatory responses, oxidative stress, and matrix metalloproteinase (MMP)-2/9 activity. EP2 receptor deletion exacerbated brain injury, brain swelling/edema, neuronal death, and neurobehavioral deficits, whereas EP2 receptor activation by the highly selective agonist AE1-259-01 reversed these outcomes. EP2 receptor deletion also exacerbated brain edema and neurologic deficits in the blood ICH model. These findings support the premise that neuronal EP2 receptor activation by PGE 2 protects brain against ICH injury in middle-aged mice through its anti-inflammatory and anti-oxidant effects and anti-MMP-2/9 activity. PGE 2 /EP2 signaling warrants further investigation for potential use in ICH treatment.

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Prostaglandin E2 Induces Matrix Metalloproteinase 9 Expression in Dendritic Cells through Two Independent Signaling Pathways Leading to Activator Protein 1 (AP-1) Activation

Cited by 75 publications

References 45 publications

Matrix Metalloproteinase-19 Is a Key Regulator of Lung Fibrosis in Mice and Humans

Matrix Metalloproteinase-19 Is a Key Regulator of Lung Fibrosis in Mice and Humans

Transforming Growth Factor β2 Promotes Transcription of COX2 and EP4 , Leading to a Prostaglandin E ₂ -Driven Autostimulatory Loop That Enhances Virulence of Theileria annulata-Transformed Macrophages

Cerebroprotection by the neuronal PGE₂ receptor EP2 after intracerebral hemorrhage in middle-aged mice

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Prostaglandin E2 Induces Matrix Metalloproteinase 9 Expression in Dendritic Cells through Two Independent Signaling Pathways Leading to Activator Protein 1 (AP-1) Activation

Cited by 75 publications

References 45 publications

Matrix Metalloproteinase-19 Is a Key Regulator of Lung Fibrosis in Mice and Humans

Matrix Metalloproteinase-19 Is a Key Regulator of Lung Fibrosis in Mice and Humans

Transforming Growth Factor β2 Promotes Transcription of COX2 and EP4 , Leading to a Prostaglandin E 2 -Driven Autostimulatory Loop That Enhances Virulence of Theileria annulata-Transformed Macrophages

Cerebroprotection by the neuronal PGE2 receptor EP2 after intracerebral hemorrhage in middle-aged mice

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Transforming Growth Factor β2 Promotes Transcription of COX2 and EP4 , Leading to a Prostaglandin E ₂ -Driven Autostimulatory Loop That Enhances Virulence of Theileria annulata-Transformed Macrophages

Cerebroprotection by the neuronal PGE₂ receptor EP2 after intracerebral hemorrhage in middle-aged mice