共查询到20条相似文献,搜索用时 31 毫秒
1.
《Prostaglandins & other lipid mediators》2010,93(1-4):8-12
The present study examines the effect of chondroitin-4-sulfate (C4S) on the immediate (non-inflammatory conditions) and the delayed (inflammatory conditions) prostaglandin E2 (PGE2) release from rat calvarial osteoblasts. An immediate low release of PGE2 was induced by PAF, phorbol ester and arachidonic acid but not by IL1β, TNF-α and LPS whereas a delayed high release of PGE2 was induced by the inflammatory agents IL1β, TNF-α and LPS but not by PAF, phorbol ester and arachidonic acid. C4S had no effect on the immediate PGE2 release but inhibited the delayed release of PGE2. IL1β, TNF-α and LPS enhanced the expression of COX-2 and mPGES1 whereas phorbol ester enhanced COX-2 expression only. PAF and arachidonic acid had no effect on the expression of COX-2 and mPGES1. C4S inhibited the enhanced expression of COX-2 and mPGES1 but had no effect on the IL1β-induced decrease of I-κBα and nuclear translocation of NF-κB. These results indicate that the beneficial effects of C4S in bone inflammatory diseases might be due to a specific inhibition of the delayed high PGE2 release from osteoblasts. 相似文献
2.
Sailaja Polavarapu Arul M. Mani Naveen K. V. Gundala Anasuya D. Hari Siresha Bathina Undurti N. Das 《PloS one》2014,9(12)
In the present study, we noted that bleomycin induced growth inhibitory action was augmented by all the polyunsaturated fatty acids (PUFAs) tested on human neuroblastoma IMR-32 (0.5×104 cells/100 µl of IMR) cells (EPA> DHA> ALA = GLA = AA> DGLA = LA: ∼60, 40, 30, 10–20% respectively) at the maximum doses used. Of all the prostaglandins (PGE1, PGE2, PGF2α, and PGI2) and leukotrienes (LTD4 and LTE4) tested; PGE1, PGE2 and LTD4 inhibited the growth of IMR-32 cells to a significant degree at the highest doses used. Lipoxin A4 (LXA4), 19,20-dihydroxydocosapentaenoate (19, 20 DiHDPA) and 10(S),17(S)-dihydroxy-4Z,7Z,11E,13Z,15E,19Z-docosahexaenoic acid (protectin: 10(S),17(S)DiHDoHE), metabolites of DHA, significantly inhibited the growth of IMR-32 cells. Pre-treatment with AA, GLA, DGLA and EPA and simultaneous treatment with all PUFAs used in the study augmented growth inhibitory action of bleomycin. Surprisingly, both indomethacin and nordihydroguaiaretic acid (NDGA) at 60 and 20 µg/ml respectively enhanced the growth of IMR-32 cells even in the presence of bleomycin. AA enhanced oxidant stress in IMR-32 cells as evidenced by an increase in lipid peroxides, superoxide dismutase levels and glutathione peroxidase activity. These results suggest that PUFAs suppress growth of human neuroblastoma cells, augment growth inhibitory action of bleomycin by enhancing formation of lipid peroxides and altering the status of anti-oxidants and, in all probability, increase the formation of lipoxins, resolvins and protectins from their respective precursors that possess growth inhibitory actions. 相似文献
3.
Pankaj K Bhavsar Bruce D Levy Mark J Hew Michael A Pfeffer Shamsah Kazani Elliot Israel Kian Fan Chung 《Respiratory research》2010,11(1):71
Background
An imbalance in the generation of pro-inflammatory leukotrienes, and counter-regulatory lipoxins is present in severe asthma. We measured leukotriene B4 (LTB4), and lipoxin A4 (LXA4) production by alveolar macrophages (AMs) and studied the impact of corticosteroids.Methods
AMs obtained by fiberoptic bronchoscopy from 14 non-asthmatics, 12 non-severe and 11 severe asthmatics were stimulated with lipopolysaccharide (LPS,10 μg/ml) with or without dexamethasone (10-6M). LTB4 and LXA4 were measured by enzyme immunoassay.Results
LXA4 biosynthesis was decreased from severe asthma AMs compared to non-severe (p < 0.05) and normal subjects (p < 0.001). LXA4 induced by LPS was highest in normal subjects and lowest in severe asthmatics (p < 0.01). Basal levels of LTB4 were decreased in severe asthmatics compared to normal subjects (p < 0.05), but not to non-severe asthma. LPS-induced LTB4 was increased in severe asthma compared to non-severe asthma (p < 0.05). Dexamethasone inhibited LPS-induced LTB4 and LXA4, with lesser suppression of LTB4 in severe asthma patients (p < 0.05). There was a significant correlation between LPS-induced LXA4 and FEV1 (% predicted) (rs = 0.60; p < 0.01).Conclusions
Decreased LXA4 and increased LTB4 generation plus impaired corticosteroid sensitivity of LPS-induced LTB4 but not of LXA4 support a role for AMs in establishing a pro-inflammatory balance in severe asthma. 相似文献4.
Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, has anticancer effect on many cancers associated with chronic inflammation by both COX-2-dependent and COX-2-independent mechanisms. The non-COX-2 targets of celecoxib, however, are still a matter of research. Leukotriene B4 (LTB4) has been implicated in prostate and colon carcinogenesis, but little is known about the potential role of LTB4 in celecoxib-mediated anticancer effect. In this study, we evaluated whether LTB4 was involved in celecoxib-mediated inhibitory effect on human colon cancer HT-29 cells and human prostate cancer PC-3 cells. Our data showed that survival of both cell lines was obviously suppressed after celecoxib treatment for 72 h in a concentration-dependent manner. However, only in HT-29 cells, this inhibitory effect could be reversed by LTB4, which promoted survival of HT-29 cells rather than PC-3 cells. Consistent with these results, lioxygenase (LOX) potent inhibitor nordihydroguaiaretic acid (NDGA) had a higher inhibitory effect on HT-29 cells than PC-3 cells. Additionally, ELISA results showed that celecoxib could suppress expression of LTB4 in both cell lines, whereas, inhibition of PGE2 was only detected in HT-29 cells. These results indicate that the anticancer effect of celecoxib is COX-2-independent in HT-29 and PC-3 cells and in HT-29 cells primarily via down-regulating LTB4 production. 相似文献
5.
Pro-inflammatory and anti-inflammatory mediators derived from arachidonic acid (AA) modulate peripheral inflammation and its
resolution. Aspirin (ASA) is a unique non-steroidal anti-inflammatory drug, which switches AA metabolism from prostaglandin
E2 (PGE2) and thromboxane B2 (TXB2) to lipoxin A4 (LXA4) and 15-epi-LXA4. However, it is unknown whether chronic therapeutic doses of ASA are anti-inflammatory in the brain. We hypothesized that
ASA would dampen increases in brain concentrations of AA metabolites in a rat model of neuroinflammation, produced by a 6-day
intracerebroventricular infusion of bacterial lipopolysaccharide (LPS). In rats infused with LPS (0.5 ng/h) and given ASA-free
water to drink, concentrations in high-energy microwaved brain of PGE2, TXB2 and leukotriene B4 (LTB4) were elevated. In rats infused with artificial cerebrospinal fluid, 6 weeks of treatment with a low (10 mg/kg/day) or high
(100 mg/kg/day) ASA dose in drinking water decreased brain PGE2, but increased LTB4, LXA4 and 15-epi-LXA4 concentrations. Both doses attenuated the LPS effects on PGE2, and TXB2. The increments in LXA4 and 15-epi-LXA4 caused by high-dose ASA were significantly greater in LPS-infused rats. The ability of ASA to increase anti-inflammatory
LXA4 and 15-epi-LXA4 and reduce pro-inflammatory PGE2 and TXB2 suggests considering aspirin further for treating clinical neuroinflammation. 相似文献
6.
Objective
To explore the effects of atorvastatin on expression of cyclooxygenase-2 (COX-2) in human pulmonary epithelial cells (A549).Methods
A549 cells were incubated in DMEM medium containing lipopolysaccharide (LPS) in the presence or absence of atorvastatin. After incubation, the medium was collected and the amount of prostaglandin E2 (PGE2) was measured by enzyme-linked immunosorbent assay (ELISA). The cells were harvested, and COX-2 mRNA and protein were analyzed by RT-PCR and western-blot respectively.Results
LPS increased the expression of COX-2 mRNA and production of PGE2 in a dose- and time-dependent manner in A549. Induction of COX-2 mRNA and protein by LPS were inhibited by atorvastatin in a dose-dependent manner. Atorvastatin also significantly decreased LPS-induced production of PGE2. There was a positive correlation between reduced of COX-2 mRNA and decreased of PGE2 (r = 0.947, P < 0.05).Conclusion
Atorvastatin down-regulates LPS-induced expression of the COX-2 and consequently inhibits production of PGE2 in cultured A549 cells. 相似文献7.
《生物化学与生物物理学报:疾病的分子基础》2020,1866(3):165574
The functions of eicosanoids, a family of potent biologically active lipid mediators, are not restricted to inflammatory responses and they also act as mediators of the pathogenesis process. However, the role of eicosanoids in tuberculosis remains controversial. To investigate the specific role of LTB4 in Mycobacterium tuberculosis (Mtb) infection, we used 5-lipoxygenase-deficient (5-LO−/−) mice and WT (sv129) mice inoculated intranasally with LTB4 (encapsulated in PLGA microspheres). We showed that deficiency of the 5-LO pathway was related to resistance to Mtb infection. LTB4 inoculation increased susceptibility to Mtb in 5-LO−/− mice but not in WT mice, resulting in worsening of lung inflammation and tissue damage. In infected WT mice, most supplementary LTB4 was metabolized to the inactive form 12-oxo-LTB4 in the lung. A high amount of PGE2 was detected during Mtb infection, and pharmacological inhibition of COX-2 induced a significant reduction of bacterial load and an improved innate immune response in the lungs, independently of baseline LTB4 levels. COX-2 inhibition with celecoxib significantly reduced PGE2 levels, enhanced IFN-γ production and NO release, and increased macrophage phagocytosis of Mtb. The results suggest that a balance between PGE2/LTB4 is essential in the pathogenesis process of tuberculosis to prevent severe inflammation. Moreover, optimal levels of PGE2 are required to induce an effective innate response in the early phase of Mtb infection. Thus, pharmacological modulation of eicosanoid production may provide an important host-directed therapy in tuberculosis. 相似文献
8.
Kiritikara Kanyawim Laulederkind Stanley J. F. Raghow Rajendra Kanekura Takuro Ballou Leslie R. 《Molecular and cellular biochemistry》1998,188(1-2):41-48
Interleukin-1 (IL-1) is a potent inducer of prostaglandin E2 (PGE2) synthesis. We previously showed that ceramide accumulates in fibroblasts treated with IL-1 and that it enhances IL-1-induced PGE2 production. The present study was undertaken to determine the mechanism(s) by which ceramide and IL-1 interact to enhance PGE2 production by examining their respective effects on the rate-limiting enzymes in PGE2 synthesis, cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), and cytosolic phospholipase A2 (cPLA2). IL-1-induced PGE2 synthesis required 8 h even though COX-1 was constitutively expressed (both mRNA and protein) and enzymatically active in untreated cells. Conversely, COX-2 mRNA was barely detectable in untreated cells but within 2 h, ceramide or IL-1 alone induced a 5 and 20 fold increase in COX-2 mRNA, respectively. However, IL-1 induced COX-2 protein synthesis was only detectable 6-7 h after maximal COX-2 mRNA induction; COX-2 protein accumulation was not induced by ceramide alone. Ceramide however, reduced the length of time required for IL- 1 to induce COX-2 protein accumulation and increased COX-2 protein accumulation. IL-1 induced a 15 fold increase in COX-1 mRNA including an alternatively spliced form of COX-1. IL-1, but not ceramide induced cPLA2 mRNA and protein expression which corresponded with the initiation of PGE2 synthesis. These observations indicate that, (1) while either ceramide or IL-1 rapidly induced COX-2 mRNA, COX-2 protein only accumulated in IL- 1 treated cells after a delay of 6-7 h, (2) IL-1-induced PGE2 synthesis required both COX-2 and cPLA2 protein synthesis and, (3) ceramide enhanced (temporally and quantitatively) IL-1-induced COX-2 protein accumulation resulting in enhanced PGE2 production. 相似文献
9.
Kelitha Maxis Aline Delalandre Johanne Martel-Pelletier Jean-Pierre Pelletier Nicolas Duval Daniel Lajeunesse 《Arthritis research & therapy》2007,8(6):R181
Osteoarthritis (OA) is characterized by articular cartilage degradation and hypertrophic bone changes with osteophyte formation
and abnormal bone remodeling. Two groups of OA patients were identified via the production of variable and opposite levels
of prostaglandin E2 (PGE2) or leukotriene B4 (LTB4) by subchondral osteoblasts, PGE2 levels discriminating between low and high subgroups. We studied whether the expression of 5-lipoxygenase (5-LO) or 5-LO-activating
protein (FLAP) is responsible for the shunt from prostaglandins to leukotrienes. FLAP mRNA levels varied in low and high OA
groups compared with normal, whereas mRNA levels of 5-LO were similar in all osteoblasts. Selective inhibition of cyclooxygenase-2
(COX-2) with NS-398-stimulated FLAP expression in the high OA osteoblasts subgroup, whereas it was without effect in the low
OA osteoblasts subgroup. The addition of PGE2 to the low OA osteoblasts subgroup decreased FLAP expression but failed to affect it in the high OA osteoblasts subgroup.
LTB4 levels in OA osteoblasts were stimulated about twofold by 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) plus transforming growth factor-β (TGF-β), a situation corresponding to their effect on FLAP mRNA levels. Treatments with
1,25(OH)2D3 and TGF-β also modulated PGE2 production. TGF-β stimulated PGE2 production in both OA osteoblast groups, whereas 1,25(OH)2D3 alone had a limited effect but decreased the effect of TGF-β in the low OA osteoblasts subgroup. This modulation of PGE2 production was mirrored by the synthesis of COX-2. IL-18 levels were only slightly increased in a subgroup of OA osteoblasts
compared with normal; however, no relationship was observed overall between IL-18 and PGE2 levels in normal and OA osteoblasts. These results suggest that the shunt from the production of PGE2 to LTB4 is through regulation of the expression of FLAP, not 5-LO, in OA osteoblasts. The expression of FLAP in OA osteoblasts is
also modulated differently by 1,25(OH)2D3 and TGF-β depending on their endogenous low and high PGE2 levels. 相似文献
10.
Beibei Zhai Huiqing Yang Arturo Mancini QingWen He John Antoniou John A. Di Battista 《The Journal of biological chemistry》2010,285(31):23568-23580
11.
Zhen-Yu Du Tao Ma Synnøve Winterthun Karsten Kristiansen Livar Frøyland Lise Madsen 《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》2010,1801(4):526-536
The ability of n-3 PUFA to competitively inhibit the use of arachidonic acid (AA) for membrane phospholipid synthesis and prostaglandin E2 (PGE2) production has been well demonstrated in single cell models. In the present study, we investigated the metabolic competition between AA and eicosapentaenoic acid (EPA) for PGE2 synthesis in a rat hepatocyte–Kupffer cell (HPC/KC) co-culture system when the cellular oxidation capacity was enhanced by exogenous l-carnitine. We demonstrate that in the absence of l-carnitine, 1) β-oxidation rates of EPA and AA were comparable in HPCs and in KCs; 2) AA and not EPA was preferentially incorporated into glycerolipids; and 3) addition of EPA significantly decreased AA-dependent PGE2 synthesis in HPCs and cyclooxygenase-2 (COX-2) expression in co-cultured HPCs/KCs. However, enhancing the cellular oxidation capacity by the addition of l-carnitine 1) significantly increased β-oxidation of EPA in HPCs, but only marginally elevated the oxidation of AA in HPCs and the oxidation of both fatty acids in KCs; 2) decreased the esterification, but did not alter the preferential incorporation of AA into glycerolipids; and 3) alleviated the significant competitive inhibition of AA-dependent PGE2 synthesis and COX-2 expression by EPA. Taken together, the results strongly suggest that l-carnitine affects competition between AA and EPA in PG synthesis in liver cells by enhancing oxidation of EPA in HPCs. This implies that the beneficial effects of n-3 PUFA, especially EPA, are affected by the cellular oxidation capacity. 相似文献
12.
Rasmuson A Kock A Fuskevåg OM Kruspig B Simón-Santamaría J Gogvadze V Johnsen JI Kogner P Sveinbjörnsson B 《PloS one》2012,7(1):e29331
Background
Prostaglandin E2 (PGE2) is an important mediator in tumor-promoting inflammation. High expression of cyclooxygenase-2 (COX-2) has been detected in the embryonic childhood tumor neuroblastoma, and treatment with COX inhibitors significantly reduces tumor growth. Here, we have investigated the significance of a high COX-2 expression in neuroblastoma by analysis of PGE2 production, the expression pattern and localization of PGE2 receptors and intracellular signal transduction pathways activated by PGE2.Principal Findings
A high expression of the PGE2 receptors, EP1, EP2, EP3 and EP4 in primary neuroblastomas, independent of biological and clinical characteristics, was detected using immunohistochemistry. In addition, mRNA and protein corresponding to each of the receptors were detected in neuroblastoma cell lines. Immunofluorescent staining revealed localization of the receptors to the cellular membrane, in the cytoplasm, and in the nuclear compartment. Neuroblastoma cells produced PGE2 and stimulation of serum-starved neuroblastoma cells with PGE2 increased the intracellular concentration of calcium and cyclic AMP with subsequent phosphorylation of Akt. Addition of 16,16-dimethyl PGE2 (dmPGE2) increased cell viability in a time, dose- and cell line-dependent manner. Treatment of neuroblastoma cells with a COX-2 inhibitor resulted in a diminished cell growth and viability that was reversed by the addition of dmPGE2. Similarly, PGE2 receptor antagonists caused a decrease in neuroblastoma cell viability in a dose-dependent manner.Conclusions
These findings demonstrate that PGE2 acts as an autocrine and/or paracrine survival factor for neuroblastoma cells. Hence, specific targeting of PGE2 signaling provides a novel strategy for the treatment of childhood neuroblastoma through the inhibition of important mediators of tumor-promoting inflammation. 相似文献13.
Background
Marine-derived n-3 polyunsaturated fatty acids (PUFA) may have a beneficial effect on inflammation via lowering pro-inflammatory eicosanoid concentrations. We aimed to assess the effect of marine-derived n-3 PUFA on prostaglandin E2 (PGE2), thromboxane B2 (TXB2), and leukotriene B4 (LTB4) through systematic review and meta-analysis of randomized controlled trials.Method and Findings
A structured search strategy on PubMed, Web of Science and Cochrane up to November 2015 was undertaken in this meta-analysis. Standard mean difference was used to calculate the effect size of marine-derived n-3 PUFA on PGE2, TXB2 and LTB4 in a random-effect model. A total of 18 RCTs with 826 subjects were included in this systematic review and meta-analysis. Supplementation of marine-derived n-3 PUFA significantly decreased concentrations of TXB2 in serum/plasma in subjects with high risk of cardiovascular diseases (SMD:-1.26; 95% CI: -1.65, -0.86) and LTB4 in neutrophils in unhealthy subjects (subjects with non-autoimmune chronic diseases or auto-immune diseases) (SMD:-0.59: 95% CI: -1.02, -0.16). Subgroup analyses showed a significant reduction of LTB4 in subjects with rheumatoid arthritis (SMD: -0.83; 95% CI: -1.37, -0.29), but not in non-autoimmune chronic disease patients (SMD: -0.33; 95% CI: -0.97, 0.31). No significant publication bias was shown in the meta-analysis.Conclusions
Marine-derived n-3 PUFA had a beneficial effect on reducing the concentration of TXB2 in blood of subjects with high risk of CVD as well as LTB4 in neutrophils in unhealthy subjects, and that subjects with RA showed lower LTB4 content with supplementation of marine-derived n-3 PUFA. 相似文献14.
Claire C. Berthelot Shizuo George Kamita Romina Sacchi Jun Yang Malin L. Nording Katrin Georgi Christine Hegedus Karbowski J. Bruce German Robert H. Weiss Ronald J. Hogg Bruce D. Hammock Angela M. Zivkovic 《PloS one》2015,10(12)
Introduction
There is a high degree of inter-individual variability among people in response to intervention with omega-3 fatty acids (FA), which may partly explain conflicting results on the effectiveness of omega-3 FA for the treatment and prevention of chronic inflammatory diseases. In this study we sought to evaluate whether part of this inter-individual variability in response is related to the regulation of key oxylipin metabolic genes in circulating peripheral blood mononuclear cells (PBMCs).Methods
Plasma FA and oxylipin profiles from 12 healthy individuals were compared to PBMC gene expression profiles following six weeks of supplementation with fish oil, which delivered 1.9 g/d eicosapentaenoic acid (EPA) and 1.5 g/d docosahexaenoic acid (DHA). Fold changes in gene expression were measured by a quantitative polymerase chain reaction (qPCR).Results
Healthy individuals supplemented with omega-3 FA had differential responses in prostaglandin-endoperoxide synthase 1 (PTGS1), prostaglandin-endoperoxide synthase 2 (PTGS2), arachidonate 12-lipoxygenase (ALOX12), and interleukin 8 (IL-8) gene expression in isolated PBMCs. In those individuals for whom plasma arachidonic acid (ARA) in the phosphatidylethanolamine (PE) lipid class decreased in response to omega-3 intervention, there was a corresponding decrease in gene expression for PTGS1 and ALOX12. Several oxylipin product/FA precursor ratios (e.g. prostaglandin E2 (PGE2)/ARA for PTGS1 and 12-hydroxyeicosatetraenoic acid (12-HETE)/ARA for ALOX12) were also associated with fold change in gene expression, suggesting an association between enzyme activity and gene expression. The fold-change in PTGS1 gene expression was highly positively correlated with ALOX12 gene expression but not with PTGS2, whereas IL-8 and PTGS2 were positively correlated.Conclusions
The regulation of important oxylipin metabolic genes in PBMCs varied with the extent of change in ARA concentrations in the case of PTGS1 and ALOX12 regulation. PBMC gene expression changes in response to omega-3 supplementation varied among healthy individuals, and were associated with changes in plasma FA and oxylipin composition to different degrees in different individuals.Trial Registration
clinicaltrials.gov NCT01838239相似文献15.
Cytosolic phospholipases A2 (cPLA2) and cyclooxygenases-1 and -2 (COX-1 and -2) play a pivotal role in the metabolism of arachidonic acid (AA) and in eicosanoid production. The coordinate regulation and expression of these enzymes is not well defined. In this study, the effect of phorbol 12-myristate 13-acetate (PMA), tumor necrosis factor (TNF), lipopolysaccharide (LPS) and macrophage-colony stimulating factor (M-CSF) on AA release and prostaglandin E2 (PGE2) production and the expression of cPLA2 and COX-1 and -2 were investigated in U937 human pre-monocytic cells and fully differentiated macrophages. Treatment of U937 cells with PMA or macrophages with LPS increased AA release and PGE2 production. Incubation of U937 cells or macrophages for 8 h with all stimuli elevated cPLA2 expression. In contrast, cPLA2 expression was reduced upon further incubation of U937 cells or macrophages for 24 h with all stimuli indicating a bi-phasic expression pattern of this enzyme. PMA induced COX-1 expression in U937 cells whereas LPS induced COX-2 expression in macrophages. Although TNF and M-CSF induced a significant amount of AA release in both cell models, they failed to induce a comparable production of PGE2 since they were unable to induce the coordinate expression of the downstream key enzymes, COX-1 or COX-2. The results suggest that the enhancement of AA release in both U937 cells and macrophages may be caused by both increased cPLA2 activity and elevated cPLA2 protein expression. In addition, PMA stimulates PGE2 production via up-regulation of COX-1, and likely COX-2, expression in U937 cells whereas LPS stimulates PGE2 production via induction of COX-2 expression in macrophages. 相似文献
16.
Stephanie Georgina Dakin Jayesh Dudhia Natalie Jayne Werling Dirk Werling Dilkush Robert Ephrem Abayasekara Roger Kenneth Whealands Smith 《PloS one》2012,7(11)
The contribution of inflammation to the pathogenesis of tendinopathy and high prevalence of re-injury is not well established, although recent evidence suggests involvement of prostaglandins. We investigated the roles of prostaglandins and inflammation-resolving mediators in naturally occurring equine tendon injury with disease stage and age. Levels of prostaglandins E2 (PGE2), F2α (PGF2α), lipoxin A4 (LXA4) and its receptor FPR2/ALX were analysed in extracts of normal, sub-acute and chronic injured tendons. To assess whether potential changes were associated with altered PGE2 metabolism, microsomal prostaglandin E synthase-1 (mPGES-1), prostaglandin dehydrogenase (PGDH), COX-2 and EP4 receptor expression were investigated. The ability of tendons to resolve inflammation was determined by assessing FPR2/ALX expression in natural injury and IL-1β stimulated tendon explants.Alterations in the profile of lipid mediators during sub-acute injury included low PGE2 and elevated LXA4 levels compared to normal and chronic injuries. In contrast, PGF2α levels remained unchanged and were three-fold lower than PGE2. The synthetic capacity of PGE2 as measured by the ratio of mPGES-1:PGDH was elevated in sub-acute injury, suggesting aberrations in tendon prostaglandin metabolism, whilst COX-2 and EP4 receptor were unchanged. Paradoxically low tendon PGE2 levels in early injury may be attributed to increased local clearance via PGDH or the class switching of lipid mediators from the prostaglandin to the lipoxin axis. PGE2 is therefore implicated in the development of tendon inflammation and its ensuing resolution. Whilst there was no relationship between age and tendon LXA4 levels, there was an age-associated decline in FPR2/ALX receptor expression with concurrent increased PGE2 levels in injury. Furthermore, uninjured tendon explants from younger (<10 years) but not older horses (≥10 years) treated with IL-1β responded by increasing FPR2/ALX suggesting aged individuals exhibit a reduced capacity to resolve inflammation via FPR2/ALX, which may present a potential mechanism for development of chronic tendinopathy and re-injury. 相似文献
17.
Gheorghe KR Thurlings RM Westman M Boumans MJ Malmström V Trollmo C Korotkova M Jakobsson PJ Tak PP 《PloS one》2011,6(1):e16378
Introduction
B cells may play an important role in promoting immune activation in the rheumatoid synovium and can produce prostaglandin E2 (PGE2) when activated. In its turn, PGE2 formed by cyclooxygenase (COX) and microsomal prostaglandin E2 synthase 1 (MPGES1) contributes to the rheumatoid arthritis (RA) pathological process. Therapeutic depletion of B cells results in important improvement in controlling disease activity in rheumatoid patients. Therefore we investigated the expression of PGE2 pathway enzymes in RA B cells and evaluated the effects of B cell depleting therapy on their expression in RA tissue.Methods
B cells expressing MPGES1 and COX-2 were identified by flow cytometry in in vitro stimulated and control mononuclear cells isolated from synovial fluid and peripheral blood of RA patients. Synovial biopsies were obtained from 24 RA patients before and at two consecutive time points after rituximab therapy. Expression of MPGES1, COX-1 and COX-2, as well as interleukin (IL)-1β and IL-6, known inducers of MPGES1, was quantified in immunostained biopsy sections using computerized image analysis.Results
Expression of MPGES1 or COX-2 was significantly upregulated upon stimulation of B cells from blood and synovial fluid while control cells displayed no detectable enzymes. In synovial biopsy sections, the expression of MPGES1, COX-1 or COX-2 was resistant to rituximab therapy at 8 or 16 weeks after start of treatment. Furthermore expression of IL-1β in the synovial tissue remained unchanged, while IL-6 tended to decrease after therapy.Conclusions
Therapy with B cell depleting agents, although efficient in achieving good clinical and radiographic response in RA patients, leaves important inflammatory pathways in the rheumatoid synovium essentially unaffected. 相似文献18.
19.
Purpose
The differentiated superficial cells of the urothelium restrict urine flow into the bladder wall. We have demonstrated that urothelial cells isolated from bladders of patients with interstitial cystitis/painful bladder syndrome (IC/PBS) fail to release PGE2 in response to tryptase. This study examines the expression of PGE2 synthesis and degradation enzymes in urothelial cells during differentiation.Materials and Methods
We measured immunoprotein expression of cyclooxygenase-2 (COX-2), prostaglandin E2 synthase (PGES) and 15-hydroxyprostaglandin dehydrogenase (PGDH) in human urothelial cells and in immortalized urothelial cells isolated from the bladders of IC/PBS patients or normal subjects during stratification and differentiation produced by increased calcium and fetal bovine serum (Ca/FBS) in the culture medium for 1, 3 and 7 days.Results
PGES immunoprotein expression increased during differentiation in normal and IC/PBS urothelial cells. COX-2 expression also increased in cells from normal patients following differentiation. Remarkably, no COX-2 expression was detectable in urothelial cells isolated from 3 out of 4 IC/PBS patients. PGDH immunoprotein expression decreased in normal cells after 1 and 3 days of Ca/FBS addition, but returned to normal after 7 days. PGDH expression was unchanged during differentiation at 1 and 3 days, but was more than 2-fold higher at 7 days compared to day 0 in the IC/PBS cells. Urothelial cells isolated from IC/PBS patients demonstrated no PGE2 release in response to tryptase under any of the experimental conditions studied.Conclusions
Taken together, our results indicate that PGE2 release is compromised during stratification and differentiation in IC/PBS urothelium and may contribute to impaired barrier function. 相似文献20.