Cyclic nucleotide phosphodiesterases (PDE) 3 and 4 in normal, malignant, and HTLV-1 transformed human lymphocytes

Intracellular cyclic AMP, determined in part by cyclic nucleotide phosphodi esterases (PDEs), regulates proliferation and immune functions in lymphoid cells. Total PDE, PDE3, and PDE4 activities were measured in phytohemagglut inin (PHA)-activated peripheral blood mononuclear cells (PBMC-PHA), normal natural killer (NK) cells, Jurkat and Kit225-K6 leukemic T-cells, T-cell li nes transformed with human T-lymphotropic virus (HTLV)-1 (a retrovirus that causes adult T cell leukemia/lymphoma) and HTLV-II (a nonpathogenic retrov irus), normal B-cells, and B-cells transformed with Epstein Barr virus (EBV ). All cells exhibited PDES and PDE4 activities but in different proportion s. In EBV-transformed B cells, PDE4 was much higher than PDE3. HTLV-I+ T-ce lls differed significantly from other T-lymphocyte-derived cells in also ha ving a higher proportion of PDE4 activities, which apparently were not rela ted to selective induction of any one PDE4 mRNA (judged by reverse transcri ption-polymerase chain reaction) or expression of the HTLV-I regulatory pro tein 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 ac tivity. Growth of MJ cells was inhibited by herbimycin A and a protein kina se C (PKC) inhibitor, and was arrested in G(1) by rolipram, a specific PDE4 inhibitor. Proliferation of several HTLV-I+ T-cell lines, PBMC-PHA, and Ju rkat cells was inhibited differentially by forskolin (which activates adeny lyl cyclase), the selective PDE inhibitors cilostamide and rolipram, and th e nonselective PDE inhibitors pentoxifylline and isobutyl methylxanthine. T hese 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 neoplast ic diseases. BIOCHEM PHARMACOL 58;6: 935-950, 1999. (C) 1999 Elsevier Scien ce Inc.