A selective type 4 phosphodiesterase inhibitor, T-440, modulates intracellular cyclic AMP level and interleukin-2 production of Jurkat cells.
Effect of a selective type 4 phosphodiesterase (PDE4) inhibitor, T-440, on intracellular cyclic AMP (cAMP) level and interleukin (IL)-2 production of Jurkat cells was investigated. T-440 suppressed both cAMP-PDE activities in cytosolic and membrane fractions of Jurkat cells. Intracellular cAMP level in Jurkat cells was elevated by PGE2 and forskolin but not by T-440. T-440, however, significantly enhanced the increase of cAMP by PGE2. PGE2 and forskolin inhibited IL-2 production of Jurkat cells stimulated with concanavalin A. T-440 by itself did not affect IL-2 production, but significantly enhanced the effect of PGE2 on IL-2 production. The increase of intracellular cAMP by T-440, PGE2, forskolin and T-440 plus PGE2 was well correlated with the inhibition of IL-2 production. These results indicate that IL-2 production of T cells is regulated by cAMP-PDE activity. Immunomodulatory effects of PDE4 inhibitors like T-440 should further be explored in vivo.
Kaminuma
O
O
Lead Optimization Research Laboratory, Tanabe Seiyaku Co., Ltd., Toda, Saitama, Japan.
Mori
A
A
Wada
K
K
Kikkawa
H
H
Ikezawa
K
K
Suko
M
M
Okudaira
H
H
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D003208:Concanavalin A; D000242:Cyclic AMP / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis*; D019169:Jurkat Cells / Q000187:drug effects / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology*
D000276:Adjuvants, Immunologic; D007376:Interleukin-2; D009281:Naphthalenes; D010726:Phosphodiesterase Inhibitors; D011728:Pyridones; C101791:T 440; D003208:Concanavalin A; D005576:Colforsin; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D015232:Dinoprostone