Cyclic nucleotides promote monocyte differentiation toward a DC-SIGN+ (CD209) intermediate cell and impair differentiation into dendritic cells.
Recruitment of monocytes into tissues and their differentiation into macrophages or dendritic cells (DCs) depend on the microenvironment of the inflammatory site. Although many factors affecting this process have been identified, the intracellular signaling pathways implicated are poorly understood. We found that cyclic nucleotides regulate certain steps of monocyte differentiation into DCs. Increased levels of the cyclic nucleotides, cAMP or cGMP, inhibit differentiation of CD14(+)/CD1a(low) monocytes into CD14(-)/CD1a(high) DCs. However, DC-specific ICAM-3-grabbing nonintegrin (CD209) up-regulation was not affected by cyclic nucleotides, indicating that DC development was not blocked at the monocyte stage. Interestingly, Ag-presenting function was increased by cyclic nucleotides, as measured by the higher expression of MHC class II, CD86, and an increased ability to stimulate CD4(+) T cell proliferation in allogeneic MLRs. Although cyclic nucleotides do not completely block DC differentiation, they do block the ability of DCs to be induced to mature by LPS. Treatment during DC differentiation with either cAMP or cGMP analogues hampered LPS-induced expression of CD83, DC-LAMP, and CCR7 and the ability of DCs to migrate toward CCL19/macrophage-inflammatory protein 3beta. Interestingly, the induction of a CD16(+) subpopulation of cells was also observed. Thus, signals causing an increase in either cAMP or cGMP levels during monocyte recruitment to inflammatory sites may restrain the activation of acquired immunity by blocking DC development and migration to lymph nodes. At the same time, these signals promote development of an active intermediate cell type having properties between those of macrophages and DCs, which might contribute to the innate immune response in the periphery.
Giordano
Daniela
D
Department of Immunology, University of Washington, Seattle, WA 98195, USA.
Magaletti
Dario M
DM
Clark
Edward A
EA
Beavo
Joseph A
JA
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000276:Adjuvants, Immunologic / Q000096:biosynthesis / Q000502:physiology; D017951:Antigen Presentation / Q000502:physiology; D015703:Antigens, CD / Q000096:biosynthesis; D015815:Cell Adhesion Molecules / Q000096:biosynthesis*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D054415:Chemokine CCL19; D019742:Chemokines, CC / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D000242:Cyclic AMP / Q000096:biosynthesis / Q000502:physiology*; D006152:Cyclic GMP / Q000096:biosynthesis / Q000502:physiology*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000502:physiology*; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D037181:Lectins, C-Type / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology; D051907:Lysosomal Membrane Proteins; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D054400:Receptors, CCR7; D011956:Receptors, Cell Surface / Q000096:biosynthesis*; D019707:Receptors, Chemokine / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D000097802:CD83 Antigen; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D015124:8-Bromo Cyclic Adenosine Monophosphate; D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D054415:Chemokine CCL19; D019742:Chemokines, CC; D000242:Cyclic AMP; D006152:Cyclic GMP; D016207:Cytokines; D006131:Growth Inhibitors; D007136:Immunoglobulins; D037181:Lectins, C-Type; D008070:Lipopolysaccharides; D051907:Lysosomal Membrane Proteins; D008562:Membrane Glycoproteins; D054400:Receptors, CCR7; D011956:Receptors, Cell Surface; D019707:Receptors, Chemokine; D000097802:CD83 Antigen; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C515460:CCL19 protein, human; C515370:CCR7 protein, human