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

Histaminergic neurons solely originate from the tuberomammillary nucleus (TMN) in the posterior hypothalamus and send widespread projections to the whole brain. Experiments in rats show that histamine release in the central nervous system is positively correlated with wakefulness and the histamine released is 4 times higher during wake episodes than during sleep episodes. Endogeneous prostaglandin E2 and orexin activate histaminergic neurons in the TMN to release histamine and promote wakefulness. Conversely, prostaglandin D2 and adenosine inhibit histamine release by increasing GABA release in the TMN to induce sleep. This paper reviews the effects and mechanisms of action of the histaminergic system on sleep-wake regulation, and briefly discusses the possibility of developing novel sedative-hypnotics and wakefulness-promoting drugs related to the histaminergic system.
Adenosine ; physiology ; Animals ; Dinoprostone ; physiology ; Histamine ; metabolism ; physiology ; Hypothalamic Area, Lateral ; physiology ; Intracellular Signaling Peptides and Proteins ; physiology ; Neurons ; physiology ; Neuropeptides ; physiology ; Orexins ; Prostaglandin D2 ; physiology ; Sleep ; physiology ; Wakefulness ; physiology ; gamma-Aminobutyric Acid ; metabolism

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

delta12-Prostaglandin (PG) J2 is known to elicit an anti-neoplastic effects via apoptosis induction. Previous study showed delta12-PGJ2-induced apoptosis utilized caspase cascade through cytochrome c-dependent pathways in HeLa cells. In this study, the cellular mechanism of delta12-PGJ2- induced apoptosis in HeLa cells, specifically, the role of two mitochondrial factors; bcl-2 and apoptosis-inducing factor (AIF) was investigated. Bcl-2 attenuated delta12-PGJ2-induced caspase activation, loss of mitochondrial transmembrane potential (delta psi m), nuclear fragmentation, DNA laddering, and growth curve inhibition for approximately 24 h, but not for longer time. AIF was not released from mitochondria, even if the delta psi m was dissipated. One of the earliest events observed in delta12-PGJ2-induced apoptotic events was dissipation of delta psi m, the process known to be inhibited by bcl-2. Pre-treatment of z-VAD- fmk, the pan-caspase inhibitor, resulted in the attenuation of delta psi m depolarization in delta12-PGJ2- induced apoptosis. Up-regulation of Sox-4 protein by delta12-PGJ2 was observed in HeLa and bcl-2 overexpressing HeLa B4 cell lines. Bcl-2 overexpression did not attenuate the expression of Sox-4 and its expression coincided with other apoptotic events. These results suggest that delta12-PGJ2 induced Sox-4 expression may activate another upstream caspases excluding the caspase 9-caspase 3 cascade of mitochondrial pathway. These and previous findings together suggest that delta12-PGJ2-induced apoptosis in HeLa cells is caspase-dependent, AIF-independent events which may be affected by Sox-4 protein expression up-regulated by delta12-PGJ2.
Amino Acid Chloromethyl Ketones/pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects/*physiology ; Caspases/physiology ; Cytochromes c/physiology ; Female ; Flavoproteins/metabolism/*physiology ; Hela Cells ; High Mobility Group Proteins/*physiology ; Humans ; Membrane Proteins/metabolism/*physiology ; Mitochondria/metabolism/physiology ; Prostaglandin D2/*pharmacology ; Protein Transport/physiology ; Proto-Oncogene Proteins c-bcl-2/biosynthesis/*physiology ; Research Support, Non-U.S. Gov't ; Trans-Activation (Genetics) ; Trans-Activators/*physiology

Cyclopentenone prostaglandins (PGs) have antiproliferative activity on various tumor cell growth in vitro. Particularly, 9-deoxy-(9,12)-13,14-dihydro PGD2( delta12-PGJ2) was reported for its antineoplastic and apoptotic effects on various cancer cells, but its mechanism inducing apoptosis is still not clear. In this study, we have characterized apoptosis induced by delta12-PGJ2in HeLa cells. Treatment of delta12-PGJ2induced apoptosis as indicated by DNA fragmentation, chromatin condensation, and formation of apoptotic body. We also observed release of cytochrome c from mitochondria and activation of caspase cascade including caspase-3, -8, and -9. And the pan-caspase inhibitor z-Val-Ala-Asp (OMe) fluoromethyl-ketone (z-VAD-fmk) and Q-Val-Asp (OMe)-CH2-OPH (Q-VD (OMe)-OPH) prevented cell death induced by delta12-PGJ2 showing participation of caspases in this process. However, protein expression level of Bcl-2 family was not altered by delta12-PGJ2, seems to have no effect on HeLa cell apoptosis. And ZB4, an antagonistic Fas-antibody, exerted no effect on the activation of caspase 8 indicating that Fas receptor-ligand interaction was not involved in this pathway. Treatment of delta12-PGJ2 also leads to suppression of nuclear factor kappaB (NF-kappaB) as indicated by nuclear translocation of p65/RelA and c-Rel and its DNA binding ability analyzed by EMSA. Taken together, our results suggest that delta12-PGJ2-induced apoptosis in HeLa cell utilized caspase cascade without Fas receptor-ligand interaction and accompanied with NF-kappaB inactivation.
Antigens, CD95/metabolism ; Apoptosis/*physiology ; Caspases/metabolism ; Cytochromes c/*metabolism ; Hela Cells ; Human ; NF-kappa B/metabolism ; Prostaglandin D2/*analogs & derivatives/*metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism

BACKGROUNDExperimental evidence indicates that cyclooxygenase-2 (COX-2) plays a critical role in blastocyst implantation; however, little is known of the role of COX-2 in unexplained recurrent spontaneous abortion (URSA).

METHODSWe evaluated the expression level and potential signaling pathway of COX-2 in 30 cases of URSA who were excluded the abnormality of chromosomes, anatomy, endocrine, infectious, autoimmune diseases and in 30 normal pregnancies.

RESULTSThe mRNA and the protein expression level of COX-2 in the URSA group (-0.238 +/- 0.848, 0.368 +/- 0.089, respectively) were significantly lower than that in the control group (1.943 +/- 3.845, 1.046 +/- 0.108, respectively) (both, P < 0.01). The expression of prostaglandins PGF(2a), PGD(2), PGE(2), and PGI(2), in the URSA group ((2326.0 +/- 295.6) pg/ml, (2164.0 +/- 240.5) pg/ml, (238.7 +/- 26.4) pg/ml, (2337.0 +/- 263.0) pg/ml, respectively) were significantly lower than that in the control group ((3450.0 +/- 421.7) pg/ml, (3174.0 +/- 415.6) pg/ml, (323.5 +/- 43.8) pg/ml, (3623.0 +/- 460.4) pg/ml, respectively) (P < 0.05). The mRNA expression level of PPARbeta and RXRalpha (0.859 +/- 0.653, -0.172 +/- 0.752, respectively) in URSA group was significantly lower than that in the control group (1.554 +/- 1.735, 0.777 +/- 2.482, respectively) (both P< 0.05). The mRNA and protein expression levels of vascular endothelial growth factor-A (VEGF-A) in the URSA group (2.010 +/- 1.522, 0.35 +/- 0.46) was significantly lower than that in the control group (4.569 +/- 2.430, 0.750 +/- 0.350) (both P < 0.05).

CONCLUSIONSCOX-2 and the COX-2-derived PGI(2) signaling pathway possibly play an important role in successful embryo implantation, and their decreased expression may result in URSA. The decreased expression may influence the expression of VEGF-A which interferes with placental angiogenesis causing failure of embryo implantation, leading to spontaneous abortion.

Abortion, Habitual ; enzymology ; genetics ; Adult ; Blotting, Western ; Cyclooxygenase 2 ; genetics ; metabolism ; Dinoprost ; metabolism ; Dinoprostone ; metabolism ; Enzyme-Linked Immunosorbent Assay ; Epoprostenol ; metabolism ; Female ; Humans ; Polymerase Chain Reaction ; Pregnancy ; Prostaglandin D2 ; metabolism ; Signal Transduction ; genetics ; physiology ; Vascular Endothelial Growth Factor A ; metabolism

Animals ; Autoimmune Diseases ; drug therapy ; immunology ; Cytokines ; biosynthesis ; Immunohistochemistry ; Ligands ; Myocarditis ; drug therapy ; immunology ; NF-kappa B ; metabolism ; PPAR gamma ; analysis ; physiology ; Prostaglandin D2 ; analogs & derivatives ; therapeutic use ; Rats ; Rats, Inbred Lew

Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a ligand-activated transcription factor and plays an important role in growth, differentiation, and inflammation in different tissues. In this study, we investigated the effects of 15d-PGJ2, a high-affinity ligand of PPAR-gamma, on dedifferentiation and on inflammatory responses such as COX-2 expression and PGE2 production in rabbit articular chondrocytes with a focus on ERK-1/-2, p38 kinase, and PPAR-gamma activation. We report here that 15d-PGJ2 induced dedifferentiation and/or COX-2 expression and subsequent PGE2 production. 15d-PGJ2 treatment stimulated activation of ERK-1/-2, p38 kinase, and PPAR-gamma. Inhibition of ERK-1/-2 with PD98059 recovered 15d-PGJ2-induced dedifferentiation and enhanced PPAR-gamma activation, whereas inhibition of p38 kinase with SB203580 potentiated dedifferentiation and partially blocked PPAR-gamma activation. Inhibition of ERK-1/-2 and p38 kinase abolished 15d-PGJ2-induced COX-2 expression and subsequent PGE2 production. Our findings collectively suggest that ERK-1/-2 and p38 kinase oppositely regulate 15d-PGJ2-induced dedifferentiation through a PPAR-gamma-dependent mechanism, whereas COX-2 expression and PGE2 production is regulated by ERK-1/-2 through a PPAR-gamma-independent mechanism but not p38 kinase in articular chondrocytes. Additionally, these data suggest that targeted modulation of the PPAR-gamma and mitogen-activated protein kinase pathway may offer a novel approach for therapeutic inhibition of joint tissue degradation.
Animals ; Cartilage, Articular/*cytology ; Cell Differentiation/drug effects ; Chondrocytes/cytology/*drug effects/metabolism ; Cyclooxygenase 2/*analysis ; Dinoprostone/biosynthesis ; Mitogen-Activated Protein Kinase 1/*physiology ; Mitogen-Activated Protein Kinase 3/*physiology ; PPAR gamma/*physiology ; Prostaglandin D2/*analogs & derivatives/pharmacology ; Rabbits ; p38 Mitogen-Activated Protein Kinases/*physiology

During chronic inflammatory response, mono- cytes/macrophages produce 92-kDa matrix metalloproteinase-9 (MMP-9), which may contribute to their extravasation, migration and tissue remodeling. Activation of peroxisome proliferator- activated factor receptor-gamma (PPAR-gamma) has been shown to inhibit MMP-9 activity. To evaluate whether ox-LDL, a PPAR-gamma activator, inhibits PMA-induced MMP-9 expression and activity, and if so, whether CD36 and PPAR-gamma are involved in this process, we investigated the effect of ox-LDL on MMP-9 expression and activity in PMA-activated human monocytic cell line U937. PMA-induced MMP-9 expression and activity were suppressed by the treatment with ox-LDL (50 micrigram/ml) or PPAR-gamma activators such as troglitazone (5 micrometer), ciglitazone (5 micrometer), and 15d- PGJ2 (1 micrometer) for 24 h. This ox-LDL or PPAR-gamma activator-mediated inhibition of micrometer P-9 activity was diminished by the pre-treatment of cells with a blocking antibody to CD36, or PGF2a (0.3 micrometer), which is a PPAR-gamma inhibitor, as well as overexpression of a dominant-negative form of CD36. Taken together, these results suggest that ox-LDL suppresses PMA-induced MMP-9 expression and activity through CD36-mediated activation of PPAR-gamma.
Antibodies, Blocking/pharmacology ; Antigens, CD36/immunology/*physiology ; Cells, Cultured ; Chromans/pharmacology ; Gelatinase B/antagonists & inhibitors/genetics/*metabolism ; Humans ; Lipoproteins, LDL/pharmacology/*physiology ; Monocytes/drug effects/*enzymology/metabolism ; NF-kappa B/antagonists & inhibitors ; PPAR gamma/*metabolism ; Prostaglandin D2/*analogs & derivatives/pharmacology ; RNA, Messenger/analysis/metabolism ; Research Support, Non-U.S. Gov't ; Tetradecanoylphorbol Acetate/antagonists & inhibitors/pharmacology ; Thiazolidinediones/pharmacology ; Transcription, Genetic/drug effects

Apoptosis ; Cell Line, Tumor ; Colorectal Neoplasms ; drug therapy ; pathology ; HT29 Cells ; Humans ; PPAR gamma ; genetics ; physiology ; PTEN Phosphohydrolase ; Phosphatidylinositol 3-Kinases ; antagonists & inhibitors ; Phosphoric Monoester Hydrolases ; analysis ; Prostaglandin D2 ; analogs & derivatives ; pharmacology ; Protein-Serine-Threonine Kinases ; analysis ; Proto-Oncogene Proteins ; analysis ; Proto-Oncogene Proteins c-akt ; Thiazolidinediones ; pharmacology ; Tumor Suppressor Proteins ; analysis ; Up-Regulation