title: Regulation of IL-15-stimulated TNF-alpha production by rolipram.
abstract: Agents that increase intracellular cAMP have been shown to reduce joint inflammation in experimental arthritis, presumably by lowering the release of proinflammatory cytokines, such as TNF-alpha. Recent studies suggest that, in joints of patients with rheumatoid arthritis, TNF-alpha release from macrophages is triggered by their interaction with IL-15-stimulated T lymphocytes. In this report, we analyze the effect of rolipram, a cAMP-specific phosphodiesterase inhibitor, on TNF-alpha production in this experimental system. Cocultures of U937 cells with IL-15-stimulated T cells, but not control T cells, resulted in increased release of TNF-alpha. Pretreatment of T cells with rolipram or cAMP analogues inhibited the IL-15-stimulated increases in proliferation, expression of cell surface molecules CD69, ICAM-1, and LFA-1, and release of TNF-alpha from macrophages. Addition of PMA to T cells dramatically increased the expression of cell surface molecules, but had little or no effect on TNF-alpha release from either T cells or from cocultures, suggesting that other surface molecules must also be involved in T cell/macrophage contact-mediated production of TNF-alpha. Addition of PMA synergistically increased the proliferation of IL-15-stimulated T cells and the secretion of TNF-alpha from IL-15-stimulated T cell/macrophage cocultures. Rolipram and 8-(4-chlorophenylthio)-cAMP (CPT-cAMP) blocked these increases. Measurement of protein kinase A (PKA) activity and the use of inhibitory cAMP analogues (RpCPT-cAMP) confirmed that rolipram worked by stimulating PKA. These data suggest that PKA-activating agents, such as rolipram, can block secretion of TNF-alpha from macrophages by inhibiting T cell activation and expression of surface molecules.
authors.affiliation: Portland Veterans Affairs Medical Center, Department of Medicine, Oregon Health Sciences University, Portland 97201, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Kasyapa
authors.forename: C L
authors.initials: CL
authors.lastname: Stentz
authors.forename: M P
authors.initials: MP
authors.lastname: Davey
authors.forename: D W
authors.initials: DW
authors.lastname: Carr
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D002478:Cells, Cultured; D018920:Coculture Techniques; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D019409:Interleukin-15 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D037181:Lectins, C-Type; D008213:Lymphocyte Activation / Q000187:drug effects; D016169:Lymphocyte Function-Associated Antigen-1 / Q000096:biosynthesis; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D011760:Pyrrolidinones / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D020889:Rolipram; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D020298:U937 Cells; D000099192:CD69 Antigens
chemical_list: D000276:Adjuvants, Immunologic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D018799:Intercellular Adhesion Molecule-1; D019409:Interleukin-15; D037181:Lectins, C-Type; D016169:Lymphocyte Function-Associated Antigen-1; D011760:Pyrrolidinones; D020889:Rolipram; D013755:Tetradecanoylphorbol Acetate; D013873:Thionucleotides; D014409:Tumor Necrosis Factor-alpha; D000099192:CD69 Antigens; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP