Expression and regulation of mRNA for distinct isoforms of cAMP-specific PDE-4 in mitogen-stimulated and leukemic human lymphocytes.
We reported previously that the gene for PDE-1B1 is induced in isolated human peripheral blood lymphocytes (HPBL) following mitogenic stimulation (Jiang, X., Li, J., Paskind, M., and Epstein, P.M. [1996] Proc. Natl. Acad. Sci. USA 93, 11,236-11,241). Using reverse transcription-polymerase chain reaction (RT-PCR), we investigated possible changes in the expression of the four genes for cAMP-specific phosphodiesterase (PDE-4A-D) in HPBL under the same conditions. Isolated, quiescent HPBL express mRNA for PDE-4B as the principal transcript. Following mitogenic stimulation with phytohemagglutinin (PHA), mRNA for PDE-4A and PDE-4D are clearly induced. HPBL appear not to express PDE-4C under resting or stimulated conditions. The PHA induced increase in PDE-1B1, PDE-4A, and PDE-4D mRNA is mimicked by incubation of HPBL with dibutyryl cAMP (dBcAMP) and 1-methyl-3-isobutylxanthine (IBMX). The B-lymphoblastoid cell line, RPMI 8392, and the T-leukemic cell line, Molt 4, express PDE-4A mRNA as the most abundant transcript, but incubation with dBcAMP and IBMX induces an increase in the expression of mRNA for PDE-4B in both of these cell lines, and in PDE-4D3 in the RPMI 8392 cell line. These studies demonstrate that expression of mRNA for PDE-1B1 and some of the subtypes of PDE-4 are induced in HPBL following mitogenic stimulation, possibly secondarily to elevation of cAMP induced by the mitogen. As already indicated for PDE-1B1, some of these subtypes of PDE-4 might also provide additional therapeutic targets for treatment of immunoproliferative disorders and immune dysfunction.
Jiang
X
X
Department of Pharmacology, University of Connecticut Health Center, Farmington 06030, USA.
Paskind
M
M
Weltzien
R
R
Epstein
P M
PM
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000235:genetics*; D001402:B-Lymphocytes; D003994:Bucladesine / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D015458:Leukemia, T-Cell; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000201:enzymology*; D008934:Mitogens / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010835:Phytohemagglutinins / Q000494:pharmacology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D012333:RNA, Messenger / Q000032:analysis*; D013601:T-Lymphocytes; D014407:Tumor Cells, Cultured
D007527:Isoenzymes; D008934:Mitogens; D010726:Phosphodiesterase Inhibitors; D010835:Phytohemagglutinins; D012333:RNA, Messenger; D003994:Bucladesine; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D015056:1-Methyl-3-isobutylxanthine