Potential role of phosphodiesterase 7 in human T cell function: comparative effects of two phosphodiesterase inhibitors.
Even though the existence of phosphodiesterase (PDE) 7 in T cells has been proved, the lack of a selective PDE7 inhibitor has confounded an accurate assessment of PDE7 function in such cells. In order to elucidate the role of PDE7 in human T cell function, the effects of two PDE inhibitors on PDE7A activity, cytokine synthesis, proliferation and CD25 expression of human peripheral blood mononuclear cells (PBMC) were determined. Recombinant human PDE7A was obtained and subjected to cyclic AMP-hydrolysis assay. PBMC of Dermatophagoides farinae mite extract (Df)-sensitive donors were stimulated with the relevant antigen or an anti-CD3 monoclonal antibody (MoAb). PBMC produced IL-5 and proliferated in response to stimulation with Df, while stimulation with anti-CD3 MoAb induced CD25 expression and messenger RNA (mRNA) synthesis of IL-2, IL-4 and IL-5 in peripheral T cells. A PDE inhibitor, T-2585, which suppressed PDE4 isoenzyme with high potency (IC50 = 0.00013 microM) and PDE7A with low potency (IC50 = 1.7 microM) inhibited cytokine synthesis, proliferation and CD25 expression in the dose range at which the drug suppressed PDE7A activity. A potent selective inhibitor of PDE4 (IC50 = 0.00031 microM), RP 73401, which did not effectively suppress PDE7A (IC50 > 10 microM), inhibited the Df- and anti-CD3 MoAb-stimulated responses only weakly, even at 10 microM. PDE7 may play a critical role in the regulation of human T cell function, and thereby selective PDE7 inhibitors have the potential to be used to treat immunological and inflammatory disorders.
Nakata
A
A
Discovery Research Laboratory, Tanabe Seiyaku Co. Ltd, Saitama, Japan. a-nakata@tanabe.co.jp
Ogawa
K
K
Sasaki
T
T
Koyama
N
N
Wada
K
K
Kotera
J
J
Kikkawa
H
H
Omori
K
K
Kaminuma
O
O
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D000818:Animals; D039741:Antigens, Dermatophagoides; D001549:Benzamides / Q000494:pharmacology*; D019556:COS Cells; D002455:Cell Division; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7; D003546:Cysteine Endopeptidases / Q000276:immunology; D015870:Gene Expression / Q000187:drug effects; D006023:Glycoproteins / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics; D015848:Interleukin-5 / Q000096:biosynthesis / Q000235:genetics; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010793:Phthalazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D039741:Antigens, Dermatophagoides; D001549:Benzamides; D006023:Glycoproteins; D007376:Interleukin-2; D015848:Interleukin-5; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D010793:Phthalazines; D011725:Pyridines; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; C118221:T 2585; D015847:Interleukin-4; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7; C517458:PDE7A protein, human; D003546:Cysteine Endopeptidases; C087566:piclamilast