Effects of rolipram and CI-930 on IL-2 mRNA transcription in human Jurkat cells.
Interleukin-2 (IL-2) is a major mediator of immunologic responses involved in many chronic inflammatory diseases. We have investigated the effects of rolipram, a PDE-IV inhibitor, and CI-930, a PDE-III inhibitor, on IL-2 gene expression in the Jurkat human T cell line. The immunosuppressant cyclosporin A (CsA) was included as a positive control. Jurkat cells were stimulated with 1 microgram/ml phytohemagglutinin (PHA) and 50 ng/ml phorbol 12-myristate, 13-acetate (PMA) for 6 h, and mRNA was analyzed using reverse transcription and polymerase chain reaction (RT/PCR). IL-2 transcription was greatly inhibited by 1 microM CsA, whereas neither 10 microM rolipram nor 10 microM CI-930 had any effect on steady-state levels of IL-2 mRNA. Therefore, PDE inhibitors do not affect synthesis of IL-2 mRNA in this model of activated T cells. This is of interest given that these agents inhibit the proliferation of primary T cells. For murine splenocytes stimulated by 2.5 micrograms/ml concanavalin A (Con A), rolipram had an IC50 of 0.09 microM and CI-930 an IC50 of 4.4 microM. These concentrations are below those at which IL-2 mRNA synthesis was shown to be unaffected. Therefore, the mechanism by which inhibitors of PDE-III and PDE-IV affect T cell proliferation is not likely to involve suppression of IL-2 mRNA transcription.
Lewis
G M
GM
Wyeth-Ayerst Research, Princeton, NJ 08453.
Caccese
R G
RG
Heaslip
R J
RJ
Bansbach
C C
CC
D000818:Animals; D002470:Cell Survival; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020889:Rolipram; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D007376:Interleukin-2; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D011760:Pyrrolidinones; D012333:RNA, Messenger; C042528:4,5-dihydro-6-(4-(imidazol-1-yl)phenyl)-5-methyl-3(2H)-pyridazinone; D020889:Rolipram; D013755:Tetradecanoylphorbol Acetate