The role of the liver X receptors in inflammation: exploring their contribution to articular pathology

Asquith, Darren Lee (2010) The role of the liver X receptors in inflammation: exploring their contribution to articular pathology. PhD thesis, University of Glasgow.

Abstract

The Liver X receptors, LXRα and LXRβ, belong to the superfamily of nuclear receptor ligand activated transcription factors. LXRs have been well characterised in the context of metabolism through their ability to induce reverse cholesterol transport leading to the excretion of cholesterol from the body. More recently, LXRs have been shown to play a role in inflammation in which they are often ascribed an anti-inflammatory effect. Rheumatoid arthritis (RA) is a chronic auto-immune condition manifest as inflammation of the diarthrodial joints predominantly in the hands and feet. It is now well recognised that RA is not just a local but rather a systemic disease that is associated with several co-morbidities including atherosclerosis. A major focus in the field of rheumatology is now to understand how cardiovascular disease might contribute to the pathogenesis of RA and vice versa and thereby connect metabolism with inflammation. Hypothesis: Since LXRs are central to the maintenance of a cholesterol homeostasis and have been shown to regulate inflammation we hypothesised that LXR agonists would be beneficial for the treatment of RA. Methods & Results: Treatment of male DBA1 mice with GW3965 or T1317 in the murine model of collagen-induced arthritis dramatically increased the onset and severity of disease. Exacerbation of disease severity was characterised by increased concentrations of multiple serum pro-inflammatory cytokines and chemokines, increased numbers of lymph node derived Th1 and Th17 cells and elevated titres of anti-collagen auto-antibodies. The effect of LXR agonist administration was mediated specifically by LXRs as the severity of disease was not altered in LXR null mice treated with GW3965. Furthermore, activation of LXRs in primary human monocytes potentiated the secretion of multiple proinflammatory cytokines in response to stimulation with LPS. Similarly, the concentration of multiple pro-inflammatory cytokines was also increased in an in vitro model of synovitis. Conclusion: These studies demonstrate a novel pro-inflammatory role of LXR activation in the context of arthritis. Furthermore, these results suggest that the development of LXR agonists as a therapy for metabolic disorders should be done so with caution.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Liver X receptors, Inflammation, rheumatoid arthritis, cholesterol
• Subjects: R Medicine > RZ Other systems of medicine; Q Science > Q Science (General)
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Supervisor's Name: Iain, Prof. McInnes
• Date of Award: 2010
• Depositing User: Mr Darren L Asquith
• Unique ID: glathesis:2010-1796
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 14 May 2010
• Last Modified: 10 Dec 2012 13:46
• URI: https://theses.gla.ac.uk/id/eprint/1796