PGE2 potentiates tonicity-induced COX-2 expression in renal medullary cells in a positive feedback loop involving EP2-cAMP-PKA signaling

2009 ◽  
Vol 296 (1) ◽  
pp. C75-C87 ◽  
Author(s):  
Daniela Steinert ◽  
Christoph Küper ◽  
Helmut Bartels ◽  
Franz-X. Beck ◽  
Wolfgang Neuhofer
Keyword(s):  
Osmotic Stress ◽  
Cell Survival ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Mdck Cells ◽  
Dominant Negative ◽  
Dibutyryl Camp ◽  
Positive Feedback Loop ◽  
Cox 2 ◽  
Medullary Cells

Cyooxygenase-2 (COX-2)-derived PGE2 is critical for the integrity and function of renal medullary cells during antidiuresis. The present study extended our previous finding that tonicity-induced COX-2 expression is further stimulated by the major COX-2 product PGE2 and investigated the underlying signaling pathways and the functional relevance of this phenomenon. Hyperosmolality stimulated COX-2 expression and activity in Madin-Darby canine kidney (MDCK) cells, a response that was further increased by PGE2-cAMP signaling, suggesting the existence of a positive feedback loop. This effect was diminished by AH-6809, an EP2 antagonist, and by the PKA inhibitor H-89, but not by AH-23848, an EP4 antagonist. The effect of PGE2 was mimicked by forskolin and dibutyryl-cAMP, suggesting that the stimulatory effect of PGE2 on COX-2 is mediated by a cAMP-PKA-dependent mechanism. Accordingly, cAMP-responsive element (CRE)-driven reporter activity paralleled the effects of PGE2, AH-6809, AH-23848, H-89, forskolin, and dibutyryl-cAMP on COX-2 expression. In addition, the stimulatory effect of PGE2 on tonicity-induced COX-2 expression was blunted in cells transfected with dominant-negative CRE binding (CREB) protein, as was the case in a COX-2 promoter reporter construct in which a putative CRE was deleted. Furthermore, PGE2 resulted in PKA-dependent phosphorylation of the pro-apoptotic protein Bad at Ser155, a mechanism that is known to inactivate Bad, which coincided with reduced caspase-3 activity during osmotic stress. Conversely, pharmacological interruption of the PGE2-EP2-cAMP-PKA pathway abolished Ser155 phosphorylation of Bad and blunted the protective effect of PGE2 on cell survival during osmotic stress. These observations indicate the existence of a positive feedback loop of PGE2 on COX-2 expression during osmotic stress, an effect that apparently is mediated by EP2-cAMP-PKA signaling, and that contributes to cell survival under hypertonic conditions.

scholarly journals Interaction of Apoptotic Cells with Macrophages Upregulates COX-2/PGE2and HGF Expression via a Positive Feedback Loop

2014 ◽  
Vol 2014 ◽  
pp. 1-17 ◽  
Author(s):  
Ji Yeon Byun ◽  
Young-So Youn ◽  
Ye-Ji Lee ◽  
Youn-Hee Choi ◽  
So-Yeon Woo ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Tissue Repair ◽  
Feedback Loop ◽  
Apoptotic Cell ◽  
Raw 264.7 Cells ◽  
Apoptotic Cells ◽  
Positive Feedback Loop ◽  
Cox 2

Recognition of apoptotic cells by macrophages is crucial for resolution of inflammation, immune tolerance, and tissue repair. Cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) and hepatocyte growth factor (HGF) play important roles in the tissue repair process. We investigated the characteristics of macrophage COX-2 and PGE2expression mediated by apoptotic cells and then determined how macrophages exposed to apoptotic cellsin vitroandin vivoorchestrate the interaction between COX-2/PGE2and HGF signaling pathways. Exposure of RAW 264.7 cells and primary peritoneal macrophages to apoptotic cells resulted in induction of COX-2 and PGE2. The COX-2 inhibitor NS-398 suppressed apoptotic cell-induced PGE2production. Both NS-398 and COX-2-siRNA, as well as the PGE2receptor EP2 antagonist, blocked HGF expression in response to apoptotic cells. In addition, the HGF receptor antagonist suppressed increases in COX-2 and PGE2induction. Thein vivorelevance of the interaction between the COX-2/PGE2and HGF pathways through a positive feedback loop was shown in cultured alveolar macrophages followingin vivoexposure of bleomycin-stimulated lungs to apoptotic cells. Our results demonstrate that upregulation of the COX-2/PGE2and HGF in macrophages following exposure to apoptotic cells represents a mechanism for mediating the anti-inflammatory and antifibrotic consequences of apoptotic cell recognition.

scholarly journals TLR4 signaling promotes a COX-2/PGE2/STAT3 positive feedback loop in hepatocellular carcinoma (HCC) cells

2015 ◽  
Vol 5 (2) ◽  
pp. e1074376 ◽  
Author(s):  
Ang Lin ◽  
Guan Wang ◽  
Huajun Zhao ◽  
Yuyi Zhang ◽  
Qiuju Han ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Positive Feedback Loop ◽  
Tlr4 Signaling ◽  
Cox 2 ◽  
Hcc Cells

scholarly journals A Positive Feedback Loop that Regulates Cyclooxygenase-2 Expression and Prostaglandin F2α Synthesis via the F-Series-Prostanoid Receptor and Extracellular Signal-Regulated Kinase 1/2 Signaling Pathway

Endocrinology ◽  
2005 ◽  
Vol 146 (11) ◽  
pp. 4657-4664 ◽  
Author(s):  
Henry N. Jabbour ◽  
Kurt J. Sales ◽  
Sheila C. Boddy ◽  
Richard A. Anderson ◽  
Alistair R. W. Williams
Keyword(s):  
Positive Feedback ◽  
Feedback Loop ◽  
Endometrial Adenocarcinoma ◽  
Prostaglandin F2α ◽  
Receptor Activation ◽  
Receptor Interaction ◽  
Dominant Negative Mutant ◽  
Positive Feedback Loop ◽  
Fp Receptor ◽  
Cox 2

Cyclooxygenase (COX) enzymes catalyze the biosynthesis of eicosanoids, including prostaglandin (PG) F2α. PGF2α exerts its autocrine/paracrine function by coupling to its G protein-coupled receptor [F-series-prostanoid (FP) receptor] to initiate cell signaling and target gene transcription. In the present study, we found elevated expression of COX-2 and FP receptor colocalized together within the neoplastic epithelial cells of endometrial adenocarcinomas. We investigated a role for PGF2α-FP receptor interaction in modulating COX-2 expression and PGF2α biosynthesis using an endometrial adenocarcinoma cell line stably transfected with the FP receptor cDNA (FPS cells). PGF2α-FP receptor activation rapidly induced COX-2 promoter, mRNA, and protein expression in FPS cells. These effects of PGF2α on the expression of COX-2 could be abolished by treatment of FPS cells with an FP receptor antagonist (AL8810) and chemical inhibitor of ERK1/2 kinase (PD98059), or by inactivation of ERK1/2 signaling with dominant-negative mutant isoforms of Ras or ERK1/2 kinase. We further confirmed that elevated COX-2 protein in FPS cells could biosynthesize PGF2αde novo to promote a positive feedback loop to facilitate endometrial tumorigenesis. Finally, we have shown that PGF2α could potentiate tumorigenesis in endometrial adenocarcinoma explants by inducing the expression of COX-2 mRNA.

Ectodomain shedding of pro-TGF-α is required for COX-2 induction and cell survival in renal medullary cells exposed to osmotic stress

2007 ◽  
Vol 293 (6) ◽  
pp. C1971-C1982 ◽  
Author(s):  
Christoph Küper ◽  
Helmut Bartels ◽  
Maria-Luisa Fraek ◽  
Franz X. Beck ◽  
Wolfgang Neuhofer
Keyword(s):  
Osmotic Stress ◽  
Cell Survival ◽  
Transforming Growth Factor ◽  
Ectodomain Shedding ◽  
Kidney Cells ◽  
Madin Darby Canine Kidney ◽  
Cox 2 ◽  
Darby Canine Kidney ◽  
Canine Kidney ◽  
Medullary Cells

In the renal medulla, cyclooxygenase (COX)-2 is induced by osmotic stress as present in this kidney region during antidiuresis. Increasing evidence suggests that EGF receptor (EGFR) signaling is involved in this process. The aim of the present study was to examine the mechanisms responsible for COX-2 expression and PGE2 production during hypertonic conditions and to identify potential autocrine/paracrine EGFR ligands. Immunohistochemisty and Western blot analysis revealed abundant expression of the pro-EGFR ligand pro-transforming growth factor (TGF)-α in renal medullary cells in vivo and in cultured Madin-Darby canine kidney cells. In Madin-Darby canine kidney cells, hypertonicity rapidly increased TNF-α converting enzyme (TACE)-dependent ectodomain shedding of pro-TGF-α; phosphorylation of EGFR, p38, and ERK1/2; expression of COX-2; and production of PGE2. Conversely, TACE inhibition prevented TGF-α release; EGFR, p38, and ERK1/2 activation; and COX-2 expression. Furthermore, cell survival was reduced substantially, a response that could be reversed by the addition of PGE2. Simultaneous addition of recombinant TGF-α during TACE inhibition restored EGFR and MAPK phosphorylation, COX-2 expression, PGE2 production, and cell survival during osmotic stress. These results indicate that hypertonicity induces TACE-mediated ectodomain shedding of pro-TGF-α, which subsequently activates COX-2 expression in an autocrine/paracrine fashion, via EGFR and MAPKs. We conclude that tonicity-induced TGF-α release is required for COX-2 expression, PGE2 synthesis, and survival of renal medullary cells during osmotic stress.

Positive feedback loop of interleukin-1β upregulating production of inflammatory mediators in human intervertebral disc cells in vitro

2005 ◽  
Vol 2 (5) ◽  
pp. 589-595 ◽  
Author(s):  
Kotaro Jimbo ◽  
Jin Soo Park ◽  
Kimiaki Yokosuka ◽  
Kimiaki Sato ◽  
Kensei Nagata
Keyword(s):  
Intervertebral Disc ◽  
Positive Feedback ◽  
Protein Concentration ◽  
Feedback Loop ◽  
Serum Free Medium ◽  
Free Medium ◽  
Positive Feedback Loop ◽  
Content Type ◽  
Cox 2 ◽  
Fine Print

Object. Interleukin-1β (IL-1β) induces neurological symptoms in intervertebral disc herniation (IDH). Recently, the existence of a positive feedback loop of IL-1β, which encourages an inflammatory reaction or degeneration in the cells of tendon, has been reported. The authors hypothesized that there is a positive feedback loop of IL-1β in the cells of IDH. Methods. Eight human intervertebral disc specimens were harvested during spinal surgery for lumbar disc herniation. The cells were stimulated in serum-free medium with or without exogenous IL-1β. The messenger RNA (mRNA) was extracted for reverse-transcription polymerase chain reaction (PCR) and real-time PCR to quantify the mRNA of endogenous IL-1β, IL-6, cyclooxygenase-2 (COX-2), and matrix metalloproteinases (MMPs). The cells were then stimulated in serum-free medium with or without exogenous IL-1β, and then exogenous IL-1β was removed. After 2, 4, and 6 days, the medium was collected, and enzyme-linked immunosorbent assay was used to measure the protein concentration of endogenous IL-1β. The mRNA expressions of endogenous IL-1β, IL-6, COX-2, and MMPs were increased significantly depending on the concentration of exogenous IL-1β. The protein concentration of endogenous IL-1β was increased over time. Conclusions. There was a positive feedback loop of IL-1β in the cells of IDH. Furthermore, the productions of IL-6, COX-2, MMP-1, and MMP-3 were upregulated as a result of the increasing concentration of IL-1β in a positive feedback loop of IL-1β. The authors concluded that this positive feedback loop of IL-1β upregulated the production of mediators and thus can cause cessation of symptoms in IDH.

scholarly journals Rac and Cdc42 play distinct roles in regulating PI(3,4,5)P3 and polarity during neutrophil chemotaxis

2003 ◽  
Vol 160 (3) ◽  
pp. 375-385 ◽  
Author(s):  
Supriya Srinivasan ◽  
Fei Wang ◽  
Suzana Glavas ◽  
Alexander Ott ◽  
Fred Hofmann ◽  
...  
Keyword(s):  
Fluorescent Probes ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Dominant Role ◽  
Leading Edge ◽  
Membrane Lipid ◽  
Dominant Negative ◽  
Ph Domain ◽  
Positive Feedback Loop ◽  
Constitutively Active

Neutrophils exposed to chemoattractants polarize and accumulate polymerized actin at the leading edge. In neutrophil-like HL-60 cells, this asymmetry depends on a positive feedback loop in which accumulation of a membrane lipid, phosphatidylinositol (PI) 3,4,5-trisphosphate (PI[3,4,5]P3), leads to activation of Rac and/or Cdc42, and vice versa. We now report that Rac and Cdc42 play distinct roles in regulating this asymmetry. In the absence of chemoattractant, expression of constitutively active Rac stimulates accumulation at the plasma membrane of actin polymers and of GFP-tagged fluorescent probes for PI(3,4,5)P3 (the PH domain of Akt) and activated Rac (the p21-binding domain of p21-activated kinase). Dominant negative Rac inhibits chemoattractant-stimulated accumulation of actin polymers and membrane translocation of both fluorescent probes and attainment of morphologic polarity. Expression of constitutively active Cdc42 or of two different protein inhibitors of Cdc42 fails to mimic effects of the Rac mutants on actin or PI(3,4,5)P3. Instead, Cdc42 inhibitors prevent cells from maintaining a persistent leading edge and frequently induce formation of multiple, short lived leading edges containing actin polymers, PI(3,4,5)P3, and activated Rac. We conclude that Rac plays a dominant role in the PI(3,4,5)P3-dependent positive feedback loop required for forming a leading edge, whereas location and stability of the leading edge are regulated by Cdc42.

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