Phosphodiesterase 7A inhibitor ASB16165 suppresses proliferation and cytokine production of NKT cells.
A possible involvement of phosphodiesterase 7A (PDE7A) in proliferation and function of NKT cells was examined using ASB16165, a selective inhibitor for PDE7A. Stimulation of isolated murine NKT cells with anti-CD3 antibody plus IL-2 induced not only cell proliferation but production of cytokines including IFN-gamma, TNF-alpha, IL-17 and IL-22. ASB16165 significantly inhibited the CD3/IL-2-stimulated cell proliferation and production of all the cytokines examined. Forskolin (an activator of adenylyl cyclase) and dibutyryl cAMP also exerted inhibitory effects on the cell proliferation and cytokine production of NKT cells. In addition, Rp-8-Br-cAMPS, an inhibitor of protein kinase A (PKA), reversed the suppressive effects of ASB16165 against NKT cells. These results suggest that PKA/cAMP as well as PDE7A is involved in regulation of cell proliferation and cytokine production of NKT cells, and that the inhibitory effects of ASB16165 in NKT cells shown here are mediated by increase in cellular cAMP level. Our findings also raise the possibility that PDE7A inhibitor including ASB16165 may be useful for treatment of the diseases in which NKT cells have pathogenic roles.
Goto
Megumi
M
Biomedical Research Laboratories, Asubio Pharma Co., Limited, Osaka, Japan.
Murakawa
Masao
M
Kadoshima-Yamaoka
Kumiko
K
Tanaka
Yoshitaka
Y
Inoue
Hidekazu
H
Murafuji
Hidenobu
H
Hayashi
Yasuhiro
Y
Miura
Kenju
K
Nakatsuka
Takashi
T
Nagahira
Kazuhiro
K
Chamoto
Kenji
K
Fukuda
Yoshiaki
Y
Nishimura
Takashi
T
D000818:Animals; D049109:Cell Proliferation; D000242:Cyclic AMP / Q000378:metabolism; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000187:drug effects* / Q000276:immunology; D011720:Pyrazoles / 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; D016207:Cytokines; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D013876:Thiophenes; D000242:Cyclic AMP; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7; C517459:Pde7a protein, mouse