Activation of liver X receptor sensitizes human dendritic cells to inflammatory stimuli.
Dendritic cells (DCs) respond to changes in their lipid environment by altering gene expression and immunophenotype. Some of these alterations are mediated via the nuclear receptor superfamily. However, little is known about the contribution of liver X receptor (LXR) to DC biology. In this study, we present a systematic analysis of LXR, activated by synthetic ligands or naturally occurring oxysterols in developing human monocyte-derived DCs. We found that LXRs are present and can be activated throughout DC differentiation in monocyte- and blood-derived DCs. Administration of LXR-specific natural or synthetic activators induced target gene expression accompanied by increased expression of DC maturation markers, such as CD80 and CD86. In mature DCs, LXR activation augmented the production of inflammatory cytokines IL-12, TNF-alpha, IL-6, and IL-8 and resulted in an increased capacity to activate CD4+ T cell proliferation upon ligation with TLR4 or TLR3 ligands. These effects appear to be underpinned by prolonged NF-kappaB signaling. Supporting such an inflammatory role, we found that LXR positive DCs are present in reactive lymph nodes in vivo. We propose that activation of LXR represents a novel lipid-signaling paradigm that alters the inflammatory response of human DCs.
Töröcsik
Dániel
D
Department of Biochemistry and Molecular Biology, University of Debrecen, Medical and Health Science Center, Hungary.
Baráth
Mónika
M
Benko
Szilvia
S
Széles
Lajos
L
Dezso
Balázs
B
Póliska
Szilárd
S
Hegyi
Zoltán
Z
Homolya
László
L
Szatmári
István
I
Lányi
Arpád
A
Nagy
László
L
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D050356:Lipid Metabolism / Q000276:immunology; D000071518:Liver X Receptors; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology; D057093:Orphan Nuclear Receptors / Q000378:metabolism* / Q000502:physiology; D020033:Protein Isoforms / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
D016207:Cytokines; D018836:Inflammation Mediators; D000071518:Liver X Receptors; D016328:NF-kappa B; D057093:Orphan Nuclear Receptors; D020033:Protein Isoforms