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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.

Original publication

DOI

10.1074/jbc.M403355200

Type

Journal article

Journal

J biol chem

Publication Date

30/07/2004

Volume

279

Pages

32507 - 32514

Keywords

8-Bromo Cyclic Adenosine Monophosphate, Blotting, Western, Cell Differentiation, Cell Division, Cells, Cultured, Chemotaxis, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Dendritic Cells, Endotoxins, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Humans, Inflammation, Interleukin-12, Lipopolysaccharides, Mitogen-Activated Protein Kinases, NF-kappa B, Phenotype, Protein Kinase C, Protein-Tyrosine Kinases, Signal Transduction, T-Lymphocytes, Time Factors, p38 Mitogen-Activated Protein Kinases, src-Family Kinases