Glucocorticoids modulate CD28 mediated pathways for interleukin 2 production in human T cells: evidence for posttranscriptional regulation.
In T cells stimulated through the T cell receptor (TCR), both cyclosporine (CsA) and glucocorticoids (GC) inhibit the transcription of the IL-2 gene. In these cells costimulation via the CD28 cell surface molecule further increases the transcription of IL-2 and stabilizes its mRNA, resulting in a 20-30 fold induction in IL-2 production. This pathway is relatively resistant to the inhibitory effect of CsA. In this study, we asked whether GC interfere with CD28-mediated costimulatory signals for T cell activation. Primary human T cells or Jurkat T cells were stimulated with anti-CD28 and phorbol myristate acetate (PMA) in the presence of dexamethasone (Dex, 10(-10)-10(-5) M). Dex inhibited both the mRNA for IL-2 and IL-2 production in a dose-dependent fashion (minimum effective dose 10(-9) M). In similar experiments employing anti-CD3 mAb and PMA, a 7-20 fold higher concentration of Dex was required to obtain comparable inhibition. To determine if transcriptional modulation is occurring, Jurkat T cells were transfected with a plasmid containing the IL-2 promoter linked to the chloramphenicol acetyl transferase reporter gene. Following stimulation with ionomycin and PMA, high doses (10(-6) M) of Dex inhibited the activity of the IL-2 promoter (approximately 50% inhibition). However, in the presence of anti-CD28 mAb, this promoter became resistant to Dex (< or = 10% inhibition). These results suggest that GC inhibit accessory pathways for IL-2 production via CD28 by predominantly posttranscriptional mechanisms. Inhibition of the CD28 pathway may be an important mechanism for the T cell directed immunosuppressive effects of low-to-moderate doses of GC.
Fessler
B J
BJ
Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, Maryland 20892, USA.
Paliogianni
F
F
Hama
N
N
Balow
J E
JE
Boumpas
D T
DT
D000906:Antibodies / Q000187:drug effects; D018106:CD28 Antigens / Q000276:immunology / Q000502:physiology*; D017252:CD3 Complex / Q000276:immunology; D003907:Dexamethasone / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics; D010703:Phorbol Esters / Q000494:pharmacology; D012323:RNA Processing, Post-Transcriptional / Q000502:physiology; D012333:RNA, Messenger / Q000502:physiology; D013601:T-Lymphocytes / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
D000906:Antibodies; D018106:CD28 Antigens; D017252:CD3 Complex; D005938:Glucocorticoids; D007376:Interleukin-2; D010703:Phorbol Esters; D012333:RNA, Messenger; D003907:Dexamethasone