Cyclic AMP modulates the functional plasticity of immature dendritic cells by inhibiting Src-like kinases through protein kinase A-mediated signaling

Mario Galgani, Veronica De Rosa, Salvatore De Simone, Antonio Leonardi, Ugo D'Oro, Giorgio Napolitani, Anna Maria Masci, Serafino Zappacosta, Luigi Racioppi

Research output: Contribution to journalArticlepeer-review

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-κB, 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 languageEnglish
Pages (from-to)32507-32514
Number of pages8
JournalJournal of Biological Chemistry
Volume279
Issue number31
DOIs
Publication statusPublished - Jul 30 2004

ASJC Scopus subject areas

  • Biochemistry

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