The cyclic AMP-Epac1-Rap1 pathway is dissociated from regulation of effector functions in monocytes but acquires immunoregulatory function in mature macrophages.
cAMP mediates its intracellular effects through activation of protein kinase A (PKA), nucleotide-gated ion channels, or exchange protein directly activated by cAMP (Epac). Although elevation of cAMP in lymphocytes leads to suppression of immune functions by a PKA-dependent mechanism, the effector mechanisms for cAMP regulation of immune functions in monocytes and macrophages are not fully understood. In this study, we demonstrate the presence of Epac1 in human peripheral blood monocytes and activation of Rap1 in response to cAMP. However, by using an Epac-specific cAMP analog (8-CPT-2'-O-Me-cAMP), we show that monocyte activation parameters such as synthesis and release of cytokines, stimulation of cell adhesion, chemotaxis, phagocytosis, and respiratory burst are not regulated by the Epac1-Rap1 pathway. In contrast, activation of PKA by a PKA-specific compound (6-Bnz-cAMP) or physiological cAMP-elevating stimuli like PGE(2) inhibits monocyte immune functions. Furthermore, we show that the level of Epac1 increases 3-fold during differentiation of monocytes into macrophages, and in monocyte-derived macrophages cAMP inhibits FcR-mediated phagocytosis via both PKA and the Epac1-Rap1 pathway. However, LPS-induced TNF-alpha production is only inhibited through the PKA pathway in these cells. In conclusion, the Epac1-Rap1 pathway is present in both monocytes and macrophages, but only regulates specific immune effector functions in macrophages.
Bryn
Tone
T
Biotechnology Centre of Oslo, University of Oslo, Norway.
Mahic
Milada
M
Enserink
Jorrit M
JM
Schwede
Frank
F
Aandahl
Einar Martin
EM
Taskén
Kjetil
K
D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors / Q000096:biosynthesis / Q000502:physiology*; D006801:Humans; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D009000:Monocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D010587:Phagocytosis / Q000276:immunology; D016897:Respiratory Burst; D015398:Signal Transduction / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020827:rap1 GTP-Binding Proteins / Q000502:physiology*
D015815:Cell Adhesion Molecules; D020662:Guanine Nucleotide Exchange Factors; C116122:RAPGEF3 protein, human; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020827:rap1 GTP-Binding Proteins