title: Inhibition of phosphodiesterase type IV suppresses human immunodeficiency virus type 1 replication and cytokine production in primary T cells: involvement of NF-kappaB and NFAT.
abstract: Rolipram, a phosphosdiesterase type IV-specific inhibitor, prevented p24 antigen release from anti-CD3-activated human immunodeficiency virus (HIV)-infected T cells and CD4(+)-cell depletion associated with viral replication in a dose-responsive manner but minimally inhibited T-cell proliferation. Moreover, rolipram reduced the production of tumor necrosis factor alpha (TNF-alpha) and interleukin-10 (IL-10) by HIV-infected T cells. The transcriptional ability of a luciferase reporter gene under control of the HIV long terminal repeat, induced by phorbol myristic acetate plus ionomycin or by TNF-alpha, in primary T and Jurkat cells was also inhibited by rolipram. Rolipram inhibited NF-kappaB and NFAT activation induced by T-cell activation in Jurkat and primary T cells, as measured by transient transfection of reporter genes and electrophoretic mobility shift assays. Exogenous addition of TNF-alpha in the presence of rolipram restored NF-kappaB but not NFAT activation or p24 release. Addition of dibutyryl-cyclic AMP (dBcAMP) mimicked the effects of rolipram on p24 antigen release, NF-kappaB activation, and TNF-alpha secretion, but it did not affect NFAT activation or IL-10 production. The protein kinase A inhibitor KT5720 prevented the inhibition of TNF-alpha secretion but not that of HIV type 1 (HIV-1) replication caused by rolipram. Our data indicate that blockade of phosphodiesterase type IV could be of benefit against HIV-1 disease by modulating cytokine secretion and transcriptional regulation of HIV replication, and they suggest an important role of NFAT in HIV replication in primary T cells. Some of those activities cannot be ascribed solely to its ability to increase cAMP.
authors.affiliation: Department of Immunology, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Navarro
authors.forename: C
authors.initials: C
authors.lastname: Punzón
authors.forename: J L
authors.initials: JL
authors.lastname: Jiménez
authors.forename: E
authors.initials: E
authors.lastname: Fernández-Cruz
authors.forename: A
authors.initials: A
authors.lastname: Pizarro
authors.forename: M
authors.initials: M
authors.lastname: Fresno
authors.forename: M A
authors.initials: MA
authors.lastname: Muñoz-Fernández
mesh_terms: D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D016325:HIV Long Terminal Repeat / Q000502:physiology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis; D016328:NF-kappa B / Q000502:physiology*; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000502:physiology*; D011760:Pyrrolidinones / Q000494:pharmacology*; D020889:Rolipram; D013601:T-Lymphocytes / Q000502:physiology / Q000821:virology*; D014157:Transcription Factors / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D004268:DNA-Binding Proteins; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D010727:Phosphoric Diester Hydrolases; D020889:Rolipram