Inhibition of lipopolysaccharide-induced gene expression by liver X receptor ligands in macrophages involves interference with early growth response factor 1.
Liver X receptors (LXRs) are nuclear receptors that act as ligand-dependent transcription factors forming permissive heterodimers with retinoid X receptors (RXRs). In this study we aimed to assess the effect of LXR/RXR activation on the transcriptional induction of pro-inflammatory genes including cyclooxygenase-2 (COX-2) and microsomal prostaglandin E2 synthase-1 (mPGES-1) in activated macrophages. Our study shows that LXR ligands such as oxysterols, GW3965 or TO901317, as well as RXR ligands like 9cis retinoic acid or SR11237, decreased LPS-induced expression of COX-2 and mPGES-1. Consequently, LPS-dependent PGE2 production was substantially reduced in macrophages treated with LXR/RXR ligands. The inhibitory effects of LXR/RXR activation on LPS-induced expression of COX-2 and mPGES-1 in macrophages, occurred by a mechanism involving interference with transcriptional activation of these genes. LXR/RXR activation interfered with the activity of transcription factors essential in the up-regulation of the expression of pro-inflammatory genes in these cells, such as NFκB, but also Egr-1, which had not been previously associated with LXR-mediated gene repression. As this transcription factor is involved in the regulation of a variety of genes involved in inflammatory processes, LXR and RXR-mediated interference with Egr-1 signaling could represent an important event mediating the anti-inflammatory effects of these receptors in macrophages.
Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Departamento de Biología Molecular, Instituto de Investigación Sanitaria Princesa, Universidad Autónoma de Madrid, Nicolás Cabrera, 1, Cantoblanco, 28049 Madrid, Spain.
Paloma
P
Guillem-Llobat
Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Departamento de Biología Molecular, Instituto de Investigación Sanitaria Princesa, Universidad Autónoma de Madrid, Nicolás Cabrera, 1, Cantoblanco, 28049 Madrid, Spain. Electronic address: mainiguez@cbm.csic.es.
Miguel A
MA
Íñiguez
D000818:Animals; D002460:Cell Line; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D008024:Ligands; D008070:Lipopolysaccharides / Q000378:metabolism*; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D009000:Monocytes / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*
C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D008024:Ligands; D008070:Lipopolysaccharides; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors
COX-2; Egr-1; LXR; Macrophages; RXR; mPGES-1