ASB16165, a novel inhibitor for phosphodiesterase 7A (PDE7A), suppresses IL-12-induced IFN-gamma production by mouse activated T lymphocytes.
Phosphodiesterase 7A (PDE7A) has been suggested to be involved in activation of T lymphocytes. In the present study, a possible involvement of PDE7A in function of preactivated T cells (i.e. T lymphoblasts) was investigated using ASB16165, an inhibitor for PDE7A. ASB16165, which has an IC50 value of 15 nM for human PDE7A, suppressed IL-12-induced IFN-gamma production by T lymphoblasts which have been prepared by stimulating mouse T cells with anti-CD3 antibody. In the same experiment, rolipram, a PDE4-specific inhibitor, showed similar effect, while calcineurin antagonist FK506 did not. Forskolin (an adenylyl cyclase activator) and dibutyryl cAMP also inhibited the IL-12-induced IFN-gamma synthesis. Rp-8-Br-cAMPS, an inhibitor of protein kinase A (PKA), reduced the suppressive effect of ASB16165 on the IFN-gamma production by T lymphoblasts. The rescue of IFN-gamma production by Rp-8-Br-cAMPS was also observed in the inhibition by rolipram and forskolin. These findings suggest that PDE7A may regulate function of activated T cells in a cAMP/PKA-dependent manner, and that PDE4 might share the role. The data in our study also indicate that PDE7 inhibitors such as ASB16165 will be beneficial for the patients with immunological disorders.
Kadoshima-Yamaoka
Kumiko
K
Biomedical Research Laboratories, Asubio Pharma Co., Limited, Osaka, Japan.
Murakawa
Masao
M
Goto
Megumi
M
Tanaka
Yoshitaka
Y
Inoue
Hidekazu
H
Murafuji
Hidenobu
H
Nagahira
Asako
A
Hayashi
Yasuhiro
Y
Nagahira
Kazuhiro
K
Miura
Kenju
K
Nakatsuka
Takashi
T
Chamoto
Kenji
K
Fukuda
Yoshiaki
Y
Nishimura
Takashi
T
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7 / Q000037:antagonists & inhibitors*; D007371:Interferon-gamma / Q000378:metabolism*; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D058988:Phosphodiesterase 4 Inhibitors; D011720:Pyrazoles / Q000494:pharmacology*; D020889:Rolipram / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D013873:Thionucleotides / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology*
C539237:1-cyclohexyl-N-(6-(4-hydroxy-1-piperidinyl)-3-pyridinyl)-3-methyl-1H-thieno(2,3-c)pyrazole-5-carboxamide; C105593:8-bromoadenosine-3',5'-cyclic monophosphorothioate; D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D058988:Phosphodiesterase 4 Inhibitors; D011720:Pyrazoles; D013873:Thionucleotides; D013876:Thiophenes; D018664:Interleukin-12; D015124:8-Bromo Cyclic Adenosine Monophosphate; D007371:Interferon-gamma; D017868:Cyclic AMP-Dependent Protein Kinases; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7; C517459:Pde7a protein, mouse; D020889:Rolipram