t0901317 and Arthritis--Rheumatoid

Fibroblast-like synoviocyte (FLS) invasiveness correlates with articular damage in rheumatoid arthritis (RA), yet little is known about its regulation. In this study we aimed to determine the role of the nuclear receptor liver X receptor (LXR) in FLS invasion. FLS were isolated from synovial tissues obtained from RA patients and from DA rats with pristane-induced arthritis. Invasion was tested on Matrigel-coated chambers in the presence of the LXR agonist T0901317, or control vehicle. FLS were cultured in the presence or absence of T0901317, and supernatants were used to quantify matrix metalloproteinase 1 (MMP-1), MMP-2, MMP-3, interleukin-6 (IL-6), tumor necrosis factor-α and C-X-C motif chemokine ligand 10 (CXCL10). Nuclear factor-κB (NF-κB) (p65) and Akt activation, actin cytoskeleton, cell morphology and lamellipodia formation were also determined. The LXR agonist T0901317 significantly reduced DA FLS invasion by 99% (P ≤ 0.001), and RA FLS invasion by 96% (P ≤ 0.001), compared with control. T0901317-induced suppression of invasion was associated with reduced production of activated MMP-2, IL-6 and CXCL10 by RA FLS, and with reduction of actin filament reorganization and reduced polarized formation of lamellipodia. T0901317 also prevented both IL-1β-induced and IL-6-induced FLS invasion. NF-κB (p65) and Akt activation were not significantly affected by T0901317. This is the first description of a role for LXR in the regulation of FLS invasion and in processes and pathways implicated both in invasion as well as in inflammatory responses. These findings provide a new rationale for considering LXR agonists as therapeutic agents aimed at reducing both inflammation and FLS-mediated invasion and destruction in RA.

Topics: Animals; Arthritis, Rheumatoid; Cell Movement; Cell Polarity; Cell Shape; Chemokine CXCL10; Enzyme Activation; Fibroblasts; Humans; Hydrocarbons, Fluorinated; Interleukin-1beta; Interleukin-6; Liver X Receptors; Matrix Metalloproteinase 2; Matrix Metalloproteinase 3; NF-kappa B; Orphan Nuclear Receptors; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Stearoyl-CoA Desaturase; Sulfonamides; Synovial Membrane

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.. 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.. 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.. 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.

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Cartilage, Articular; Cells, Cultured; Disease Models, Animal; DNA-Binding Proteins; Humans; Hydrocarbons, Fluorinated; Inflammation; Interleukin-17; Interleukin-1alpha; Interleukin-6; Lipopolysaccharides; Liver X Receptors; Male; Mice; Mice, Inbred DBA; Monocytes; Orphan Nuclear Receptors; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Sulfonamides