Prostaglandin E2 and the increase of intracellular cAMP inhibit the expression of interleukin 2 receptors in human T cells.
We have analyzed the effect mediated by prostaglandin E2 (PGE2) and different reagents that increase intracellular cAMP on the expression of the p55 subunit (CD25) of interleukin 2 receptors (IL 2R), on the levels of CD25-specific mRNA and on the expression of high affinity IL 2R. In purified T cells, activated either by an anti-CD3 monoclonal antibody or phytohemagglutinin, the addition of PGE2 (10(-6) M), forskolin (5 X 10(-5) M), cholera toxin (0.2 microgram/ml) or dibutyryl cAMP (dBcAMP) (10(-4) M) decreased the cell surface expression of IL 2R by reducing (40%-78% inhibition) the proportions of CD25+ cells as well as the expression of high affinity IL 2R, detectable after 24 h. Furthermore, it was observed that PGE2 reduced the concentration of IL 2R-specific mRNA after a 6-h period of activation, indicating that its regulatory activity takes place at a pretranslational level. The addition of exogenous recombinant IL 2 only partially reversed the inhibition, thus suggesting that PGE2 and increased intracellular concentration of cAMP directly interfered with CD25 expression and that their effect could not be merely attributed to a lack of IL 2-dependent positive feedback. Cells cultured under the same conditions in the presence of phorbol myristate acetate, that activates protein kinase C, were refractory to the cAMP-mediated regulation. Finally, we demonstrate that both PGE2 and dBcAMP inhibit the generation of inositol metabolites after T cell activation, thus indicating that these reagents interfere with early signal transduction mechanisms which precede the synthesis of IL 2R.
Rincón
M
M
Department of Immunology, Hospital de la Princesa, Universidad Autónoma, Madrid, Spain.
Tugores
A
A
López-Rivas
A
A
Silva
A
A
Alonso
M
M
De Landázuri
M O
MO
López-Botet
M
M
D000937:Antigen-Antibody Reactions; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D017252:CD3 Complex; D000242:Cyclic AMP / Q000502:physiology*; D015232:Dinoprostone / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000502:physiology; D008213:Lymphocyte Activation / Q000187:drug effects; D010716:Phosphatidylinositols / Q000378:metabolism; D011493:Protein Kinase C / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000235:genetics / Q000502:physiology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D007295:Inositol Phosphates; D010716:Phosphatidylinositols; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D000242:Cyclic AMP; D011493:Protein Kinase C; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate