Crosstalk between PKA and Epac regulates the phenotypic maturation and function of human dendritic cells.
The cAMP-dependent signaling pathways that orchestrate dendritic cell (DC) maturation remain to be defined in detail. Although cAMP was previously thought to signal exclusively through protein kinase A (PKA), it is now clear that cAMP also activates exchange protein activated by cAMP (Epac), a second major cAMP effector. Whether cAMP signaling via PKA is sufficient to drive DC maturation or whether Epac plays a role has not been examined. In this study, we used cAMP analogs to selectively activate PKA or Epac in human monocyte-derived DCs and examined the effect of these signaling pathways on several hallmarks of DC maturation. We show that PKA activation induces DC maturation as evidenced by the increased cell-surface expression of MHC class II, costimulatory molecules, and the maturation marker CD83. PKA activation also reduces DC endocytosis and stimulates chemotaxis to the lymph node-associated chemokines CXCL12 and CCL21. Although PKA signaling largely suppresses cytokine production, the net effect of PKA activation translates to enhanced DC activation of allogeneic T cells. In contrast to the stimulatory effects of PKA, Epac signaling has no effect on DC maturation or function. Rather, Epac suppresses the effects of PKA when both pathways are activated simultaneously. These data reveal a previously unrecognized crosstalk between the PKA and Epac signaling pathways in DCs and raise the possibility that therapeutics targeting PKA may generate immunogenic DCs, whereas those that activate Epac may produce tolerogenic DCs capable of attenuating allergic or autoimmune disease.
Garay
Jone
J
Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Science Center, New Orleans, LA 70112, USA.
D'Angelo
June A
JA
Park
YongKeun
Y
Summa
Christopher M
CM
Aiken
Martha L
ML
Morales
Eric
E
Badizadegan
Kamran
K
Fiebiger
Edda
E
Dickinson
Bonny L
BL
D000818:Animals; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D004789:Enzyme Activation / Q000276:immunology; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D016130:Immunophenotyping; D051379:Mice; D011485:Protein Binding / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology
D020662:Guanine Nucleotide Exchange Factors; D047428:Protein Kinase Inhibitors; C116122:RAPGEF3 protein, human; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases