Liver X receptor regulates rheumatoid arthritis fibroblast-like synoviocyte invasiveness, matrix metalloproteinase 2 activation, interleukin-6 and CXCL10.
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.
Laboratory of Experimental Rheumatology, Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, New York 11030, United States of America.
Teresina
T
Laragione
Pércio S
PS
Gulko
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000201:enzymology / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects; D016764:Cell Polarity / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D054357:Chemokine CXCL10 / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D000071518:Liver X Receptors; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013583:Synovial Membrane / Q000473:pathology*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D054357:Chemokine CXCL10; D006845:Hydrocarbons, Fluorinated; D053583:Interleukin-1beta; D015850:Interleukin-6; D000071518:Liver X Receptors; D020778:Matrix Metalloproteinase 2; D019278:Matrix Metalloproteinase 3; D016328:NF-kappa B; D057093:Orphan Nuclear Receptors; D051057:Proto-Oncogene Proteins c-akt; D013230:Stearoyl-CoA Desaturase; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides