The dual role of the cAMP-dependent protein kinase C alpha subunit in T-cell receptor-triggered T-lymphocytes effector functions.
In order to directly evaluate the role of the cAMP-dependent protein kinase (PKA) catalytic (C) subunit in T-cell receptor- (TCR) triggered cytotoxic T-lymphocytes (CTL) effector functions, cells were studied after pretreatment with antisense oligomers complementary to mRNA for the C alpha or C beta subunits. C alpha subunit is shown to be predominantly expressed in CTL. In some experiments the pretreatment of the CTL with the C alpha antisense, but not with the control or C beta antisense oligomers, resulted in the inhibition of cAMP-independent PKA activity without significantly affecting the level of total cAMP-inducible PKA activity. In parallel assays, CTL which were pretreated with the C alpha antisense oligomer had enhanced antigen-bearing target cell-triggered-, anti-TCR monoclonal antibody-triggered-, and phorbol 12-myristate 13-acetate/A23187-triggered exocytosis of granules, as well as enhanced antigen-specific cytotoxicity. In contrast, the TCR-triggered gamma-interferon mRNA expression and gamma-interferon secretion were inhibited in C alpha antisense-pretreated CTL. These results suggest that the C alpha subunit of PKA may have a dual role in regulation of T-lymphocytes effector functions: (i) it may down-regulate TCR-triggered protein-synthesis independent responses such as cytotoxicity and exocytosis, thereby counteracting TCR-triggered activation even in the absence of the second messenger, cAMP, and (ii) the C alpha subunit activity is likely to be required for the nuclear and/or cytoplasmic events in CTL's activation involved in lymphokine synthesis and secretion.
D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D002999:Clone Cells; D003602:Cytotoxicity, Immunologic; D015870:Gene Expression / Q000187:drug effects; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D007700:Kinetics; D046911:Macromolecular Substances; D051379:Mice; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism*; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism / Q000502:physiology*; D013329:Structure-Activity Relationship; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*
D046911:Macromolecular Substances; D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D012313:RNA; D007371:Interferon-gamma; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D011493:Protein Kinase C