Selective activation of cAMP-dependent protein kinase type I inhibits rat natural killer cell cytotoxicity.
The present study examines the expression and involvement of cAMP-dependent protein kinase (PKA) isozymes in cAMP-induced inhibition of natural killer (NK) cell-mediated cytotoxicity. Rat interleukin-2-activated NK cells express the PKA alpha-isoforms RIalpha, RIIalpha, and Calpha and contain both PKA type I and type II. Prostaglandin E2, forskolin, and cAMP analogs all inhibit NK cell lysis of major histocompatibility complex class I mismatched allogeneic lymphocytes as well as of standard tumor target cells. Specific involvement of PKA in the cAMP-induced inhibition of NK cell cytotoxicity is demonstrated by the ability of a cAMP antagonist, (Rp)-8-Br-adenosine 3',5'-cyclic monophosphorothioate, to reverse the inhibitory effect of complementary cAMP agonist (Sp)-8-Br-adenosine 3',5'-cyclic monophosphorothioate. Furthermore, the use of cAMP analog pairs selective for either PKA isozyme (PKA type I or PKA type II), shows a preferential involvement of the PKA type I isozyme, indicating that PKA type I is necessary and sufficient to completely abolish killer activatory signaling leading to NK cell cytotoxicity. Finally, combined treatment with phorbol ester and ionomycin maintains NK cell cytotoxicity and eliminates the cAMP-mediated inhibition, demonstrating that protein kinase C and Ca2+-dependent events stimulate the cytolytic activity of NK cells at a site distal to the site of cAMP/PKA action.
Torgersen
K M
KM
Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway. k.m.torgersen@basalmed.uio.no
Vaage
J T
JT
Levy
F O
FO
Hansson
V
V
Rolstad
B
B
Taskén
K
K
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D000242:Cyclic AMP / Q000494:pharmacology; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism* / Q000494:pharmacology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004789:Enzyme Activation; D007376:Interleukin-2 / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D015759:Ionomycin / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000166:cytology*; D008214:Lymphocytes / Q000201:enzymology / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology
D002352:Carrier Proteins; D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; C015482:protein kinase modulator; C053907:8-cyclopentyl-1,3-dimethylxanthine; D015759:Ionomycin; D013806:Theophylline; D000242:Cyclic AMP; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium