title: Cyclic nucleotide phosphodiesterases (PDE) 3 and 4 in normal, malignant, and HTLV-I transformed human lymphocytes.
abstract: Intracellular cyclic AMP, determined in part by cyclic nucleotide phosphodiesterases (PDEs), regulates proliferation and immune functions in lymphoid cells. Total PDE, PDE3, and PDE4 activities were measured in phytohemagglutinin (PHA)-activated peripheral blood mononuclear cells (PBMC-PHA), normal natural killer (NK) cells, Jurkat and Kit225-K6 leukemic T-cells, T-cell lines transformed with human T-lymphotropic virus (HTLV)-I (a retrovirus that causes adult T-cell leukemia/lymphoma) and HTLV-II (a nonpathogenic retrovirus), normal B-cells, and B-cells transformed with Epstein-Barr virus (EBV). All cells exhibited PDE3 and PDE4 activities but in different proportions. In EBV-transformed B cells, PDE4 was much higher than PDE3. HTLV-I+ T-cells differed significantly from other T-lymphocyte-derived cells in also having a higher proportion of PDE4 activities, which apparently were not related to selective induction of any one PDE4 mRNA (judged by reverse transcription-polymerase chain reaction) or expression of the HTLV-I regulatory protein Tax. In MJ cells (an HTLV-I+ T-cell line), Jurkat cells, and PBMC-PHA cells, the tyrosine kinase inhibitor herbimycin A strongly inhibited PDE activity. Growth of MJ cells was inhibited by herbimycin A and a protein kinase C (PKC) inhibitor, and was arrested in G1 by rolipram, a specific PDE4 inhibitor. Proliferation of several HTLV-I+ T-cell lines, PBMC-PHA, and Jurkat cells was inhibited differentially by forskolin (which activates adenylyl cyclase), the selective PDE inhibitors cilostamide and rolipram, and the nonselective PDE inhibitors pentoxifylline and isobutyl methylxanthine. These results suggest that PDE4 isoforms may be functionally up-regulated in HTLV-I+ T-cells and may contribute to the virus-induced proliferation, and that PDEs could be therapeutic targets in immune/inflammatory and neoplastic diseases.
authors.affiliation: Pulmonary-Critical Care Medicine Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1434, USA.
authors.forename: D
authors.initials: D
authors.lastname: Ekholm
authors.forename: J C
authors.initials: JC
authors.lastname: Mulloy
authors.forename: G
authors.initials: G
authors.lastname: Gao
authors.forename: E
authors.initials: E
authors.lastname: Degerman
authors.forename: G
authors.initials: G
authors.lastname: Franchini
authors.forename: V C
authors.initials: VC
authors.lastname: Manganiello
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D001402:B-Lymphocytes / Q000201:enzymology; D016227:Benzoquinones; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed / Q000201:enzymology; D002472:Cell Transformation, Viral; D005576:Colforsin / Q000494:pharmacology; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016356:Gene Products, tax / Q000096:biosynthesis / Q000378:metabolism; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D019169:Jurkat Cells / Q000201:enzymology; D007694:Killer Cells, Natural / Q000201:enzymology; D047029:Lactams, Macrocyclic; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D008214:Lymphocytes / Q000201:enzymology* / Q000821:virology; D047428:Protein Kinase Inhibitors; D011809:Quinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017828:Rifabutin / Q000031:analogs & derivatives; D013601:T-Lymphocytes / Q000201:enzymology
chemical_list: D016227:Benzoquinones; D004791:Enzyme Inhibitors; D016356:Gene Products, tax; D007376:Interleukin-2; D047029:Lactams, Macrocyclic; D047428:Protein Kinase Inhibitors; D011809:Quinones; D012333:RNA, Messenger; D005576:Colforsin; D017828:Rifabutin; C020754:herbimycin; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4