Prostaglandin E2 and other cyclic AMP-elevating agents modulate IL-2 and IL-2R alpha gene expression at multiple levels.
cAMP is an intracellular second messenger that conveys inhibitory signals for T cell activation and clonal proliferation. cAMP also inhibits the production of IL-2 and IL-2R alpha-chain expression. To determine the mechanisms of this inhibition, human peripheral blood T lymphocytes were stimulated with anti-CD3 mAb, PHA, PMA, or ionomycin, alone or in combination. cAMP elevation by PGE2, cholera toxin, or the cell-permeable analogue 8-bromo-cAMP inhibited the tyrosine phosphorylation of a protein of 100 kDa. This inhibition was associated with decreased IL-2 production and IL-2R alpha expression at both the protein product and the mRNA levels. Nuclear run-off assays showed that the inhibitory effect of cAMP on IL-2 and IL-2R alpha gene expression is mediated at the transcriptional level. H-8, an inhibitor of protein kinase A, reversed the inhibitory effect of cAMP on nuclear transcription of the IL-2 gene, suggesting that this is mediated through activation of protein kinase A. Post-transcriptionally, cAMP elevation decreased the t1/2 of IL-2 mRNA by more than 50%. These data indicate that cAMP inhibits cell membrane, cytoplasmic, and nuclear events associated with T cell activation and highlight the complexities of its action of lymphocyte function.
Anastassiou
E D
ED
Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
Paliogianni
F
F
Balow
J P
JP
Yamada
H
H
Boumpas
D T
DT
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D015152:Blotting, Northern; D002772:Cholera Toxin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology*; D015232:Dinoprostone / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis*; D007546:Isoquinolines / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D010835:Phytohemagglutinins; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D012313:RNA / Q000032:analysis; D012323:RNA Processing, Post-Transcriptional; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis*; D013755:Tetradecanoylphorbol Acetate; D014158:Transcription, Genetic / Q000187:drug effects
D007376:Interleukin-2; D007546:Isoquinolines; D010835:Phytohemagglutinins; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D015124:8-Bromo Cyclic Adenosine Monophosphate; D012313:RNA; C053177:N-(2-(methylamino)ethyl)-5-isoquinolinesulfonamide; D002772:Cholera Toxin; D000242:Cyclic AMP; D011493:Protein Kinase C; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate