title: Liver X receptor is a key regulator of cytokine release in human monocytes.
abstract: Aberrant regulation of innate immune responses and uncontrolled cytokine bursts are hallmarks of sepsis and endotoxemia. Activation of the nuclear liver X receptor (LXR) was recently demonstrated to suppress inflammatory genes. Our aim was to investigate the expression of LXR in human monocytes under normal and endotoxemic conditions and to study the influence of LXR activation on endotoxin-induced cytokine synthesis and release. Adherent human monocytes or whole blood were pretreated with a synthetic LXR agonist (3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-acetic acid) and subsequently challenged with LPS (from Escherichia coli) or peptidoglycan (from Staphylococcus aureus). Cytokine release was assessed by a Multiplex antibody bead kit, and cytokine mRNA levels were measured by real-time reverse-transcriptase-polymerase chain reaction. We found that LXRalpha mRNA was up-regulated in CD14+ monocytes in LPS-challenged blood, whereas LXRbeta mRNA was not altered. Addition of 3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-acetic acid to monocytes suppressed the LPS-induced release of IL-1beta, IL-6, IL-8, IL-10, IL-12p40, TMF-alpha, macrophage inflammatory protein 1alpha, macrophage inflammatory protein 1beta, and monocyte chemoattractant protein 1 in a concentration-dependent manner. Surprisingly, an accompanying decrease in cytokine mRNA accumulation was not observed. The suppressed cytokine release could not be explained by a diminished transport of mRNA out of the nucleus or a decreased secretion of cytokines. We propose that LXR is a key regulator of cytokine release in LPS-challenged human monocytes, possibly by interfering with translational events.
authors.affiliation: Institute for Surgical Research, Rikshospitalet-Radiumhospitalet Medical Centre, Oslo, Norway.
authors.forename: Anders E
authors.initials: AE
authors.lastname: Myhre
authors.forename: Joanna
authors.initials: J
authors.lastname: Agren
authors.forename: Maria K
authors.initials: MK
authors.lastname: Dahle
authors.forename: Margareth V
authors.initials: MV
authors.lastname: Tamburstuen
authors.forename: Ståle P
authors.initials: SP
authors.lastname: Lyngstadaas
authors.forename: A Jon L
authors.initials: AJ
authors.lastname: Collins
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Foster
authors.forename: Christoph
authors.initials: C
authors.lastname: Thiemermann
authors.forename: Ansgar O
authors.initials: AO
authors.lastname: Aasen
authors.forename: Jacob E
authors.initials: JE
authors.lastname: Wang
mesh_terms: D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000032:analysis; D008070:Lipopolysaccharides / Q000494:pharmacology; D000071518:Liver X Receptors; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D057093:Orphan Nuclear Receptors; D010457:Peptidoglycan / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D001565:Benzoates; D001596:Benzylamines; D016207:Cytokines; D004268:DNA-Binding Proteins; C473027:GW 3965; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D000071518:Liver X Receptors; D019402:Macrophage Inflammatory Proteins; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D010457:Peptidoglycan; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12