Dexamethasone and prostaglandin E2 modulate T-cell receptor signaling through a cAMP-independent mechanism.
One possible explanation for the link between stress and increased incidence of infection can be attributed to concomitant increases in levels of glucocorticoids (GS) and prostaglandin E2 (PGE2), both of which possess potent immunoregulatory activities. We have previously demonstrated that concentrations of PGE2 and the synthetic glucocorticoid, dexamethasone (DEX), which individually do not inhibit human T-cell responsiveness to anti-CD3 monoclonal antibody (mAb), act synergistically to inhibit IL-2 secretion and subsequent T-cell proliferation. In the present paper, we demonstrate that treatment of anti-CD3 mAb-stimulated T-cells with low (10(-8) and 10(-9) M) concentrations of DEX and PGE2 results in the inhibition of steady-state levels of IL-2 mRNA. Initial studies to elucidate the biochemical mechanisms involved indicate that the inhibitory effects of DEX and PGE2 cannot be correlated with increased levels of intracellular cAMP or the induction of apoptosis. However, the data indicate that DEX and PGE2 when added together interrupt anti-CD3 mAb-induced tyrosine phosphorylation of substrate proteins. Furthermore, the synergistic effect of DEX and PGE2 is mimicked by agonists for the cAMP-independent EP3 subtype of the PGE2 receptor. These data suggest that DEX and PGE2 elicit cAMP-independent signaling pathways which interact to inhibit the T-cell receptor-linked signal transduction cascade in anti-CD3 mAb-stimulated T-cells.
Elliott
L H
LH
Department of Microbiology and Immunology, College of Medicine, University of Kentucky, Lexington, 40536-0084, USA.
Levay
A K
AK
Sparks
B
B
Miller
M
M
Roszman
T L
TL
D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology*; D015232:Dinoprostone / Q000494:pharmacology*; D004347:Drug Interactions; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013601:T-Lymphocytes / Q000378:metabolism*
D005938:Glucocorticoids; D011948:Receptors, Antigen, T-Cell; D003907:Dexamethasone; D000242:Cyclic AMP; D015232:Dinoprostone