Converse regulation of CCR7-driven human dendritic cell migration by prostaglandin E₂ and liver X receptor activation.
Migration and homing of DCs to lymphoid organs is pivotal for inducing adaptive immunity and tolerance. DC homing depends on the chemokine receptor CCR7. However, expression of CCR7 alone is not sufficient for effective DC migration. A second signal, mediated by prostaglandin E(2) (PGE(2)), is critical for the development of a migratory DC phenotype. PGE(2) is important for inducing efficient immune responses, but, if deregulated, contributes to chronic inflammation, autoimmune diseases through Th17-cell development and tumorigenesis. In contrast, activation of liver X receptor (LXR)α has recently been shown to interfere with CCR7 expression and migration of DCs resulting in a reduced immune response. Here, we demonstrate that PGE(2) downregulates LXRα expression in human monocyte derived as well as ex vivo DCs. Moreover, PGE(2) stimulation dampens LXR activation, auto-regulation and LXR-mediated gene transcription. Consequently, we show that PGE(2) enhances CCR7 expression and migration of LXR-activated DCs. Furthermore, we provide evidence that PGE(2) signaling and LXR activation specifically elicit converse effects on CCR7 expression and DC migration. In contrast, production of MMP9, CCL4, COX-2, and IL-23 is solely regulated by PGE(2) , but not by LXR activation, offering new perspectives for therapeutic interventions.
Biotechnology Institute Thurgau, University of Konstanz, Kreuzlingen, Switzerland.
Markus
M
Bruckner
Denise
D
Dickel
Eva
E
Singer
Daniel F
DF
Legler
D056704:Adaptive Immunity / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D054407:Chemokine CCL4 / Q000235:genetics / Q000276:immunology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D015232:Dinoprostone / Q000235:genetics / Q000276:immunology*; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D053759:Interleukin-23 / Q000235:genetics / Q000276:immunology; D007963:Leukocytes, Mononuclear; D000071518:Liver X Receptors; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000276:immunology; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000276:immunology*; D012313:RNA / Q000737:chemistry / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D054400:Receptors, CCR7 / Q000276:immunology*; D015398:Signal Transduction
D054407:Chemokine CCL4; D053759:Interleukin-23; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D054400:Receptors, CCR7; D012313:RNA; D051546:Cyclooxygenase 2; D020780:Matrix Metalloproteinase 9; D015232:Dinoprostone