Liver X receptor agonism promotes articular inflammation in murine collagen-induced arthritis.
OBJECTIVE
Liver X receptors (LXRs) have previously been implicated in the regulation of inflammation and have, in general, been ascribed an antiinflammatory role. This study was therefore undertaken to explore the biologic mechanisms of LXRs in vivo and in vitro in an experimental inflammatory arthritis model.


METHODS
Male DBA/1 mice were immunized with type II collagen and treated from an early or established stage of arthritis with 2 different concentrations of the LXR agonists T1317 and GW3965 or vehicle control. The mice were monitored for articular inflammation and cartilage degradation by scoring for clinical signs of arthritis, histologic examination of the joints, and analysis of serum cytokine and antibody levels. In vitro, primary human monocytes and T cells were cultured in the presence of GW3965 or T1317, and the concentrations of proinflammatory cytokines were measured by multiplex assay.


RESULTS
Contrary to expectations, LXR agonism with the use of 2 discrete, specific molecular entities led to substantial exacerbation of articular inflammation and cartilage destruction in this murine collagen-induced arthritis model. This was associated ex vivo with elevated cytokine expression, with enhanced Th1 and Th17 cellular responses, and with elevated collagen-specific autoantibody production. In vitro, LXR agonists, in concert with lipopolysaccharide, promoted cytokine and chemokine release from human monocytes, and similar effects were observed in a T cell-macrophage coculture model that closely recapitulates the pathways that drive synovial cytokine release.


CONCLUSIONS
Since LXRs are present in rheumatoid arthritis (RA) synovium, these results suggest that LXR-mediated pathways could exacerbate the chronic inflammatory response typical of RA.
Asquith
Darren L
DL
Glasgow Biomedical Research Center, Division of Infection, Immunity and Inflammation, University of Glasgow, 120 University Place, Glasgow, UK. d.asquith.1@research.gla.ac.uk
Miller
Ashley M
AM
Hueber
Axel J
AJ
McKinnon
Heather J
HJ
Sattar
Naveed
N
Graham
Gerry J
GJ
McInnes
Iain B
IB
D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D020381:Interleukin-17 / Q000378:metabolism; D053582:Interleukin-1alpha / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D020381:Interleukin-17; D053582:Interleukin-1alpha; D015850:Interleukin-6; D008070:Lipopolysaccharides; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides