Prostaglandin D2 (PGD2) is a major prostanoid, produced mainly by mast cells, in allergic diseases, including bronchial asthma. PGD2-induced vasodilatation and increased permeability are well-known classical effects that may be involved in allergic inflammation. Recently, novel functions of PGD2 have been identified. To date, D prostanoid receptor (DP) and chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) have been shown to be major PGD2-related receptors. These two receptors have pivotal roles mediating allergic diseases by regulating the functions of various cell types, such as TH2 cells, eosinophils, basophils, mast cells, dendritic cells, and epithelial cells. This review will focus on the current understanding of the roles of PGD2 and its metabolites in TH2 inflammation and the pathogenesis of bronchial asthma.
Asthma/*etiology/immunology ; Basophils/physiology ; Eosinophils/physiology ; Humans ; Mast Cells/physiology ; Prostaglandin D2/*physiology ; Receptors, Immunologic/physiology ; Receptors, Prostaglandin/physiology ; Th2 Cells/*immunology

Prostaglandin E2 (PGE2) is a cyclooxygenase metabolite of arachidonic acid. It acts as a bioactive lipid and plays an important role in regulating many biological processes. PGE2 binds to 4 different G protein-coupled receptors including prostaglandin E2 receptor subtypes EP1, EP2, EP3 and EP4. The EP4 receptor is widely expressed in most of human organs and tissues. Increasing evidence demonstrates that EP4 is essential for cardiovascular homeostasis and participates in the pathogenesis of many cardiovascular diseases. Here we summarize the role of EP4 in the regulation of cardiovascular function and discuss potential mechanisms by which EP4 is involved in the development of cardiovascular disorders with a focus on its effect on inflammation.
Cardiovascular Diseases ; physiopathology ; Cyclooxygenase 2 ; Dinoprostone ; physiology ; Humans ; Receptors, Prostaglandin E, EP4 Subtype ; physiology

Adipose tissue is the energy storage organ of the body, and excess energy is stored in adipocytes in the form of lipid droplets. The homeostasis of adipose tissue is the basis for the body to maintain normal metabolic activity. Prostaglandin E (PGE) is an important lipid mediator in the body. It is synthesized in almost all tissues and participates in the regulation of many physiological processes such as blood pressure, glucose and lipid metabolism, and inflammation. PGE is abundant in white adipose tissue, where it is involved in the regulation of fat metabolism. PGE plays its biological role through binding to four G protein coupled receptors (prostaglandin E receptors), including EP-1, -2, -3, and -4. The EP4 subtype has been proved to play an important role in adipogenesis and adipose metabolism: it could inhibit adipogenesis while it was activated, whereas its knockout could promote lipolysis. This review summarized the relationship between EP4 and adipose metabolism, hoping to identify new targets of drug development for metabolic disorders.
Adipocytes ; Adipogenesis ; Adipose Tissue ; metabolism ; Humans ; Receptors, Prostaglandin E, EP4 Subtype ; physiology

OBJECTIVETo investigate the effect of peroxisome proliferator-activated receptors (PPARs) activators on plasminogen activator inhibitor 1 (PAI-1) expression in human umbilical vein endothelial cells and elucidate a possible mechanism.

METHODSHuman umbilical vein endothelial cells (HUVECs) were obtained from normal fetus, and cultured conventionally. Then the HUVEC were exposed to fatty acids and prostaglandin J(2) in varying concentrations with fresh media. RT-PCR and ELISA were used to determine the expression of PPAR and PAI-1 in HUVECs. Transient co-transfection of PAI-1 promoter and PPARalpha gene or PPARgamma gene to ECV304 was performed.

RESULTSPPARalpha, PPARdelta and PPARgamma mRNA in HUVECs were detected by RT-PCR. Treatment of HUVECs with PPARalpha and PPARgamma activators-linolenic acid, linoleic acid, oleic acid and prostaglandin J(2), but not with stearic acid could augment PAI-I mRNA expression and protein secretion in a concentration-dependent manner. Proportional induction of PAI-1 promoter activity was observed through increasing amounts of PPARalpha DNA in HUVECs through a transient gene transfection assay, although the mRNA expression of the 3 subtypes of PPAR with their activators were not changed compared with controls.

CONCLUSIONSHUVECs express PPARs. PPARs activators may increase PAI-1 expression in endothelial cells (EC). Although PPARs expression was not enhanced after being stimulated by their activators in EC, the functionally active PPARalpha is probably involved in regulating PAI-1 expression in EC.

Cells, Cultured ; Fatty Acids ; pharmacology ; Gene Expression Regulation ; drug effects ; Humans ; Plasminogen Activator Inhibitor 1 ; genetics ; Prostaglandin D2 ; analogs & derivatives ; pharmacology ; RNA, Messenger ; analysis ; Receptors, Cytoplasmic and Nuclear ; genetics ; physiology ; Transcription Factors ; genetics ; physiology ; Transcription, Genetic ; drug effects

Prostaglandin (PG) E plays critical roles during pregnancy and parturition. Emerging evidence indicates that human labour is an inflammatory event. We sought to investigate the effect of PGE on the output of proinflammatory cytokines in cultured human uterine smooth muscle cells (HUSMCs) from term pregnant women and elucidate the role of subtypes of PGE receptors (EP, EP, EP and EP). After drug treatment and/or transfection of each receptor siRNA, the concentrations of inflammatory secreting factors in HUSMCs culture medium were detected by the corresponding ELISA kits. The results showed that, PGE increased interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα) output, decreased chemokine (c-x-c motif) ligand 8 (CXCL8) output in a dose-dependent manner, but had no effect on IL-1β and chemokine (c-c motif) ligand 2 (CCL-2) secretion of HUSMCs. EP/EP agonist 17-phenyl-trinor-PGE stimulated IL-6 and TNFα whilst suppressing IL-1β and CXCL8 output. The effects of 17-phenyl-trinor-PGE on IL-1β and CXCL8 secretion were remained whereas its effect on IL-6 and TNFα output did not occur in the cells with EP knockdown. The stimulatory effects of 17-phenyl-trinor-PGE on IL-6 and TNFα were remained whereas the inhibitory effects of 17-phenyl-trinor-PGE on IL-1β secretion was blocked in the cells with EP knockdown. Either of EP and EP agonists stimulated IL-1β and TNFα output, which was reversed by EP and EP siRNA, respectively. The inhibitors of phospholipase C (PLC) and protein kinase C (PKC) blocked EP/EP modulation of TNFα and CXCL8 output. PI3K inhibitor LY294002 and P38 inhibitor SB202190 blocked 17-phenyl-trinor-PGE-induced IL-1β and IL-6 output, respectively. The inhibitors of adenylyl cyclase and PKA prevented EP and EP stimulation of IL-1β and TNFα output, whereas PLC and PKC inhibitors blocked EP- and EP-induced TNFα output but not IL-1β output. Our data suggest that PGE receptors exhibit different effects on the output of various cytokines in myometrium, which can subtly modulate the inflammatory microenvironment in myometrium during pregnancy.
Cells, Cultured ; Chromones ; pharmacology ; Cytokines ; metabolism ; Female ; Humans ; Imidazoles ; pharmacology ; Inflammation ; Morpholines ; pharmacology ; Myocytes, Smooth Muscle ; cytology ; Myometrium ; cytology ; Phosphatidylinositol 3-Kinases ; Pregnancy ; Pyridines ; pharmacology ; Receptors, Prostaglandin E ; physiology

BACKGROUNDThe level of basic fibroblast growth factor (bFGF) increases rapidly after cerebral ischemia. However, the molecular mechanisms for the effects of bFGF on cerebral microvascular endothelial cells (cMVECs) have not yet been fully elucidated. In this study, a murine cMVEC line, bEnd.3, was employed to study the effects of bFGF on cyclooxygenase (COX) expression and its downstream effects in cMVECs.

METHODSAfter treatment with bFGF, RT-PCR and Western blotting analyses were carried out to evaluate the changes in COX-2 mRNA and protein expression, respectively. MTT assays were performed to measure cell proliferation. The prostaglandin E2 (PGE2) and vascular endothelial growth factor (VEGF) concentrations in the culture medium were measured by enzyme-linked immunosorbent assay (ELISA).

RESULTSCOX-2 mRNA and protein expressions in bEnd.3 cells were induced by bFGF in time- and dose-dependent manners. The bFGF-induced COX-2 upregulation led to enhanced PGE2 production by bEnd.3 cells, and this effect was abolished by the selective COX-2 inhibitor NS-398. bFGF also increased VEGF production by bEnd.3 cells, and this effect was blocked by NS-398 and the EP1/2 (PGE2 receptors) antagonist AH6809. Furthermore, exogenous PGE2 increased VEGF production in bEnd.3 cells, and AH6809 blocked this effect.

CONCLUSIONbFGF increases VEGF production in an autocrine manner by increasing COX-2-generated PGE2 in cMVECs and subsequently stimulates MVEC proliferation and angiogenesis.

Blotting, Western ; Cell Line ; Cell Proliferation ; drug effects ; Cyclooxygenase 2 ; genetics ; metabolism ; physiology ; Dinoprostone ; metabolism ; pharmacology ; Endothelial Cells ; cytology ; drug effects ; metabolism ; Enzyme-Linked Immunosorbent Assay ; Fibroblast Growth Factor 2 ; pharmacology ; Humans ; Receptors, Prostaglandin E ; antagonists & inhibitors ; Reverse Transcriptase Polymerase Chain Reaction ; Vascular Endothelial Growth Factor A ; metabolism ; Xanthones ; pharmacology

Lysophosphatidic acid (LPA) is a bioactive phospholipids and involves in various cellular events, including tumor cell migration. In the present study, we investigated LPA receptor and its transactivation to EGFR for cyclooxygenase-2 (COX-2) expression and cell migration in CAOV-3 ovarian cancer cells. LPA induced COX-2 expression in a dose-dependent manner, and pretreatment of the cells with pharmacological inhibitors of Gi (pertussis toxin), Src (PP2), EGF receptor (EGFR) (AG1478), ERK (PD98059) significantly inhibited LPA- induced COX-2 expression. Consistent to these results, transfection of the cells with selective Src siRNA attenuated COX-2 expression by LPA. LPA stimulated CAOV-3 cell migration that was abrogated by pharmacological inhibitors and antibody of EP2. Higher expression of LPA2 mRNA was observed in CAOV-3 cells, and transfection of the cells with a selective LPA2 siRNA significantly inhibited LPA-induced activation of EGFR and ERK, as well as COX-2 expression. Importantly, LPA2 siRNA also blocked LPA-induced ovarian cancer cell migration. Collectively, our results clearly show the significance of LPA2 and Gi/Src pathway for LPA-induced COX-2 expression and cell migration that could be a promising drug target for ovarian cancer cell metastasis.
Butadienes/pharmacology ; Cell Line, Tumor ; Cell Movement/drug effects/*physiology ; Cyclooxygenase 2/*biosynthesis ; Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors/metabolism ; Female ; Flavonoids/pharmacology ; GTP-Binding Protein alpha Subunits, Gi-Go/antagonists & inhibitors/*metabolism ; Humans ; Lysophospholipids/pharmacology ; Nitriles/pharmacology ; Ovarian Neoplasms/metabolism/*pathology ; Pertussis Toxin/pharmacology ; Protein-Tyrosine Kinases/antagonists & inhibitors/*metabolism ; Proto-Oncogene Proteins/antagonists & inhibitors/*metabolism ; Pyrimidines/pharmacology ; Receptor, Epidermal Growth Factor/antagonists & inhibitors/metabolism ; Receptors, Lysophosphatidic Acid/*metabolism ; Receptors, Prostaglandin E/metabolism ; Signal Transduction ; Transcriptional Activation ; Tyrphostins/pharmacology