Liver X receptor agonist prevents the evolution of collagen-induced arthritis in mice.
OBJECTIVE
Liver X receptors (LXRs) have been characterized as regulators of macrophage inflammatory pathways. Synthetic LXR agonists inhibit the macrophage response to bacterial pathogens and antagonize the induction of a number of pro-inflammatory genes. The aim of this study was to investigate the preventive effects of synthetic LXR agonist, GW3965, treatment on the evolution of arthritis and inflammatory response in a murine CIA model.


METHODS
Intradermal injection of bovine type II CIA in DBA/1 mice. Along with the induction of CIA, mice were treated with oral GW3965 (0.1, 0.3 or 1.0 mg/kg/day) or vehicle from Day 1 to Day 40. Clinical assessment for arthritis scores and histopathological assessment of joint sections were performed. The expression of inflammatory mediators was evaluated by immunohistochemical staining. Serum pro-inflammatory cytokine levels were determined using ELISA.


RESULTS
The CIA incidence was 100% on Day 27 and the severity progressed until Day 35 with histological features of cartilage erosion in vehicle-treated mice. GW3965 treatment significantly reduced the arthritis incidence and attenuated the clinical and histological severity, compared with vehicle-treated mice. GW3965 treatment also significantly reduced inflammatory mediator production in joint sections and serum pro-inflammatory cytokine levels in a dose-dependent manner.


CONCLUSIONS
These results indicate that activation of LXRs suppresses the onset of CIA and reduces inflammation and joint destruction in CIA mice. The data could suggest that LXR treatment is an effective prophylactic approach to suppress the evolution of synovitis and resultant joint destruction observed in RA.
Department of Internal Medicine, Division of Rheumatology, Yonsei University College of Medicine, Seoul, South Korea. mcpark@yuhs.ac
Min-Chan
MC
Park
Yong-Jin
YJ
Kwon
Soo-Jin
SJ
Chung
Yong-Beom
YB
Park
Soo-Kon
SK
Lee
D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism* / Q000517:prevention & control; D001565:Benzoates / Q000378:metabolism*; D001596:Benzylamines / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D018836:Inflammation Mediators / Q000378:metabolism*; D000071518:Liver X Receptors; D051379:Mice; D008811:Mice, Inbred DBA; D057093:Orphan Nuclear Receptors / Q000819:agonists* / Q000378:metabolism
D001565:Benzoates; D001596:Benzylamines; D016207:Cytokines; C473027:GW 3965; D018836:Inflammation Mediators; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors