Costimulation with dexamethasone and prostaglandin E2: a novel paradigm for the induction of T-cell anergy.
In this report, data are presented which indicate that anti-CD3 mAb-stimulated human peripheral blood T-cells treated with both dexamethasone (DEX) and prostaglandin E2 (PGE2) become anergic. This anergy can be reversed by the addition of IL-2. Further, experiments were performed to investigate this T-cell anergy. The results show that addition of DEX and PGE2 to anti-CD3 mAb-stimulated T-cells inhibits the induction of p56lck but not p59fyn kinase activity nor is the tyrosine phosphorylation of PLC gamma altered appreciably. Additionally, this treatment of anti-CD3 mAb-stimulated T-cells also results in decreased tyrosine phosphorylation of ERK1, suggesting that the Ras activation pathway may be inhibited. Interestingly, the induction of T-cell anergy is reproduced when an agonist for the cAMP-independent EP3 subtype of the PGE2 receptor is substituted for PGE2. Thus, while the mechanisms responsible for the dual action of DEX and PGE2 on the induction of T-cell anergy is unknown, these data suggest that a cAMP-independent mechanism may be involved. These data indicate that a state of anergy can be induced in normal human T-cells by the activation of these cells in the presence of physiologic concentrations of DEX and PGE2.
Elliott
L H
LH
Department of Microbiology and Immunology, College of Medicine, University of Kentucky, Lexington 40536-0084, USA.
Levay
A K
AK
D017252:CD3 Complex / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000187:drug effects*; D003907:Dexamethasone / Q000008:administration & dosage*; D015232:Dinoprostone / Q000008:administration & dosage*; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D005938:Glucocorticoids / Q000008:administration & dosage*; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D051966:Phospholipase C gamma; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D018078:Receptors, Prostaglandin E / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects*; D010738:Type C Phospholipases / Q000378:metabolism
D017252:CD3 Complex; D005938:Glucocorticoids; D007376:Interleukin-2; D007527:Isoenzymes; D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; D018078:Receptors, Prostaglandin E; D019000:Phosphotyrosine; D003907:Dexamethasone; C494957:FYN protein, human; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051076:Proto-Oncogene Proteins c-fyn; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D015232:Dinoprostone