title: Liver X receptors inhibit macrophage proliferation through downregulation of cyclins D1 and B1 and cyclin-dependent kinases 2 and 4.
abstract: Macrophages serve essential functions as regulators of immunity and homeostasis, and their proliferation contributes to pathogenesis of certain disorders. In this report, we show that induction of macrophage proliferation by the growth factor M-CSF is negatively modulated by agonists that activate the nuclear receptor liver X receptor (LXR), both in vitro and in vivo. Both isoforms LXR α and β are involved in the antiproliferative actions of LXR ligands in macrophages. In contrast, M-CSF does not exert negative effects on LXR-mediated gene expression. Treatment with LXR agonists results in the accumulation of macrophages in the G(0)/G(1) phase of the cell cycle without affecting ERK-1/2 phosphorylation. The use of small interfering RNA or genetically modified mice revealed that, in contrast to other cellular models, functional expression of either the cyclin-dependent kinase inhibitor p27KIP1 or the cholesterol transporters ATP-binding cassette A1 or ATP-binding cassette G1 was not required for the antiproliferative effects of LXR agonists in macrophages. Western blot analysis revealed that protein expression of key molecules that regulate progression through the cell cycle, such as cyclins D1 and B1 and cyclin-dependent kinases 2 and 4, was downregulated upon LXR activation. These observations suggest a role for LXR agonists in limiting macrophage proliferative responses associated to pathogenic disorders.
authors.affiliation: Nuclear Receptor Group, Department of Physiology, School of Biology, University of Barcelona, 08028 Barcelona, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Pascual-García
authors.forename: José M
authors.initials: JM
authors.lastname: Carbó
authors.forename: Theresa
authors.initials: T
authors.lastname: León
authors.forename: Jonathan
authors.initials: J
authors.lastname: Matalonga
authors.forename: Ruud
authors.initials: R
authors.lastname: Out
authors.forename: Theo
authors.initials: T
authors.lastname: Van Berkel
authors.forename: Maria-Rosa
authors.initials: MR
authors.lastname: Sarrias
authors.forename: Francisco
authors.initials: F
authors.lastname: Lozano
authors.forename: Antonio
authors.initials: A
authors.lastname: Celada
authors.forename: Annabel F
authors.initials: AF
authors.lastname: Valledor
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D056744:Cyclin B1 / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism*; D015536:Down-Regulation; D005434:Flow Cytometry; D057809:HEK293 Cells; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D007739:L Cells; D000071518:Liver X Receptors; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D001565:Benzoates; D001596:Benzylamines; D056744:Cyclin B1; D019938:Cyclin D1; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D016213:Cyclins; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D016173:Macrophage Colony-Stimulating Factor; D057093:Orphan Nuclear Receptors; D020033:Protein Isoforms; D013449:Sulfonamides; C473027:GW 3965; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides