Abstract
cAMP inhibits biochemical events leading to T cell activation by triggering of an inhibitory protein kinase A (PKA)-C-terminal Src kinase pathway assembled in lipid rafts. In this study, we demonstrate that activation of PKA type I by Sp-8-bromo-cAMPS (a cAMP agonist) has profound inhibitory effects on Ag-specific immune responses in peripheral effector T cells. Activation of PKA type I inhibits both cytokine production and proliferative responses in both CD4(+) and CD8(+) T cells in a concentration-dependent manner. The observed effects of cAMP appeared to occur endogenously in T cells and were not dependent on APC. The inhibition of responses was not due to apoptosis of specific T cells and was reversible by a PKA type I-selective cAMP antagonist. This supports the notion of PKA type I as a key enzyme in the negative regulation of immune responses and a potential target for inhibiting autoreactive T cells.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antigen-Presenting Cells / drug effects
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Antigen-Presenting Cells / enzymology
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Antigen-Presenting Cells / immunology
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Antigens, Bacterial / immunology
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Antigens, Bacterial / physiology*
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Apoptosis / immunology
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / enzymology
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CD4-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / drug effects
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CD8-Positive T-Lymphocytes / enzymology
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CD8-Positive T-Lymphocytes / immunology
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Cyclic AMP / agonists
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Cyclic AMP / analogs & derivatives
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Cyclic AMP / biosynthesis
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Cyclic AMP / physiology
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Cyclic AMP-Dependent Protein Kinase Type II
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Cyclic AMP-Dependent Protein Kinases / physiology*
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Cyclic GMP / analogs & derivatives*
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Cyclic GMP / pharmacology
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Cytokines / antagonists & inhibitors*
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Cytokines / biosynthesis*
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Dinoprostone / pharmacology
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Down-Regulation / immunology*
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Enterotoxins / antagonists & inhibitors
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Enterotoxins / immunology
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Enterotoxins / physiology*
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Enzyme Activation / drug effects
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Enzyme Activation / immunology
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Epitopes, T-Lymphocyte / physiology*
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Humans
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Interferon-gamma / antagonists & inhibitors
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Interferon-gamma / biosynthesis
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Interleukin-2 / antagonists & inhibitors
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Interleukin-2 / biosynthesis
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Lymphocyte Activation / drug effects
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Lymphocyte Activation / immunology*
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins pp60(c-src)*
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Thionucleotides
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / biosynthesis
Substances
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Antigens, Bacterial
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Cytokines
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Enterotoxins
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Epitopes, T-Lymphocyte
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Interleukin-2
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Thionucleotides
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Tumor Necrosis Factor-alpha
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8-bromoguanosino-3',5'-cyclic monophosphorothioate
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enterotoxin B, staphylococcal
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Interferon-gamma
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Cyclic AMP
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Matk protein, mouse
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Protein-Tyrosine Kinases
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Proto-Oncogene Proteins pp60(c-src)
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Cyclic AMP-Dependent Protein Kinase Type II
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Cyclic AMP-Dependent Protein Kinases
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Cyclic GMP
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Dinoprostone