Dexamethasone inhibits the early steps of antigen receptor signaling in activated T lymphocytes.
Glucocorticoids are very effective in inhibiting inflammatory and immune responses. In particular, the synthetic analogue dexamethasone has been shown to inhibit T cell proliferation and IL-2 production by interfering with the transcriptional activation of the IL-2 gene. The experiments described in this report were performed to determine whether dexamethasone treatment affects the early steps of TCR signal transduction in T cell hybrids. Incubation of murine T cell hybrids in the presence of dexamethasone prevents the intracellular calcium increase that normally follows TCR/CD3 aggregation. Accordingly, dexamethasone treatment decreases inositol phosphates production and phospholipase-Cgamma1 tyrosine phosphorylation induced after TCR/CD3 stimulation. Dexamethasone has no effect on cell surface expression of TCR-associated structures nor does it inhibit calcium responses induced by a heterologous G protein-coupled muscarinic receptor, suggesting that this hormone analogue specifically inhibits the TCR signaling pathway at a postreceptor stage. We also show that inhibition of membrane proximal events by dexamethasone requires binding to the intracellular glucocorticoid receptor and de novo protein synthesis. When splenic T cells were assayed, only activated but not resting T cells were found to be sensitive to this new immunomodulatory effect of dexamethasone. These findings indicate that in addition to their previously described inhibitory effects on cytokine gene transcription, glucocorticoids block IL-2 production in activated T cells by interfering with an early step of the signal transduction cascade initiated by TCR/CD3 cross-linking.
Baus
E
E
Animal Physiology Laboratory, Molecular Biology Department, Free University of Brussels, Rhode-St-Genèse, Belgium.
Andris
F
F
Dubois
P M
PM
Urbain
J
J
Leo
O
O
D000818:Animals; D017252:CD3 Complex / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D005938:Glucocorticoids / Q000494:pharmacology*; D006727:Hormone Antagonists / Q000494:pharmacology; D007295:Inositol Phosphates / Q000378:metabolism; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D015735:Mifepristone / Q000494:pharmacology; D019000:Phosphotyrosine / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
D017252:CD3 Complex; D005938:Glucocorticoids; D006727:Hormone Antagonists; D007295:Inositol Phosphates; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D019000:Phosphotyrosine; D015735:Mifepristone; D003907:Dexamethasone; D002118:Calcium