Bacterial clearance of Pseudomonas aeruginosa is enhanced by the inhibition of COX-2

Prostanoids generated by COX-2 are involved in the regulation of inflammation but their exact role in the innate immune response has not been defined. We investigated whether COX-2 is involved in host defense against Pseudomonas aeruginosa pneumonia. In vitro studies, in a macrophage cell line, showed that cytotoxic strain of P aeruginosa (PA103) induced significant COX-2 protein expression and enzymatic function. In vivo data showed that infection with PA103 increased COX-2 protein production in whole lung tissue compared to mice that were infected with mutant bacteria that lack ExoU (DeltaU) or ExoU and ExoT (DeltaUT). COX-2(-/-) mice had accentuated clearance of cytotoxic P. aeruginosa from the lungs. We further tested the effects of COX-2 products such as prostaglandin E(2) on the function of phagocytic cells. Our studies indicate that prostaglandin E(2) may be involved through interacting with the EP2 receptors in modulating the host response because treatment of macrophages with prostaglandin E(2) suppressed production of reactive oxygen species. Furthermore there was enhanced bacterial clearance in EP2 receptor(-/-) mice compared to the wild-type controls. Thus it is possible that inhibition of COX-2 or EP2 receptors could be an effective adjunctive treatment for severe or resistant P. aeruginosa pneumonia.     

Targeting COX-2 and EP4 to control tumor growth, angiogenesis, lymphangiogenesis and metastasis to the lungs and lymph nodes in a breast cancer model

We reported that cyclo-oxygenase (COX)-2 expression in human breast cancer stimulated cancer cell migration and invasiveness, production of vascular endothelial growth factor (VEGF)-C and lymphangiogenesis in situ, largely from endogenous PGE2-mediated stimulation of prostaglandin E (EP)1 and EP4 receptors, presenting them as candidate therapeutic targets against lymphatic metastasis. As human breast cancer xenografts in immuno-compromised mice have limitations for preclinical testing, we developed a syngeneic murine breast cancer model of spontaneous lymphatic metastasis mimicking human and applied it for mechanistic and therapeutic studies. We tested the roles of COX-2 and EP receptors in VEGF-C and -D production by a highly metastatic COX-2 expressing murine breast cancer cell line C3L5. These cells expressed all EP receptors and produced VEGF-C and -D, both inhibited with COX-2 inhibitors or EP4 (but not EP1, EP2 or EP3) antagonists. C3H/HeJ mice, when implanted SC in both inguinal regions with C3L5 cells suspended in growth factor-reduced Matrigel, exhibited rapid tumor growth, tumor-associated angiogenesis and lymphangiogenesis (respectively measured with CD31 and LYVE-1 immunostaining), metastasis to the inguinal and axillary lymph nodes and the lungs. Chronic oral administration of COX-1/COX-2 inhibitor indomethacin, COX-2 inhibitor celecoxib and an EP4 antagonist ONO-AE3-208, but not an EP1 antagonist ONO-8713 at nontoxic doses markedly reduced tumor growth, lymphangiogenesis, angiogenesis, and metastasis to lymph nodes and lungs. Residual tumors in responding mice revealed reduced VEGF-C and -D proteins, AkT phosphorylation and increased apoptotic/proliferative cell ratios consistent with blockade of EP4 signaling. We suggest that EP4 antagonists deserve clinical testing for chemo-intervention of lymphatic metastasis in human breast cancer.     

Immunohistochemical expression of COX-2, mPGES and EP2 receptor in normal and reactive canine bone and in canine osteosarcoma

Accumulating evidence suggests that cyclooxygenase (COX)-2 is involved in the pathogenesis of human and canine osteosarcoma. The aim of this study was to investigate the expression of COX-2 in normal, reactive and neoplastic canine bone and the events downstream to COX-2 that lead to prostaglandin E(2) (PGE(2)) production. COX-2, microsomal PGE(2) synthase-1 (mPGES-1) and the PGE(2) receptor (EP2) were assessed by immunohistochemistry in 12 samples of normal bone, 14 cases of fracture callus and 27 appendicular osteosarcomas. No immunoreactivity to COX-2, mPGES-1 or EP2 receptor was observed in normal bone. Fifty percent of reactive bone samples expressed COX-2 and 57% expressed mPGES-1 and EP2 receptor, although with weak labelling intensity. Ninety-three percent of osteosarcomas expressed COX-2, while mPGES-1 was expressed by 85% and EP2 receptor by 89% of the tumours. The data confirm that COX-2 is expressed at high level in osteosarcoma and support the use of COX-2 inhibitors to improve the response to chemotherapy. The possibility of blocking the EP2 or the selective inhibition of mPGES-1, rather than COX-2 activity, might decrease the incidence of adverse effects that occur due to the inhibition of prostanoids other than PGE(2).     

Misoprostol, an anti-ulcer agent and PGE2 receptor agonist, protects against cerebral ischemia

Induction of COX-2 activity in cerebral ischemia results in increased neuronal injury and infarct size. Recent studies investigating neurotoxic mechanisms of COX-2 demonstrate both toxic and paradoxically protective effects of downstream prostaglandin receptor signaling pathways. We tested whether misoprostol, a PGE(2) receptor agonist that is utilized clinically as an anti-ulcer agent and signals through the protective PGE(2) EP2, EP3, and EP4 receptors, would reduce brain injury in the murine middle cerebral artery occlusion-reperfusion (MCAO-RP) model. Administration of misoprostol, at the time of MCAO or 2h after MCAO, resulted in significant rescue of infarct volume at 24 and 72h. Immunocytochemistry demonstrated dynamic regulation of the EP2 and EP4 receptors during reperfusion in neurons and endothelial cells of cerebral cortex and striatum, with limited expression of EP3 receptor. EP3-/- mice had no significant changes in infarct volume compared to control littermates. Moreover, administration of misoprostol to EP3+/+ and EP3-/- mice showed similar levels of infarct rescue, indicating that misoprostol protection was not mediated through the EP3 receptor. Taken together, these findings suggest a novel function for misoprostol as a protective agent in cerebral ischemia acting via the PGE(2) EP2 and/or EP4 receptors.     

Cyclooxygenase-2 and the renal renin-angiotensin system

In the kidney, cyclooxygenase-2 (COX-2) is expressed in the macula densa/cTALH and medullary interstitial cells. The macula densa is involved in regulating afferent arteriolar tone and renin release by sensing alterations in luminal chloride via changes in the rate of Na(+)/K(+)/2Cl(-) cotransport, and administration of non-specific cyclooxygenase inhibitors will blunt increases in renin release mediated by macula densa sensing of decreases in luminal NaCl. High renin states [salt deficiency, angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers, diuretic administration or experimental renovascular hypertension] are associated with increased macula densa/cTALH COX-2 expression. Furthermore, there is evidence that angiotensin II and/or aldosterone may inhibit COX-2 expression. In AT1 receptor knockout mice, COX-2 expression is increased similar to increases with ACE inhibitors or AT1 receptor blockers. Direct administration of angiotensin II inhibits macula densa COX-2 expression. Previous studies demonstrated that alterations in intraluminal chloride concentration are the signal for macula densa regulation of tubuloglomerular feedback and renin secretion, with high chloride stimulating tubuloglomerular feedback and low chloride stimulating renin release. When cultured cTALH or macula densa cells were incubated in media with selective substitution of chloride ions, COX-2 expression and prostaglandin production were significantly increased. A variety of studies have indicated a role for COX-2 in the macula densa mediation of renin release. In isolated perfused glomerular preparations, renin release induced by macula densa perfusion with a low chloride solution was inhibited by a COX-2 inhibitor but not a COX-1 inhibitor. In vivo studies in rats indicated that increased renin release in response to low-salt diet, ACE inhibitor, loop diuretics or aortic coarctation could be inhibited by administration of COX-2-selective inhibitors. In mice with genetic deletion of COX-2, ACE inhibitors or low-salt diet failed to increase renal renin expression, although renin significantly increased in wild type mice. In contrast, in COX-1 null mice there were no significant differences in either the basal or ACE inhibitor-stimulated level of renal renin activity from plasma or renal tissue compared with wild type mice. In summary, there is increasing evidence that COX-2 expression in the macula densa and surrounding cortical thick ascending limb cells is regulated by angiotensin II and is a modulator of renal renin production. These interactions of COX-2 derived prostaglandins and the renin-angiotensin system may underlie physiological and pathophysiological regulation of renal function.     

PGE2-receptor subtype EP4-dependent adherence of mastocytoma P-815 cells to matrix components in subcutaneous tissues overlaying inside surface of air pouch cavity in CDF1 mouse

OBJECTIVES: It remains to be fully clarified how adhesion of mast cells is regulated in vivo. We previously reported that PGE(2)-receptor EP4 stimulated the adhesion of mouse mastocytoma P-815 cells to plate-bound fibronectin. Our purpose in this study is to evaluate the adhesion using a system, which can mimic the in vivo adhesion. METHODS: P-815 cells were transplanted in an air pouch produced in the transplantable mice, CDF1. The number of cells that adhere to the subcutaneous tissues overlaying the inside cavity surface was determined. RESULTS: The number of adhered cells was decreased in mice administered with ibuprofen or an EP4 antagonist, ONO AE3-208. A local administration of PGE(2) or a phorbol ester, PMA, increased the number of adhered cells, which was also suppressed in the mice treated with ONO AE3-208. CONCLUSION: Our results suggest that PGE(2)-mediated adhesion of P-815 cells in the subcutaneous tissues of the air pouch is mediated by the EP4 subtype.     

Seminal plasma activates cyclooxygenase-2 and prostaglandin E2 receptor expression and signalling in cervical adenocarcinoma cells

Enhanced cyclooxygenase (COX) expression and prostaglandin E2 (PGE2) synthesis are regarded as promoters of neoplastic cell proliferation and angiogenesis. Expression of COX-2 and synthesis of PGE2 are up-regulated in cervical carcinomas. In sexually active women, growth and invasiveness of neoplastic cervical epithelial cells may be also under the direct influence of PGE2 present in seminal plasma. The aims of this study were to investigate the effect of seminal plasma and PGE2 on the expression of COX-2 and expression and signalling of the PGE2 receptor subtypes (EP1-EP4) in HeLa (cervical adenocarcinoma) cells. Treatment of HeLa cells with seminal plasma or PGE2 resulted in up-regulation of COX-2 expression (P < 0.05). In addition, seminal plasma induced the mRNA expression of EP1, EP2 and EP4 receptors, whilst PGE2 treatment of HeLa cells induced the expression of the EP4 receptor (P < 0.05). This was coincident with a rapid accumulation of adenosine 3',5'-cyclic monophosphate (cAMP) in HeLa cells stimulated with seminal plasma or PGE2, which was greater in seminal plasma stimulated cells compared with PGE2 stimulated cells (P < 0.05). Subsequently, we investigated whether the effect of seminal plasma on cAMP signalling in HeLa cells was mediated via the cAMP-linked EP2/EP4 receptors. Stimulation of HeLa cells with seminal plasma or PGE2 resulted in an augmented cAMP accumulation in cells transfected with the EP2 or EP4 receptor cDNA compared with control transfected cells (P < 0.05). These data suggest that, in sexually active women, seminal plasma may play a role in modulating neoplastic cell function and cervical tumorigenesis.     

Group V Secretory Phospholipase A(2) Enhances the Progression of Angiotensin II-Induced Abdominal Aortic Aneurysms but Confers Protection against Angiotensin II-Induced Cardiac Fibrosis in ApoE-Deficient Mice

Abdominal aortic aneurysms (AAAs) and heart failure are complex life-threatening diseases whose etiology is not completely understood. In this study, we investigated whether deficiency of group V secretory phospholipase A(2) (GV sPLA(2)) protects from experimental AAA. The impact of GV sPLA(2) deficiency on angiotensin (Ang) II-induced cardiac fibrosis was also investigated. Apolipoprotein E (apoE)(-/-) mice and apoE(-/-) mice lacking GV sPLA(2) (GV DKO) were infused with 1000 ng/kg per minute Ang II for up to 28 days. Increases in systolic blood pressure, plasma aldosterone level, and urinary and heart prostanoids were similar in apoE(-/-) and GV DKO mice after Ang II infusion. The incidence of aortic rupture in Ang II-infused GV DKO mice (10%) was significantly reduced compared with apoE(-/-) mice (29.4%). Although the incidence of AAA in GV DKO mice (81.3%) and apoE(-/-) mice (100%) was similar, the mean percentage increase in maximal luminal diameter of abdominal aortas was significantly smaller in GV DKO mice (68.5% ± 7.7%) compared with apoE(-/-) mice (92.6% ± 8.3%). Deficiency of GV sPLA(2) resulted in increased Ang II-induced cardiac fibrosis that was most pronounced in perivascular regions. Perivascular collagen, visualized by picrosirius red staining, was associated with increased TUNEL staining and increased immunopositivity for macrophages and myofibroblasts and nicotinamide adenine dinucleotide phosphate oxidase (NOX)-2 and NOX-4, respectively. Our findings indicate that GV sPLA(2) modulates pathological responses to Ang II, with different outcomes for AAA and cardiac fibrosis.     

机动车尾气诱发大鼠慢性阻塞性肺疾病并上调气道上皮细胞COX-2/PGE2/EP受体信号通路

目的：探究机动车尾气(MVE)长期暴露引起大鼠慢性阻塞性肺疾病(COPD)发生时,气道上皮细胞中环加氧酶2(COX-2)/前列腺素E₂(PGE₂)/E-前列腺素类激素(EP)受体信号通路成员的表达变化。方法：(1)动物实验：健康雄性SD纯系大鼠(SPF级)16只,随机分为2组：MVE暴露组(n=8)和空白对照(CTL)组(n=8)。采用MVE暴露6个月的方法建立COPD大鼠模型。造模结束后,使用Buxco小动物有创肺功能仪检测大鼠肺功能;肺组织切片行HE染色并评估肺组织病理变化;ELISA法检测大鼠支气管肺泡灌洗液(BALF)中炎症因子白细胞介素6(IL-6)、肿瘤坏死因子α(TNF-α)和PGE₂的水平,评估大鼠肺部炎症情况;采用免疫荧光及Western blot法检测肺组织COX-2及EP受体蛋白水平;提取肺组织核蛋白,Western blot检测MVE对肺组织NF-κB核转位的影响。(2)细胞实验：采用MVE细颗粒物(PM2.5)标准品刺激人正常支气管上皮细胞BEAS-2B。ELISA法检测细胞培养液中PGE     

Suppression of allergic inflammation by the prostaglandin E receptor subtype EP3

Prostaglandins, including PGD(2) and PGE(2), are produced during allergic reactions. Although PGD(2) is an important mediator of allergic responses, aspirin-like drugs that inhibit prostaglandin synthesis are generally ineffective in allergic disorders, suggesting that another prostaglandin-mediated pathway prevents the development of allergic reactions. Here we show that such a pathway may be mediated by PGE(2) acting at the prostaglandin E receptor EP3. Mice lacking EP3 developed allergic inflammation that was much more pronounced than that in wild-type mice or mice deficient in other prostaglandin E receptor subtypes. Conversely, an EP3-selective agonist suppressed the inflammation. This suppression was effective when the agonist was administered 3 h after antigen challenge and was associated with inhibition of allergy-related gene expression. Thus, the PGE(2)-EP3 pathway is an important negative modulator of allergic reactions.     

Pathological function of prostaglandin E2 receptors in transitional cell carcinoma of the upper urinary tract

The prostaglandin E2 receptor, EP4 receptor (EP4R), plays an important role in the development of transitional cell carcinoma of the upper urinary tract (TCC-UUT). However, the clinical significance of other EP receptors (EP1R–3R) is not clear. Furthermore, the pathological function of EP receptors in such patients is not understood. In the present study, we examined the expression of EP1R–3R in 101 TCC-UUT tissues by immunohistochemistry. Furthermore, we defined the relationship between cyclooxygenase (COX)-2 and EP receptor expression, proliferation index (PI), microvessel density (MVD), and expression of metalloproteinase-2 (MMP-2), urokinase-type plasminogen activator (uPA), and exon v6 containing CD44 isoform (CD44 v6) by multivariate analysis. The expression of EP1R, EP2R, and EP3R was positive in 20 (19.8%), 26 (25.7%), and 14 (13.9%) tumor samples, respectively. Expression of these receptors was not associated with pathological findings or survival. COX-2 and EP4R were independently associated with MVD and MMP-2, and uPA or PI and MMP-2, respectively. Other EP receptors were not influenced by any factors. Our results suggest that EP1R–3R play a minimal role in cancer progression in patients with TCC-UUT. On the other hand, EP4R regulates tumor progression via cancer cell proliferation and MMP-2, distinct from COX-2.This study was not funded by any commercial organization. It was supported in part by a Grant-in-Aid from the Japanese Society of the Promotion of Science.     

Interaction of eosinophils with endothelial cells is modulated by prostaglandin EP4 receptors

Eosinophil extravasation across the endothelium is a key feature of allergic inflammation. Here, we investigated the role of PGE(2) and its receptor, E-type prostanoid receptor (EP)-4, in the regulation of eosinophil interaction with human pulmonary microvascular endothelial cells. PGE(2) and the EP4 receptor agonist ONO AE1-329 significantly reduced eotaxin-induced eosinophil adhesion to fibronectin, and formation of filamentous actin and gelsolin-rich adhesive structures. These inhibitory effects were reversed by a selective EP4 receptor antagonist, ONO AE3-208. PGE(2) and the EP4 agonist prevented the activation and cell-surface clustering of β2 integrins, and L-selectin shedding of eosinophils. Under physiological flow conditions, eosinophils that were treated with the EP4 agonist showed reduced adhesion to endothelial monolayers upon stimulation with eotaxin, as well as after TNF-α-induced activation of the endothelial cells. Selective activation of EP1, EP2, and EP3 receptors did not alter eosinophil adhesion to endothelial cells, whereas the EP4 antagonist prevented PGE(2) from decreasing eosinophil adhesion. Finally, eosinophil transmigration across thrombin- and TNF-α-activated endothelial cells was effectively reduced by the EP4 agonist. These data suggest that PGE(2) -EP4 signaling might be protective against allergic responses by inhibiting the interaction of eosinophils with the endothelium and might hence be a useful therapeutic option for controlling inappropriate eosinophil infiltration.     

PGE2受体EP2和EP4调节CIA小鼠脾B细胞表面分子和细胞因子表达

目的: 探讨前列腺素E₂(PGE₂)受体EP2和EP4在胶原诱导性关节炎(CIA)小鼠脾B细胞免疫调节中的作用。方法: 建立CIA小鼠模型,用CD19⁺ 免疫磁珠分选脾B细胞,流式细胞术检测MHCⅡ、CD80和CD86的表达,实时荧光定量PCR技术检测EPs 和细胞因子IFN-γ、TNF-α、IL-6、IL-4、IL-10和TGF-β的表达。结果: 小鼠脾B细胞表达EP的4个亚型,CIA模型小鼠EP2和EP4表达增加;EP2阻断剂可以降低MHCⅡ、CD80和CD86的表达,而EP4阻断剂对CD80没有明显影响;EP2和EP4阻断剂均可以降低IFN-γ、TNF-α 和IL-6 的表达(P<0.05或P<0.01),促进IL-10的表达(P<0.01或P<0.05),并可以分别促进IL-4和TGF-β的表达(P<0.01)。结论: PGE₂可通过EP2/EP4调节B细胞表面分子和细胞因子参与CIA发病,EP2/EP4有可能成为类风湿关节炎治疗的新靶点。     

Exploration of prostanoid receptor subtype regulating estradiol and prostaglandin E2 induction of spinophilin in developing preoptic area neurons

The prostaglandin E2 (PGE2) mediates estradiol-induced masculinization of sexual behavior in the rat during a perinatal sensitive period. PGE2 induces formation of dendritic spines on preoptic area (POA) neurons and this synaptic pattern change is associated with the ability to express male sexual behavior as an adult. Whether PGE2 is released from astrocytes or neurons in the developing POA is unknown. To further understanding of how PGE2 induces dendritic spine formation at the cellular level, we have explored the PGE2 receptor subtype mediating this response. There are four receptors for PGE2, EP1, EP2, EP3 and EP4, each having unique but interacting signal transduction profiles. Treatment of newborn female rats with the EP receptor agonists iloprost, butaprost and sulprostone indicated that stimulation of both the EP2 and EP3 receptors significantly increased spinophilin, a protein whose levels positively correlate to the presence of dendritic spines and masculinization of the POA. Use of antisense oligonucleotides against the mRNA for each receptor reveals that either EP2 or EP3 receptor knockdown reduces spinophilin in PGE2- or estradiol-treated females, whereas reducing EP1 or EP4 receptor levels by the same means has a smaller but also significant effect. A developmental profile of EP receptor expression indicates EP1 in particular is elevated for the first few days of life, corresponding to the critical period for masculinization, whereas mRNA levels for the other three receptors remain relatively constant.     

Leptin controls ketone body utilization in hypothalamic neuron

Neonatal hypoxic-ischemic encephalopathy (HIE) is a leading cause of severe and permanent neurologic disability after birth. The inducible cyclooxygenase COX-2, which along with COX-1 catalyzes the first committed step in prostaglandin (PG) synthesis, elicits significant brain injury in models of cerebral ischemia; however its downstream PG receptor pathways trigger both toxic and paradoxically protective effects. Here, we investigated the function of PGE₂ E-prostanoid (EP) receptors in the acute outcome of hypoxic-ischemic (HI) injury in the neonatal rat. We determined the temporal and cellular expression patterns of the EP1-4 receptors before and after HIE and tested whether modulation of EP1-4 receptor function could protect against cerebral injury acutely after HIE. All four EP receptors were expressed in forebrain neurons and were induced in endothelial cells after HIE. Inhibition of EP1 signaling with the selective antagonist SC-51089 or co-activation of EP2-4 receptors with the agonist misoprostol significantly reduced HIE cerebral injury 24 h after injury. These receptor ligands also protected brain endothelial cells subjected to oxygen glucose deprivation, suggesting that activation of EP receptor signaling is directly cytoprotective. These data indicate that the G-protein coupled EP receptors may be amenable to pharmacologic targeting in the acute setting of neonatal HIE.     

Dendritic cell infiltration pattern along the colorectal adenoma-carcinoma sequence

We have previously reported that the dendritic cell (DC) functional index cytokine interleukin-12 was significantly decreased in colorectal carcinoma (CRC) tissues. In this study, the DC infiltration pattern and the density of mature DCs (mDCs; labeled by anti-CD83 and anti-CD208) and immature DCs (iDCs; labeled by anti-CD1alpha) were characterized using immunohistochemistry (IHC) in tissue samples from 23 patients with CRC, 33 patients with colorectal adenoma (CRA), and 19 healthy controls. In addition, the DC function inhibitor cyclooxygenase-2 (COX-2) and the downstream signal molecule prostaglandin E2 (PGE2) and related receptors EP2/EP4 were measured by quantitative real-time PCR and double immunofluorescence staining. The IHC analyses revealed changed densities of mDCs and iDCs in the tumor microenvironment; in CRA and CRC, the density of mDCs was decreased, but the density of iDCs was gradually increased. Furthermore, the distribution patterns of DCs were also altered. In CRA, mDCs were abundantly distributed in the subepithelial stroma of the adenomatous mass. In CRC, the distribution of mDCs in the tumor stroma was not homogeneous, and mDCs residing in the stroma at invading edges were more frequently found compared with in the intratumoral stroma (P<0.05). Increased iDCs were found in the intratumoral mass in CRC, and some infiltrated into the malignant epithelium. By quantitative real-time PCR, a gradually increased level of COX-2 mRNA was demonstrated in the local tissues along the adenoma-carcinoma sequence, and double immunofluorescence staining showed a colocalization of PGE2 receptors EP2/EP4 with mDCs in the stroma of CRC. In conclusion, our current findings revealed an altered DC infiltration pattern along the adenoma-carcinoma sequence; gradually increased COX-2 expression might contribute to the DC functional defect.     

Prostaglandin E2 modulates dendritic cell function via EP2 and EP4 receptor subtypes

We have reported previously that PGE(2) inhibits dendritic cells (DC) functions. Because E prostanoid receptor (EPR) subtypes involved in this action are unknown, expression and functions of these receptors were examined in DC. Western blot and flow cytometry analyses showed that all EPRs were coexpressed in DC. In a dose-dependent manner, lipopolysaccharide (LPS) enhanced EP(2)R/EP(4)R but not EP(1)R/EP(3)R expressions. NS-398, a cyclooxygenase (COX)-2-selective inhibitor, suppressed LPS-enhanced EP(2)R/EP(4)R expression, suggesting that COX-2-issued prostaglandin E(2) (PGE(2)) modulates DC function through stimulation of specific EPR subtypes. Using selective agonists, we found that butaprost, an EP(2)R agonist, and PGE(1) alcohol, an EP(2)R and EP(2)R/EP(4)R agonist, inhibited major histocompatibility complex class II expression and enhanced interleukin-10 production from DC. However, no effect was observed with sulprostone and 17-phenyl-omega-trinor-PGE(2), selective agonists for EP(1)R and EP(1)R/EP(3)R, respectively. Treatment of DC with dibutyryl cyclic adenosine monophosphate (cAMP), an analog of cAMP, mimics PGE(2)-induced, inhibitory effects. Taken together, our data demonstrate that EP(2)R/EP(4)R are efficient for mediating PGE(2)-induced modulation of DC functions.     

PGE2 EP1 receptor exacerbated neurotoxicity in a mouse model of cerebral ischemia and Alzheimer's disease

Stroke and Alzheimer's disease (AD) are major age-related neurodegenerative diseases that may worsen the prognosis of each other. Our study was designed to delineate the prostaglandin E(2) EP1 receptor role in AD and in the setting of cerebral ischemia. Genetic deletion of the prostaglandin EP1 receptor significantly attenuated the more severe neuronal damage (38.5 ± 10.6%) and memory loss induced by ischemic insult observed in AD transgenic mice (percentage of viable hippocampal CA1 neurons: 11.2 ± 2.9%) when compared with wild type mice (45.1 ± 9.1%). In addition, we found that the amyloid plaques were reduced in EP1 deleted AD mice. β-amyloid-induced toxicity (18.0 ± 7.1%) and Ca(2+) response (91.8 ± 12.9%) were also reduced in EP1(-/-) neurons compared with control neurons in in vitro. Hence, EP1 might mediate most of the toxicity associated with cyclooxygenase-2 and contribute substantially to the cell death pathways in AD and stroke. Exploring potential therapeutic agent targeting EP1 receptor could potentially benefit treatments for stroke and AD patients.