prostaglandin-d2 and Cell-Transformation--Viral

Invasive cytotrophoblasts play a key role in the development of human placenta and is therefore essential for subsequent development of the embryo. Human implantation is characterized by a major trophoblastic invasion that offers a unique model of a controlled and oriented tumor-like process. The ligand-activated nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) modulates cell growth and differentiation and might be therefore considered as a tumor suppressor. We have recently reported that PPARgamma, in synergy with its dimerization partner retinoid X receptor (RXR)alpha, controls the invasion of human primary cytotrophoblasts. Because these cells are unable to replicate in culture, we have, in the present study, transformed these primary cells with the simian virus 40 large T antigen for studying the role of PPARgamma in cell invasion process. Our results show that the cell line human invasive proliferative extravillous cytotrophoblast (HIPEC) 65 expressed markers of human invasive primary cytotrophoblast as determined by immunocytochemistry, immunobloting and real-time RT-PCR, and were highly invasive in vitro. We have next studied the role of PPARgamma/RXRalpha heterodimers in cell proliferation and invasion. Our results show that PPARgamma and RXRalpha are co-expressed by HIPEC 65 and that, as commonly observed, activation of PPARgamma/RXRalpha heterodimers with the specific PPARgamma agonist rosiglitazone induced lipid droplet accumulation as revealed by oil red O staining. Treatment with rosiglitazone or with the natural PPARgamma agonist 15-deoxy-delta-(12,14) PGJ2 did not modify cell growth, but interestingly, activation of PPARgamma by this synthetic (rosiglitazone) or natural (15d-PGJ2) ligand markedly inhibited cell invasion in a concentration-dependent manner. Finally, we showed that other potential natural PPARgamma ligand such as oxidized-but not native-low-density lipoprotein inhibited cell invasion. This proliferative and invasive human cytotrophoblast cell line from extravillous origin provides a new tool for studying specifically the role of PPARgamma in the control of cell invasion.

Topics: Antigens, Polyomavirus Transforming; Cell Division; Cell Transformation, Viral; Cells, Cultured; DNA Primers; Dose-Response Relationship, Drug; Humans; Immunoblotting; Nuclear Proteins; Prostaglandin D2; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Retinoid X Receptors; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Rosiglitazone; Simian virus 40; Thiazoles; Thiazolidinediones; Transcription Factors; Transfection; Trophoblasts

We studied the effect of prostaglandins (PGs) A1, delta 7-A1, A2, D2, E1, E2, F2 alpha, J2 and delta 12-J2 on the replication of herpes simplex virus type 2 (HSV-2). Of nine PGs we tested, delta 7-PGA1 was found to have the most potent inhibitory effect; 50% inhibitory dose (ID50) was 0.35 microgram/ml in the plaque reduction assays and HSV-2 induced protein synthesis was strongly suppressed at 0.5 microgram/ml whereas at this dose, the protein synthesis of uninfected cells was not inhibited. Dot blot hybridization analysis revealed that delta 7-PGA1 and delta 12-PGJ2 inhibited the primary transcription of HSV-2. Thus we suggest that those PGs are primarily active at the level of mRNA synthesis.

Topics: Cell Transformation, Viral; DNA Replication; Fibroblasts; Humans; Kinetics; Prostaglandin D2; Prostaglandins; Prostaglandins A, Synthetic; Prostaglandins D; Simplexvirus; Structure-Activity Relationship; Virus Replication

Acquired immune deficiency syndrome (AIDS)-associated virus is thought to be transmitted effectively through semen during sexual activities from male to male or from male to female. Prostaglandin (PG) E2 is one of the immunosuppressive compounds present in high concentrations in human semen. We, therefore, investigated direct effects of PGE2 and other PGs on AIDS-associated virus infection and replication in vitro. First, type III human T-lymphotropic virus (HTLV-III) was used to infect a T-cell line (MT-4) in culture. PGE2 (10 nM to 10 microM) added to the culture medium enhanced the production of infectious virus in a dose-dependent fashion. In the presence of 5 microM PGE2, 2.5-fold more virus were released from the infected MT-4 cells as compared to untreated control cells on day 3 after infection. Second, when we used an HTLV-III continuous-producer cell line (Molt-4/HTLV-III), PGE2 and PGD2 added to the culture medium increased the number of viruses released from Molt-4/HTLV-III cells. Other PGs such as PGF2 alpha and 13,14-dihydro-15-keto PGE2 did not affect the replication of HTLV-III in this system. These results indicate that some PGs including seminal PGs enhance the AIDS-associated virus replication in vitro. We propose that PGE2 in human semen might directly facilitate the infection of AIDS-associated virus and cause the efficient transmission of the virus during sexual activities.

Topics: Cell Transformation, Viral; Cells, Cultured; Deltaretrovirus; Dinoprost; Dinoprostone; Dose-Response Relationship, Drug; Humans; Prostaglandin D2; Prostaglandins D; Prostaglandins E; Prostaglandins F; Semen; T-Lymphocytes; Virus Replication

Several prostaglandins including PGE1, PGE2 and PGF2 alpha affect the course of viral infection. There is no report about the effect of PGD2 on virus infections, although there are reports about its antitumor effect. In the present study, we examined the effect of prostaglandin D2 (PGD2) on the growth of herpes simplex virus (HSV) type 1 in human amnion FL cells. HSV yields were inhibited when FL cells were treated with PGD2 and infected with HSV at various multiplicity of infection (MOI). Treatment with PGD2 after virus adsorption inhibited HSV yields, although treatment of FL cells with PGD2 before virus adsorption did not inhibit them. PGD2 reduced the mortality of the mice infected with HSV. In conclusion, it is suggested that PGD2 has an antiherpetic activity in vitro and in vivo.

Topics: Amnion; Animals; Antiviral Agents; Cell Transformation, Viral; Cells, Cultured; Dose-Response Relationship, Drug; Female; Herpes Simplex; Humans; Mice; Prostaglandin D2; Prostaglandins D; Simplexvirus