title: Cyclic AMP modulates the functional plasticity of immature dendritic cells by inhibiting Src-like kinases through protein kinase A-mediated signaling.
abstract: Immature dendritic cells (iDCs) can be instructed to polarize the immune response toward a noninflammatory pathway by mediators that increase the intracellular concentration of cAMP. This phenomenon is associated with the ability of the cyclic nucleoside to inhibit the release of pro-inflammatory cytokines without affecting the differentiation process of the dendritic cells (DCs). Here we investigated the ability of cAMP to modulate the endotoxin signaling by exposing DCs to exogenous 8-bromium-cyclic AMP in the presence or absence of H89, a selective inhibitor of the protein kinase A, one of the major molecular targets of the cyclic nucleoside. cAMP affects the early lipopolysaccharide-induced signaling cascade dissociating the activation of NF-kappa B, p38, and ERK pathways from the stimulation of c-Src and Lyn kinases. This phenomenon was prevented by H89. The pharmacological block of Src-like tyrosine kinases induces comparable results confirming the involvement of this family of enzymes in the mechanism controlling the release of cytokines in human monocyte-derived iDCs. We propose that the cAMP-protein kinase A-dependent pathway regulates the functional plasticity of iDCs by gating the Toll-like receptor signaling at the level of Src-like kinases.
authors.affiliation: Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, I-80131 Naples, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Galgani
authors.forename: Veronica
authors.initials: V
authors.lastname: De Rosa
authors.forename: Salvatore
authors.initials: S
authors.lastname: De Simone
authors.forename: Antonio
authors.initials: A
authors.lastname: Leonardi
authors.forename: Ugo
authors.initials: U
authors.lastname: D'Oro
authors.forename: Giorgio
authors.initials: G
authors.lastname: Napolitani
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Masci
authors.forename: Serafino
authors.initials: S
authors.lastname: Zappacosta
authors.forename: Luigi
authors.initials: L
authors.lastname: Racioppi
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D002633:Chemotaxis; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism*; D004731:Endotoxins / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation; D018664:Interleukin-12 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D011493:Protein Kinase C / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D004731:Endotoxins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018664:Interleukin-12; D015124:8-Bromo Cyclic Adenosine Monophosphate; D000242:Cyclic AMP; D011505:Protein-Tyrosine Kinases; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases