Differential expression of cyclic nucleotide phosphodiesterase 3 and 4 activities in human T cell clones specific for myelin basic protein.
Little is known concerning the relative distribution and function of the different cyclic nucleotide phosphodiesterases (PDEs) in lymphocytes. Recent reports, however, have indicated that specific PDE4 inhibitors were effective in treatment of experimental allergic encephalomyelitis, an animal model of multiple sclerosis. The therapeutic effect of PDE4 inhibitors is thought to be related to inhibition of autoreactive CD4+ T cells specific for myelin basic protein (MBP) or other myelin proteins. Human autoreactive CD4+ T lymphocyte clones (TCC), specific for the immunodominant MBP epitope (amino acids 83-99), contain PDE3 and PDE4, two PDEs that exhibit a high affinity for cAMP. Amplification of TCC mRNA by reverse transcription-PCR indicated that TCC PDE3 mRNA was of the PDE3B, not PDE3A, subtype. Different TCC contained different proportions of PDE3 and PDE4, and their activities increased during Ag (MBP) stimulation. Specific PDE3 (cilostamide) and PDE4 (rolipram) inhibitors suppressed [3H]thymidine incorporation in TCC. Since it is believed that many autoimmune diseases are at least partially mediated by autoreactive CD4+ T cells, these observations may have important implications not only for the treatment of multiple sclerosis but also for other autoimmune diseases.
Ekholm
D
D
Pulmonary-Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA.
Hemmer
B
B
Gao
G
G
Vergelli
M
M
Martin
R
R
Manganiello
V
V
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D002999:Clone Cells; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology; D004676:Myelin Basic Protein / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D010446:Peptide Fragments / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000096:biosynthesis* / Q000187:drug effects; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D014316:Tritium
D016056:Immunodominant Epitopes; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; C104448:myelin basic protein 83-99; D014316:Tritium; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517287:PDE3A protein, human; C517291:PDE3B protein, human; D013936:Thymidine