scholarly journals Prostaglandin E2-synthesizing enzymes in fever: differential transcriptional regulation

2002 ◽  
Vol 283 (5) ◽  
pp. R1104-R1117 ◽  
Author(s):  
Andrei I. Ivanov ◽  
Ralph S. Pero ◽  
Adrienne C. Scheck ◽  
Andrej A. Romanovsky
Keyword(s):  
De Novo ◽  
Phase Iii ◽  
Rt Pcr ◽  
Febrile Response ◽  
Major Mechanism ◽  
High Magnitude ◽  
Cox 2 ◽  
Wistar Kyoto ◽  
The Brain ◽  
Cox 1

The febrile response to lipopolysaccharide (LPS) consists of three phases ( phases I–III), all requiring de novo synthesis of prostaglandin (PG) E2. The major mechanism for activation of PGE2-synthesizing enzymes is transcriptional upregulation. The triphasic febrile response of Wistar-Kyoto rats to intravenous LPS (50 μg/kg) was studied. Using real-time RT-PCR, the expression of seven PGE2-synthesizing enzymes in the LPS-processing organs (liver and lungs) and the brain “febrigenic center” (hypothalamus) was quantified. Phase I involved transcriptional upregulation of the functionally coupled cyclooxygenase (COX)-2 and microsomal (m) PGE synthase (PGES) in the liver and lungs. Phase II entailed robust upregulation of all enzymes of the major inflammatory pathway, i.e., secretory (s) phospholipase (PL) A2-IIA → COX-2 → mPGES, in both the periphery and brain. Phase III was accompanied by the induction of cytosolic (c) PLA2-α in the hypothalamus, further upregulation of sPLA2-IIA and mPGES in the hypothalamus and liver, and a decrease in the expression of COX-1 and COX-2 in all tissues studied. Neither sPLA2-V nor cPGES was induced by LPS. The high magnitude of upregulation of mPGES and sPLA2-IIA (1,257-fold and 133-fold, respectively) makes these enzymes attractive targets for anti-inflammatory therapy.

Intracellular-specific colocalization of prostaglandin E2 synthases and cyclooxygenases in the brain

2004 ◽  
Vol 287 (5) ◽  
pp. R1155-R1163 ◽  
Author(s):  
Alejandro Vazquez-Tello ◽  
Li Fan ◽  
Xin Hou ◽  
Jean-Sébastien Joyal ◽  
Joseph A. Mancini ◽  
...  
Keyword(s):  
Brain Tissue ◽  
Intracellular Localization ◽  
Cysteine Residue ◽  
Prostaglandin E ◽  
Cell Compartment ◽  
Cerebral Microvessels ◽  
Microsomal Membranes ◽  
Cox 2 ◽  
The Brain ◽  
Cox 1

Prostaglandin E2 (PGE2) is the major primary prostaglandin generated by brain cells. However, the coordination and intracellular localization of the cyclooxygenases (COXs) and prostaglandin E synthases (PGESs) that convert arachidonic acid to PGE2 in brain tissue are not known. We aimed to determine whether microsomal and cytosolic PGES (mPGES-1 and cPGES) colocalize and coordinate activity with either COX-1 or COX-2 in brain tissue, particularly during development. Importantly, we found that cytosolic PGES also associates with microsomes (cPGES-m) from the cerebrum and cerebral vasculature of the pig and rat as well as microsomes from various cell lines; this seemed dependent on the carboxyl terminal 35-amino acid domain and a cysteine residue (C58) of cPGES. In microsomal membranes from the postnatal brain and cerebral microvessels of mature animals, cPGES-m colocalized with both COX-1 and COX-2, whereas mPGES-1 was undetectable in these microsomes. Accordingly, in this cell compartment, cPGES could coordinate its activity with COX-2 and COX-1 (partly inhibited by NS398); albeit in microsomes of the brain microvasculature from newborns, mPGES-1 was also present. In contrast, in nuclei of brain parenchymal and endothelial cells, mPGES-1 and cPGES colocalized exclusively with COX-2 (determined by immunoblotting and immunohistochemistry); these PGESs contributed to conversion of PGH2 into PGE2. Hence, contrary to a previously proposed model of exclusive COX-2/mPGES-1 coordination, COX-2 can coordinate with mPGES-1 and/or cPGES in the brain, depending on the cell compartment and the age group.

scholarly journals Interleukin (IL)-6, But Not IL-1, Induction in the Brain Downstream of Cyclooxygenase-2 Is Essential for the Induction of Febrile Response against Peripheral IL-1α

Endocrinology ◽  
2004 ◽  
Vol 145 (11) ◽  
pp. 5044-5048 ◽  
Author(s):  
Kyoko Kagiwada ◽  
Dai Chida ◽  
Tomoya Sakatani ◽  
Masahide Asano ◽  
Aya Nambu ◽  
...  
Keyword(s):  
Prostaglandin E2 ◽  
Cyclooxygenase 2 ◽  
Signaling Cascade ◽  
Endogenous Pyrogen ◽  
Febrile Response ◽  
Cox 2 ◽  
The Brain ◽  
Deficient Mice

Abstract IL-1 is an endogenous pyrogen produced upon inflammation or infection. Previously, we showed that, upon injection with turpentine, IL-1 is induced in the brain in association with the development of fever. The role of endogenous IL-1 in the brain and the signaling cascade to activate thermosensitive neurons, however, remain to be elucidated. In this report, febrile response was analyzed after peripheral injection of IL-1α. We found that a normal febrile response was induced even in IL-1α/β-deficient mice, indicating that production of IL-1 in the brain is not necessarily required for the response. In contrast, IL-6-deficient mice did not exhibit a febrile response. Cyclooxygenase (Cox)-2 expression in the brain was strongly induced 1.5 h after injection of IL-1α, whereas IL-6 expression was observed 3 h after the injection. Cox-2 expression in the brain was not influenced by IL-6 deficiency, whereas indomethacin, an inhibitor of cyclooxygenases, completely inhibited induction of IL-6. These observations suggest a mechanism of IL-1-induced febrile response in which IL-1 in the blood activates Cox-2, with the resulting prostaglandin E2 inducing IL-6 in the brain, leading to the development of fever.

Expression of proteinase-activated receptor 2 on human primary gastrointestinal myofibroblasts and stimulation of prostaglandin synthesis

2005 ◽  
Vol 83 (7) ◽  
pp. 605-616 ◽  
Author(s):  
Michelle L Seymour ◽  
David G Binion ◽  
Steven J Compton ◽  
Morley D Hollenberg ◽  
Wallace K MacNaughton
Keyword(s):  
Small Intestine ◽  
Dependent Manner ◽  
Intestinal Epithelial ◽  
Rt Pcr ◽  
Concentration Dependent Manner ◽  
Cell Functions ◽  
Cox 2 ◽  
Colonic Cells ◽  
Cox 1 ◽  
Stimulation Of

It is known that subepithelial myofibroblast-derived prostaglandin (PG)E2 can regulate intestinal epithelial cell functions, and that proteinase-activated receptor-2 (PAR2) is abundantly expressed in the gastrointestinal tract. Since PAR2 activation has previously been associated with stimulation of PGE2 synthesis, we hypothesized that PAR2 expressed on primary human gastrointestinal myofibroblasts regulates PGE2 synthesis via cyclooxygenase (COX)-1 and (or) COX-2, and associated PGE synthases. Primary human myofibroblasts were isolated from the resection tissue of the esophagus, small intestine, and colon. Expression of functional PAR2 was determined by RT-PCR and by calcium mobilization in Fura-2/AM-loaded cells. Trypsin and the selective PAR2-activating peptide (PAR2-AP) SLIGRL-NH2 stimulated PGE2 synthesis in a concentration-dependent manner, as measured by enzyme immunoassay. Selective COX inhibition showed PAR2-induced PGE2 synthesis to be COX-1 dependent in esophageal myofibroblasts and both COX-1 and COX-2 dependent in colonic cells, consistent with the distribution of COX-1 and COX-2 expression. Although both cytosolic and microsomal PGE synthases were expressed in cells from all tissues, microsomal PGE synthases were expressed at highest levels in the colonic myofibroblasts. Activation of PAR2 on gastrointestinal myofibroblasts stimulates PGE2 synthesis via different pathways in the colon than in the esophagus and small intestine. Key words: Proteinase-activated receptor, myofibroblast, cyclooxygenase, PGE synthase, prostaglandin E2, esophagus, small intestine, colon.

scholarly journals Different Chemical Structures and Physiological/Pathological Roles of Cyclooxygenases

2020 ◽  
Author(s):  
Yalcin Faki ◽  
◽  
Ayse Er
Keyword(s):  
Chemical Structures ◽  
Inflammatory Conditions ◽  
Pathological Conditions ◽  
Living Things ◽  
The Subject ◽  
Cox 2 ◽  
The Brain ◽  
Different Levels ◽  
Cox 1 ◽  
Different Tissues

This review describes cyclooxygenase (COX), which synthesizes prostanoids that play an important role in living things. The authors conducted a national and international literature review on the subject. The COX enzyme uses arachidonic acid to form prostanoids, which play a role in several physiological and pathological conditions. This enzyme has different isoforms, mainly COX-1 and COX-2. The constitutive isoform is COX-1, while COX-2 is the inducible isoform. Both are expressed in different tissues and at different levels, but they may also coexist within the same tissue. Both isoforms show essentially the same mode of action, but their substrates and inhibitors may differ. The COX-1 isoform, which plays a role in the continuation of physiological events, has an increased expression level in various carcinomas, and the COX-2 isoform, which is increased in inflammatory conditions, is typically expressed at low physiological levels in some tissues such as the brain, kidney, and uterus. In addition to investigating the efficacies of the COX-1 and COX-2 isoforms, the discovery of potential new COX enzymes and their effect continues. This review also looks at the roles of the COX enzyme in certain physiological and pathological conditions.

Histamine-dependent prolongation by aldosterone of vasoconstriction in isolated small mesenteric arteries of the mouse

2013 ◽  
Vol 304 (8) ◽  
pp. H1094-H1102 ◽  
Author(s):  
Jeppe Schjerning ◽  
Torben R. Uhrenholt ◽  
Per Svenningsen ◽  
Paul M. Vanhoutte ◽  
Ole Skøtt ◽  
...  
Keyword(s):  
Mast Cells ◽  
Receptor Antagonist ◽  
Vascular Function ◽  
Mesenteric Arteries ◽  
Wild Type ◽  
Rt Pcr ◽  
No Donor ◽  
High K ◽  
Cox 2 ◽  
Cox 1

In arterioles, aldosterone counteracts the rapid dilatation (recovery) following depolarization-induced contraction. The hypothesis was tested that this effect of aldosterone depends on cyclooxygenase (COX)-derived products and/or nitric oxide (NO) synthase (NOS) inhibition. Recovery of the response to high K+ was observed in mesenteric arteries of wild-type and COX-2−/− mice but it was significantly diminished in preparations from endothelial NOS (eNOS)−/− mice. Aldosterone pretreatment inhibited recovery from wild-type and COX-2−/− mice. The NO donor sodium nitroprusside (SNP) restored recovery in arteries from eNOS−/− mice, and this was inhibited by aldosterone. Actinomycin-D abolished the effect of aldosterone, indicating a genomic effect. The effect was blocked by indomethacin and by the COX-1 inhibitor valeryl salicylate but not by NS-398 (10−6 mol/l) or the TP-receptor antagonist S18886 (10−7 mol/l). The effect of aldosterone on recovery in arteries from wild-type mice and the SNP-mediated dilatation in arteries from eNOS−/− mice was inhibited by the histamine H2 receptor antagonist cimetidine. RT-PCR showed expression of mast cell markers in mouse mesenteric arteries. The adventitia displayed granular cells positive for toluidine blue vital stain. Confocal microscopy of live mast cells showed loss of quinacrine fluorescence and swelling after aldosterone treatment, indicating degranulation. RT-PCR showed expression of mineralocorticoid receptors in mesenteric arteries and in isolated mast cells. These findings suggest that aldosterone inhibits recovery by stimulation of histamine release from mast cells along mesenteric arteries. The resulting activation of H2 receptors decreases the sensitivity to NO of vascular smooth muscle cells. Aldosterone may chronically affect vascular function through paracrine release of histamine.

scholarly journals Rapid and transient induction of cyclo-oxygenase 2 by epidermal growth factor in human amnion-derived WISH cells

1997 ◽  
Vol 321 (3) ◽  
pp. 677-681 ◽  
Author(s):  
Douglas J. PERKINS ◽  
Douglas A. KNISS
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Protein Expression ◽  
De Novo ◽  
Tnf Α ◽  
Mrna And Protein Expression ◽  
Epidermal Growth ◽  
Cox 2 ◽  
Dose Dependent ◽  
Cox 1

The central enzyme in the prostaglandin (PG) biosynthetic cascade is PGH2 synthase or cyclo-oxygenase (COX). At present, two distinct isoforms of PGH2 synthase/COX have been identified: COX-1 and COX-2. In many systems, COX-1 is a constitutively expressed isoform that is responsible for normal physiological production of PGs, whereas COX-2 is an inducible isoform that responds to cytokines, endotoxin and growth factors by producing high levels of PGs. The regulation of COX-2 mRNA and protein, and the subsequent production of PGE2, were therefore examined in amnion-derived WISH cells stimulated with epidermal growth factor (EGF). Treatment of WISH cells with EGF (0.01Ő100 ng/ml) elicited dose-dependent synthesis of COX-2 mRNA and protein de novo. In addition, stimulation of WISH cells with EGF (10 ng/ml) induced steady-state levels of COX-2 mRNA and protein that appeared within 30 min and then declined rapidly to near baseline levels within 2Ő4 h. In contrast, COX-1 protein was unchanged in response to treatment with EGF. PGE2 production was also rapid and transient. Preincubation of cells with the novel COX-2 enzymic inhibitor NS-398 (10-5Ő10-10 M) completely prevented PGE2 formation in a dose-dependent manner. Preincubation of cells in dexamethasone (Dex; 0.1 ƁM), however, resulted in only a 31% decrease in PGE2 formation in response to EGF (10 ng/ml) while completely attenuating PGE2 biosynthesis in tumour necrosis factor α (TNF-α)-stimulated cells. In addition, Dex (0.1 ƁM) was only partly effective at preventing EGF-induced COX-2 mRNA and protein expression de novo, whereas Dex completely inhibited TNF-α-promoted COX-2 mRNA and protein expression. Thus the results presented here demonstrate that EGF induces the rapid but transient expression of COX-2 mRNA and protein and the subsequent production of PGE2 in WISH cells.

Cyclooxygenase mRNA expression in human patellar tendon at rest and after exercise

2008 ◽  
Vol 294 (1) ◽  
pp. R192-R199 ◽  
Author(s):  
Todd A. Trappe ◽  
Chad C. Carroll ◽  
Bozena Jemiolo ◽  
Scott W. Trappe ◽  
Simon Døssing ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mrna Expression ◽  
Patellar Tendon ◽  
Expression Patterns ◽  
Rt Pcr ◽  
Tendon Tissue ◽  
Intron 1 ◽  
Cox 2 ◽  
Cox 1 ◽  
Tendon Properties

Exercise has been shown to acutely elevate several metabolic processes in tendon tissue, including collagen turnover and blood flow, and chronically induce changes in tendon properties. Many of these acute metabolic responses to exercise are regulated by the cyclooxygenase (COX) enzymes. We measured the expression levels of COX-1 [variants 1 and 2 (COX-1v1 and COX-1v2)], COX-2, and the recently discovered intron 1-retaining COX-1 variants (COX-1b1, COX-1b2, and COX-1b3) at rest and after resistance exercise (RE). Patellar tendon biopsy samples were taken from six individuals (3 men and 3 women) before and 4 h after a bout of RE (3 sets of 10 repetitions at ∼70% of 1 repetition maximum) and from a separate group of six individuals (3 men and 3 women) before and 24 h after RE and analyzed by real-time RT-PCR. The COX-1 variants were the most abundant COX mRNAs before exercise and remained unchanged ( P > 0.05) after exercise. COX-2 was also expressed in tendon tissue at rest and was unchanged ( P > 0.05) after exercise. The intron 1-retaining COX-1 variants were not detectable in tendon tissue before or after exercise. COX-1 and COX-2 were expressed at much higher levels by the patellar tendon than by quadriceps skeletal muscle, although the overall COX mRNA expression patterns were similar in skeletal muscle and tendon (COX-1v2 > COX-1v1, P < 0.05; ratio of COX-1 to COX-2 ≅ 4:1). These results suggest that COX-1 and COX-2 are constitutively expressed at relatively high levels in human patellar tendon and are likely targets of COX-inhibiting drugs at rest and after physical activity.

Increased cytokine and chemokine gene expression in the CNS of mice during heat stroke recovery

2013 ◽  
Vol 305 (9) ◽  
pp. R978-R986 ◽  
Author(s):  
Joseph C. Biedenkapp ◽  
Lisa R. Leon
Keyword(s):  
Gene Expression ◽  
Heat Stroke ◽  
Stroke Recovery ◽  
Activation Markers ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Cox Inhibitor ◽  
Cox 2 ◽  
The Brain ◽  
Cox 1

Heat stroke (HS) is characterized by a systemic inflammatory response syndrome (SIRS) consisting of profound core temperature (Tc) changes in mice. Encephalopathy is common at HS collapse, but inflammatory changes occurring in the brain during the SIRS remain unidentified. We determined the association between inflammatory gene expression changes in the brain with Tc disturbances during HS recovery in mice. Gene expression changes of heat shock protein (HSP)72, heme oxygenase (hmox1), cytokines (IL-1β, IL-6, TNF-α), cyclooxygenase enzymes (COX-1, COX-2), chemokines (MCP-1, MIP-1α, MIP-1β, CX3CR1), and glia activation markers (CD14, aif1, vimentin) were examined in the hypothalamus (HY) and hippocampus (HC) of control (Tc ∼ 36.0°C) and HS mice at Tc,Max (42.7°C), hypothermia depth (HD; 29.3 ± 0.4°C), and fever (37.8 ± 0.3°C). HSP72 (HY<HC) and IL-1β (HY only) were the only genes that showed increased expression at Tc,Max. HSP72 (HY < HC), hmox1 (HY < HC), cytokine (HY = HC), and chemokine (HY = HC) expression was highest at HD and similar to controls during fever. COX-1 expression was unaffected by HS, whereas HD was associated with approximately threefold increase in COX-2 expression (HY only). COX-2 expression was not increased during fever and indomethacin (COX inhibitor) had no effect on this Tc response indicating fever is regulated by other inflammatory pathways. CD14, aif1, and vimentin activation at HD coincided with maximal cytokine and chemokine expression suggesting glia cells are a possible source of brain cytokines and chemokines during HS recovery. The inflammatory gene expression changes during HS recovery suggest cytokines and/or chemokines may be initiating development or rewarming from hypothermia, whereas fever pathway(s) remain to be elucidated.

scholarly journals Application potential of modulation of cyclooxygenase-2 activity: a cognitive approach

2021 ◽  
Vol 75 (1) ◽  
pp. 837-846
Author(s):  
Katarzyna Stachowicz
Keyword(s):  
Fatty Acids ◽  
Immune Cells ◽  
Brain Function ◽  
Cognitive Approach ◽  
Mediate Response ◽  
Application Potential ◽  
Learning And Plasticity ◽  
Cox 2 ◽  
The Brain ◽  
Cox 1

Abstract Cognitive functions of the brain depend largely on the condition of the cell membranes and the proportion of fatty acids. It is known and accepted that arachidonic acid (AA) is one of the main ω-6 fatty acids (phospholipids) in brain cells. Metabolism of that fatty acid depends on the functionality and presence of cyclooxygenase (COX). COX is a primary enzyme in the cycle of transformation of AA to prostanoids, which may mediate response of immune cells, contributing to brain function and cognition. Two COX isoforms (COX-1 and COX-2), as well as a splice variant (COX-3), have been detected in the brain. Findings released in the last decade showed that COX-2 may play an important role in cognition. There are many preclinical and clinical reports showing its engagement in Alzheimer disease, spatial learning, and plasticity. This manuscript focuses on summarizing the above-mentioned discoveries.

Preoptic norepinephrine mediates the febrile response of guinea pigs to lipopolysaccharide

2007 ◽  
Vol 293 (3) ◽  
pp. R1135-R1143 ◽  
Author(s):  
Carlos Feleder ◽  
Vit Perlik ◽  
Clark M. Blatteis
Keyword(s):  
Core Temperature ◽  
Guinea Pigs ◽  
Preoptic Area ◽  
Noradrenergic System ◽  
Febrile Response ◽  
Cox 2 ◽  
Central Noradrenergic System ◽  
Cox 1

Norepinephrine (NE) microdialyzed in the preoptic area (POA) raises core temperature (Tc) via 1) α1-adrenoceptors (AR), quickly and independently of POA PGE2, and 2) α2-AR, after a delay and PGE2 dependently. Since systemic lipopolysaccharide (LPS) activates the central noradrenergic system, we investigated whether preoptic NE mediates LPS fever. We injected LPS (2 μg/kg iv) in guinea pigs prepared with intra-POA microdialysis probes and determined POA cerebrospinal (CSF) NE levels. We similarly microdialyzed prazosin (α1 blocker, 1 μg/μl), yohimbine (α2 blocker, 1 μg/μl), SC-560 [cyclooxygenase (COX)-1 blocker, 5 μg/μl], acetaminophen (presumptive COX-1v blocker, 5 μg/μl), or MK-0663 (COX-2 blocker, 0.5 μg/μl) in other animals before intravenous LPS and measured CSF PGE2. All of the agents were perfused at 2 μg/min for 6 h. Tc was monitored constantly. POA NE peaked within 30 min after LPS and then returned to baseline over the next 90 min. Tc increased within 12 min to a first peak at ∼60 min and to a second at ∼150 min and then declined over the following 2.5 h. POA PGE2 followed a concurrent course. Prazosin pretreatment eliminated the first Tc rise but not the second; PGE2 rose normally. Yohimbine pretreatment did not affect the first Tc rise, which continued unchanged for 6 h; the second rise, however, was absent, and PGE2 levels did not increase. SC-560 and acetaminophen did not alter the LPS-induced PGE2 and Tc rises; MK-0663 prevented both the late PGE2 and Tc rises. These results confirm that POA NE is pivotal in the development of LPS fever.

Sign in / Sign up

Export Citation Format

Share Document