Cutting Edge: Macrophage Inhibition by Cyclic AMP (cAMP): Differential Roles of Protein Kinase A and Exchange Protein Directly Activated by cAMP-1

Abstract

cAMP has largely inhibitory effects on components of macrophage activation, yet downstream mechanisms involved in these effects remain incompletely defined. Elevation of cAMP in alveolar macrophages (AMs) suppresses FcγR-mediated phagocytosis. We now report that protein kinase A (PKA) inhibitors (H-89, KT-5720, and myristoylated PKA inhibitory peptide 14–22) failed to prevent this suppression in rat AMs. We identified the expression of the alternative cAMP target, exchange protein directly activated by cAMP-1 (Epac-1), in human and rat AMs. Using cAMP analogs that are highly specific for PKA (N6-benzoyladenosine-3′,5′-cAMP) or Epac-1 (8-(4-chlorophenylthio)-2′-O-methyladenosine-3′,5′-cAMP), we found that activation of Epac-1, but not PKA, dose-dependently suppressed phagocytosis. By contrast, activation of PKA, but not Epac-1, suppressed AM production of leukotriene B4 and TNF-α, whereas stimulation of either PKA or Epac-1 inhibited AM bactericidal activity and H2O2 production. These experiments now identify Epac-1 in primary macrophages, and define differential roles of Epac-1 vs PKA in the inhibitory effects of cAMP.

Effects of prostaglandin E2 on the subcellular localization of Epac-1 and Rap1 proteins during Fcγ-receptor-mediated phagocytosis in alveolar macrophages

“…As noted above, Epac-1 is known to be involved in the inhibition of FcγR-mediated phagocytosis by cAMP-stimulating compounds such as PGE 2 [4,10]. Treatment of AMs with 1 μM PGE 2 induced a time-dependent redistribution of Epac-1 to the nuclear envelope, with changes apparent within 30 min and more pronounced by 60 min (Fig.…”

“…Such metabolites, known as eicosanoids, are generated in abundance at sites of inflammation (e.g. the host-microbial interface) and influence key components of the innate immune system, namely, phagocytosis [2,3], intracellular microbial killing [4,5], and inflammatory mediator generation [6].…”

“…Epac-1 is more generally expressed throughout cells and tissues than Epac-2 [12] and its expression has been described in diverse cell types, including cells of the innate immune system. Recently, Aronoff et al reported the PKA-independent, Epac-dependent suppression of FcγR-mediated phagocytosis in rat alveolar macrophages (AMs) [4]. This effect involved Epac-1, as AMs did not express Epac-2 protein [4].…”

“…Recently, Aronoff et al reported the PKA-independent, Epac-dependent suppression of FcγR-mediated phagocytosis in rat alveolar macrophages (AMs) [4]. This effect involved Epac-1, as AMs did not express Epac-2 protein [4]. Subsequent publications have confirmed an important role for Epac-1 in both FcγR-dependent and -independent phagocytic pathways [10,13], though the mechanisms involved remain undiscovered.…”

Rôle inattendu de l’arginine vasopressine comme inhibiteur de la réponse immunitaire

“…L'AVP induit aussi une activation du canal épithé-lial sodique (ENaC) et du canal chlorure CFTR (cystic fibrosis transmembrane conductance regulator) sensible à l'AMPc [3]. Des études antérieures ont montré qu'une augmentation de l'AMPc inhibe l'expression de molécules d'adhésion et de signalisation induite lors d'une stimulation par le TNFα, l'IL-1β ou le LPS [4,5]. Ces résultats ont suscité l'hypothèse d'un rôle de l'AVP, qui stimule l'AMPc des cellules du tubule collecteur, dans la modulation de la réponse inflammatoire induite par les bactéries uropathogènes et dans la modification de la clairance bactérienne rénale lors des infections du tractus urinaire.…”