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Selective activation of cAMP-dependent protein kinase type I inhibits rat natural killer cell cytotoxicity.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 1997 Feb 28; Vol. 272 (9), pp. 5495-500. - Publication Year :
- 1997
-
Abstract
- 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.
- Subjects :
- Animals
Calcium metabolism
Cell Survival drug effects
Cyclic AMP pharmacology
Cyclic AMP-Dependent Protein Kinase Type II
Cytotoxicity, Immunologic drug effects
Enzyme Activation
Interleukin-2 pharmacology
Ionomycin pharmacology
Lymphocytes enzymology
Lymphocytes metabolism
Protein Kinase C metabolism
Rats
Tetradecanoylphorbol Acetate pharmacology
Theophylline analogs & derivatives
Theophylline pharmacology
Carrier Proteins pharmacology
Cyclic AMP-Dependent Protein Kinases metabolism
Cyclic AMP-Dependent Protein Kinases pharmacology
Intracellular Signaling Peptides and Proteins
Isoenzymes metabolism
Killer Cells, Natural cytology
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 272
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 9038153
- Full Text :
- https://doi.org/10.1074/jbc.272.9.5495