title: Delineation of the mechanism of inhibition of human T cell activation by PGE2.
abstract: The capacity of PGE2 to inhibit human T cell responses was examined by investigating its effect on mitogen-induced IL-2 production and proliferation of highly purified CD4+ T cells. PGE2 inhibited both PHA and anti-CD3 induced proliferation and IL-2 production by an action directly on the responding T cell. Inhibition of IL-2 production reflected decreased accumulation of mRNA for IL-2. A variety of other cAMP elevating agents exerted similar inhibitory effects. Inhibition of proliferation could be overcome by supplemental IL-2, PMA, or the anti-CD28 mAb 9.3. Although PMA and 9.3 markedly increased the amount of IL-2 produced by mitogen-stimulated T cells, the percentage inhibition of IL-2 secretion caused by PGE2 and other cAMP elevating agents remained comparable in these costimulated cultures. Rescue of T cell DNA synthesis by these agents appeared to reflect the finding that, although PGE2 markedly inhibited IL-2 production, the absolute amount of IL-2 produced was increased sufficiently to sustain mitogen-induced proliferation. As anticipated, PGE2, forskolin, and cholera toxin increased T cell cAMP levels. The quantity of cellular cAMP generated in response to PGE2, cholera toxin, and forskolin could be inhibited by PMA or 2',5'-dideoxyadenosine. Using these reagents, the inhibitory effects of PGE2 were found to reflect intracellular cAMP levels, but only within a very narrow range. The results indicate that by elevating cAMP levels, PGE2 inhibits human T cell IL-2 production at a point that is common to both the CD3 and CD28 signaling pathways.
authors.affiliation: Harold C. Simmons Arthritis Research Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235.
authors.forename: R
authors.initials: R
authors.lastname: Minakuchi
authors.forename: M C
authors.initials: MC
authors.lastname: Wacholtz
authors.forename: L S
authors.initials: LS
authors.lastname: Davis
authors.forename: P E
authors.initials: PE
authors.lastname: Lipsky
mesh_terms: D015703:Antigens, CD / Q000502:physiology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology; D015152:Blotting, Northern; D018106:CD28 Antigens; D017252:CD3 Complex; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D002772:Cholera Toxin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D016048:Dideoxyadenosine / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics*; D008213:Lymphocyte Activation / Q000187:drug effects*; D010835:Phytohemagglutinins / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D013601:T-Lymphocytes / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; D017252:CD3 Complex; D007376:Interleukin-2; D010835:Phytohemagglutinins; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D005576:Colforsin; D016048:Dideoxyadenosine; D002772:Cholera Toxin; D000242:Cyclic AMP; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate