title: Antiproliferative activity of cyclopentenone prostaglandins in early HTLV-1 infection is independent of IL-2 and is associated with HSP70 induction.
abstract: Cyclopentenone prostaglandins PGA1 and PGJ2 can inhibit the growth of HTLV-1 infected cord blood-derived human mononuclear cells (CBMC), both after acute infection and in chronically infected, immortalized cells. When CBMC were exposed to HTLV-1 infection by coculturing with lethally irradiated, virus-donor allogeneic MT-2 cells, they underwent a proliferative response, that peaked within the first week and then declined. PG treatment did not inhibit the initial proliferation (day 4) of cocultured CBMC, while multiple treatments with PGA1 and more efficiently with PGJ2, suppressed the late cell proliferation (from day 8 onward). The pharmacological effects of PGA1 and PGJ2 were reversible and therefore multiple treatments were required to maintain their antiproliferative activity. Increasing concentrations (20, 40, 80 IU/ml) of recombinant IL-2 did not affect the virus-associated proliferative response of CBMC, and exogenous IL-2 did not revert the antiproliferative effect of both PGs. Arrest of proliferation in cocultured CBMC occurred concomitantly with expression of high levels of HSP70 in the cells. In fact, though HSP70 expression was induced early (day 5) after exposure to HTLV-1, its expression was further increased after multiple PG treatments and high levels were found when the antiproliferative effect of PGs became manifest. Since HSP70 protein family is involved in the control of cell cycle as well as in antigen processing and presentation during the immune response against tumor cells and pathogens, the persistent expression of this protein in PG-treated cocultures suggested that, beside inhibiting the growth of virus-infected cells, HSP70 expression might play a role in modulating the immune function of CBMC. However, unlike in most virus infection models, in which cyclopentenone PGs exert clear antiviral effects by inhibiting the synthesis and maturation of virus proteins, no antiviral activity was found in this model of infection. This strongly suggests that the main effect of these PGs against HTLV-1 infected cells consists in inhibiting proliferation in vitro without affecting viral expression.
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Italy.
authors.forename: C
authors.initials: C
authors.lastname: D'Onofrio
authors.forename: O
authors.initials: O
authors.lastname: Franzese
authors.forename: A
authors.initials: A
authors.lastname: De Marco
authors.forename: E
authors.initials: E
authors.lastname: Bonmassar
authors.forename: C
authors.initials: C
authors.lastname: Amici
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001798:Blood Proteins / Q000096:biosynthesis; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D015490:HTLV-I Infections / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D006360:Heat-Shock Proteins / Q000096:biosynthesis*; D015368:Human T-lymphotropic virus 1; D006801:Humans; D007376:Interleukin-2 / Q000502:physiology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000382:microbiology; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D011453:Prostaglandins / Q000502:physiology; D011454:Prostaglandins A / Q000494:pharmacology*; D012313:RNA / Q000096:biosynthesis; D013997:Time Factors
chemical_list: D000998:Antiviral Agents; D001798:Blood Proteins; D006360:Heat-Shock Proteins; D007376:Interleukin-2; D011453:Prostaglandins; D011454:Prostaglandins A; C037112:9-deoxy-delta-9-prostaglandin D2; D012313:RNA; D015230:Prostaglandin D2; C100573:prostaglandin A1