Control of human T-lymphocyte interleukin-2 production by a cAMP-dependent pathway.
Cyclic AMP has long been proposed to be the intracellular second messenger that conveys the inhibitory signal for T-cell activation and clonal T-cell proliferation. The present study further explores the mechanism by which the cAMP pathway regulates human T-lymphocyte interleukin-2 (IL-2) production and T-cell blastogenesis. Activation of adenylate cyclase, inhibition of cAMP-dependent phosphodiesterase, or the direct addition of the cell-permeable cAMP analog, 8-N3-cAMP, increased occupancy of intracellular cAMP receptors, inhibited IL-2 production, and reduced T-cell proliferation. However, inhibition of cAMP-dependent protein phosphorylation by N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide (H-8), a cell-permeable inhibitor of cyclic nucleotide-dependent protein kinase, partially restored IL-2 production. Our data support the conclusion that the cAMP pathway conveys an inhibitory signal for IL-2 production and T-cell proliferation via an integral protein phosphorylation step.
Averill
L E
LE
Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106.
Stein
R L
RL
Kammer
G M
GM
D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D001386:Azides / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D001386:Azides; D007166:Immunosuppressive Agents; D007375:Interleukin-1; D007376:Interleukin-2; D005576:Colforsin; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; C017042:8-azidoadenosine-3',5'-monophosphate; D000001:Calcimycin; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D013755:Tetradecanoylphorbol Acetate