Stimulus-specific inhibition of IL-5 by cAMP-elevating agents and IL-10 reveals differential mechanisms of action.
Interleukin-5 (IL-5) is a Th2 cytokine, which is implicated in the pathogenesis of eosinophilic diseases such as asthma. Peripheral blood mononuclear cells (PBMC), costimulated with phorbol 12-myristate 13-acetate (PMA) plus phytohemagglutinin (PHA) or activating antibodies to the CD3 and CD28 T-lymphocyte surface markers, produced similar patterns of IL-5 expression. However, in PMA + PHA-treated cells, 8-bromo-cAMP and PGE(2) did not affect IL-5 expression, whereas in CD3 + CD28-stimulated cells, almost total repression was observed. IL-10 failed to inhibit IL-5 mRNA from PMA + PHA-treated cells, yet reduced release by 40%. By contrast, IL-10 totally inhibited CD3 + CD28-induced IL-5 release and inhibited mRNA by 50-60%. These results highlight important biological differences in the induction of IL-5 by the nonspecific stimulus PMA + PHA and the more physiological CD3 + CD28 costimulation. Finally, the potential for downregulating Th2 responses by cAMP-elevating agents or IL-10 is demonstrated and a significant role for posttranscriptional mechanisms in the inhibition by IL-10 is suggested.
Staples
K J
KJ
Department of Thoracic Medicine, Imperial College of Science, Technology, and Medicine, National Heart and Lung Institute, Dovehouse Street, London, SW3 6LY, United Kingdom.
Bergmann
M
M
Barnes
P J
PJ
Newton
R
R
D018106:CD28 Antigens / Q000494:pharmacology; D017252:CD3 Complex / Q000494:pharmacology; D018925:Chemokines / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis*; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology*; D015848:Interleukin-5 / Q000037:antagonists & inhibitors* / Q000235:genetics; D010835:Phytohemagglutinins / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D018106:CD28 Antigens; D017252:CD3 Complex; D018925:Chemokines; D015848:Interleukin-5; D010835:Phytohemagglutinins; D012333:RNA, Messenger; D016753:Interleukin-10; D000242:Cyclic AMP; D013755:Tetradecanoylphorbol Acetate