ABSTRACT
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.
Subject(s)
Cell Movement/immunology , Dendritic Cells/immunology , Dinoprostone/immunology , Orphan Nuclear Receptors/immunology , Receptors, CCR7/immunology , Adaptive Immunity/immunology , Chemokine CCL4/genetics , Chemokine CCL4/immunology , Cyclooxygenase 2/genetics , Cyclooxygenase 2/immunology , Dendritic Cells/cytology , Dinoprostone/genetics , Flow Cytometry , Gene Expression Regulation , Humans , Interleukin-23/genetics , Interleukin-23/immunology , Leukocytes, Mononuclear , Liver X Receptors , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/immunology , Orphan Nuclear Receptors/genetics , RNA/chemistry , RNA/genetics , Real-Time Polymerase Chain Reaction , Signal TransductionABSTRACT
Dendritic cells (DCs) are key in regulating immune responses. DCs reside in tissues facing the environment and sample their surrounding for pathogens. Upon pathogen encounter, DCs mature and migrate into secondary lymphoid organs. Distinct maturation signals dictate the ability of DCs to produce distinct patterns of chemokines that orchestrate immunity. Prostaglandin E(2) (PGE(2)) is produced during inflammation and modulates DC functions. We demonstrate that PGE(2) modulates distinct chemokine expression patterns of human monocyte-derived (Mo) DCs upon maturation with various stimuli. PGE(2) dampened early production of the inflammatory chemokines CCL2, CCL4, CCL5 and attenuated the expression of the T cell attractant CXCL10. In contrast, PGE(2) enhanced CXCL8 production early during maturation, whereas CXCL16 levels were continuously elevated, contributing to innate immune cell recruitment. Moreover, PGE(2) induces transcription of the homeostatic chemokines CCL17 and CCL22. Finally, mature MoDCs produced the homing chemokine CCL19 and its expression was down-regulated by PGE(2).
