Prostaglandin E2 is generally required for human dendritic cell migration and exerts its effect via EP2 and EP4 receptors.
The control of dendritic cell (DC) migration is pivotal for the initiation of cellular immune responses. In this study, we demonstrate that the migration of human monocyte-derived (Mo)DCs as well as of ex vivo peripheral blood DCs toward CCL21, CXCL12, and C5a is stringently dependent on the presence of the proinflammatory mediator PGE2, although DCs expressed CXCR4 and C5aR on their surface and DC maturation was accompanied by CCR7 up-regulation independently of PGE2. The necessity of exogenous PGE2 for DC migration is not due to the suppression of PGE2 synthesis by IL-4, which is used for MoDC differentiation, because maturation-induced endogenous production of PGE2 cannot promote DC migration. Surprisingly, PGE2 was absolutely required at early time points of maturation to enable MoDC chemotaxis, whereas PGE2 addition during terminal maturation events was ineffective. In contrast to mouse DCs, which exclusively rely on EP4 receptor triggering for migration, human MoDCs require a signal mediated by EP2 or EP4 either alone or in combination. Our results provide clear evidence that PGE2 is a general and mandatory factor for the development of a migratory phenotype of human MoDCs as well as for peripheral blood myeloid DCs.
Legler
Daniel F
DF
Biotechnology Institute Thurgau, Tägerwilen, Switzerland. daniel.legler@bitg.ch
Krause
Petra
P
Scandella
Elke
E
Singer
Eva
E
Groettrup
Marcus
M
D001483:Base Sequence; D002454:Cell Differentiation; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology; D018076:DNA, Complementary / Q000235:genetics; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000502:physiology*; D015232:Dinoprostone / Q000096:biosynthesis / Q000494:pharmacology* / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D018793:Interleukin-13 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics; D044087:Receptor, Anaphylatoxin C5a; D054400:Receptors, CCR7; D019718:Receptors, CXCR4 / Q000235:genetics; D019707:Receptors, Chemokine / Q000235:genetics; D011951:Receptors, Complement / Q000235:genetics; D018078:Receptors, Prostaglandin E / Q000502:physiology*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D011994:Recombinant Proteins; D015398:Signal Transduction
C488033:C5AR1 protein, human; C515370:CCR7 protein, human; C515371:Ccr7 protein, mouse; D018076:DNA, Complementary; D018793:Interleukin-13; D008565:Membrane Proteins; C545644:PTGER2 protein, human; C545650:PTGER4 protein, human; C545645:Ptger2 protein, mouse; C545651:Ptger4 protein, mouse; D044087:Receptor, Anaphylatoxin C5a; D054400:Receptors, CCR7; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D011951:Receptors, Complement; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D011994:Recombinant Proteins; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D015232:Dinoprostone