title: Cyclic-AMP modulates downstream events in CD40-mediated signal transduction, but inhibition of protein kinase A has no direct effect on CD40 signaling.
abstract: The role of cAMP/protein kinase A (PKA) in CD40 signal transduction is controversial, with evidence both for and against its importance. In this study we have used a tetracycline-repressible expression system to reversibly express a dominant-negative form of the PKA regulatory subunit type I (PKA-R(G324D)) in a B lymphoma line, M12. Expression of PKA-R(G324D) in M12 lymphomas inhibits both cAMP-mediated growth inhibition and cAMP-mediated induction of B7-2. This inhibition is reversed by tetracycline treatment of the cells to turn off inhibitor expression. In contrast, the expression of the PKA-R(G324D) subunit has no effect on CD40-mediated growth inhibition in M12 cells, nor on CD40-mediated induction of B7-1, CD23, Fas, ICAM-1, or LFA-1. Thus, our data do not support a direct role for cAMP/PKA in CD40-mediated signal transduction. However, we do observe that cAMP can regulate CD40 signaling both positively and negatively. Cyclic-AMP synergizes with CD40-mediated B7-1 induction in M12 lymphomas, while inhibiting CD40-mediated CD23, Fas, and ICAM-1 induction.
authors.affiliation: Department of Immunology, University of Toronto, Ontario, Canada.
authors.forename: M D
authors.initials: MD
authors.lastname: Goldstein
authors.forename: A
authors.initials: A
authors.lastname: Cochrane
authors.forename: T H
authors.initials: TH
authors.lastname: Watts
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D018122:B7-1 Antigen / Q000096:biosynthesis; D051940:B7-2 Antigen; D019013:CD40 Antigens / Q000502:physiology*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D002455:Cell Division / Q000276:immunology; D002460:Cell Line; D000242:Cyclic AMP / Q000494:pharmacology / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D006131:Growth Inhibitors / Q000096:biosynthesis; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins; D016169:Lymphocyte Function-Associated Antigen-1 / Q000096:biosynthesis; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D012313:RNA / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000187:drug effects; D017455:Receptors, IgE / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013752:Tetracycline / Q000494:pharmacology; D019014:fas Receptor / Q000096:biosynthesis
chemical_list: D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019013:CD40 Antigens; C497964:CD86 protein, human; D002352:Carrier Proteins; C497965:Cd86 protein, mouse; D006131:Growth Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D016169:Lymphocyte Function-Associated Antigen-1; D008562:Membrane Glycoproteins; D017455:Receptors, IgE; D019014:fas Receptor; C015482:protein kinase modulator; D018799:Intercellular Adhesion Molecule-1; D012313:RNA; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D013752:Tetracycline