Effect of phosphodiesterase 7 inhibitor ASB16165 on development and function of cytotoxic T lymphocyte.
In the present study, possible role of phosphodiesterase 7 (PDE7) in development and function of cytotoxic T lymphocyte (CTL) was examined using ASB16165, a specific inhibitor for PDE7. ASB16165 inhibited generation of CTL activity in mixed lymphocyte reaction (MLR), in which splenocytes from C57BL/6N mice were stimulated with those from BALB/c mice. Flow cytometric analysis revealed that ASB16165 suppressed induction of activated CD4+ as well as CD8+ T cells in MLR. In cell division analyses using 5-carboxyfluorescein diacetate succinimide ester (CFSE), ASB16165 was shown to markedly inhibit proliferation of CD4+ and CD8+ T cells. In addition, ASB16165 reduced effector function of CTL, while the effect was less than that observed in CTL induction in MLR. Forskolin and dibutyryl cAMP also inhibited both the induction and effector function of CTL. PDE4 inhibitor rolipram showed similar but weaker inhibition for the development and proliferation of CD8+ T cells compared with ASB16165, and failed to impair effector function of CTL. These findings suggest that PDE7 but not PDE4 has the major role in induction and function of CTL in mice, and that the effect might be mediated by elevation of intracellular cAMP level. ASB16165 may be useful for treatment of the diseases in which CTL has a pathogenic role (e.g. autoimmune diseases).
Kadoshima-Yamaoka
Kumiko
K
Biomedical Research Laboratories, Asubio Pharma Co., Limited, Osaka 618-8503, Japan.
Murakawa
Masao
M
Goto
Megumi
M
Tanaka
Yoshitaka
Y
Inoue
Hidekazu
H
Murafuji
Hidenobu
H
Hayashi
Yasuhiro
Y
Nagahira
Kazuhiro
K
Miura
Kenju
K
Nakatsuka
Takashi
T
Chamoto
Kenji
K
Fukuda
Yoshiaki
Y
Nishimura
Takashi
T
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007202:Indicators and Reagents; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D020889:Rolipram / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects*; D016559:Tacrolimus / 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; D007166:Immunosuppressive Agents; D007202:Indicators and Reagents; D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; D013876:Thiophenes; D005576:Colforsin; D003994:Bucladesine; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7; D020889:Rolipram; D016559:Tacrolimus