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 LXRactivated 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.Keywords: Chemokine receptor CCR7 r Liver X receptor r Monocyte-derived DCs r Migration r Prostaglandin E 2 Supporting Information available online IntroductionDCs are professional antigen-presenting cells and critical for inducing adaptive immunity and tolerance [1,2]. DCs are found in healthy tissues as immature cells and ready to sample the environment for foreign antigens. Upon infection or inflammation, DCs mature and migrate to the draining lymph node, where the Correspondence: Prof. Daniel F. Legler e-mail: daniel.legler@bitg.ch peripherally acquired antigens are presented to T cells in the context of MHC molecules. Mature DCs acquire an enhanced capacity to stimulate T cells, which is on the one hand achieved by the upregulation of costimulatory molecules to allow efficient DC-T-cell interactions, and on the other hand by the production of cytokines that T cells need to differentiate and proliferate [3].DC migration to secondary lymphoid organs fully depends on the two chemokines CCL19 and CCL21, which are constitutively expressed by peripheral lymphatic endothelial cells and lymph node stroma cells [4,5] and its cognate receptor CCR7, which is upregulated upon DC maturation [2,5]. The fact that CCR7 and its ligands are mandatory for homing was demonstrated in CCR7 Eur. J. Immunol. 2012. 42: 2949-2958 deficient and in plt/plt mice lacking lymphoid CCL21 and CCL19 [5]. The lack of a coordinated CCR7-dependent homing to lymph nodes results in a severely impaired T-and B-cell immunity [5]. However, CCR7 expression on mature DCs alone does not necessarily mean that DCs readily migrate toward CCL19 and CCL21. We and others have discovered that CCR7-expressing DCs migrate poorly unless DCs were expo...

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).