title: Inhibition of glycogen synthase kinase-3β suppresses inflammatory responses in rheumatoid arthritis fibroblast-like synoviocytes and collagen-induced arthritis.
abstract: OBJECTIVE
  Glycogen synthase kinase (GSK)-3β, a serine/threonine protein kinase, has been implicated as a regulator of the inflammatory response. This study was performed to evaluate the effect of selective GSK-3β inhibitors in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) and collagen-induced arthritis (CIA).
  
  
  METHODS
  FLS from RA patients were treated with selective GSK-3β inhibitors, including lithium chloride, 6-bromoindirubin-3'-oxime (BIO), or 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8). The effects of GSK-3β inhibition on pro-inflammatory mediators were determined by real-time PCR and ELISA. The levels of NF-κB, phosphorylated JNK, c-jun, ATF-2 and p-38 proteins were evaluated by western blot analysis. The in vivo effects of GSK-3β inhibitors were examined in mice with CIA.
  
  
  RESULTS
  Treatment of RA FLS with GSK-3β inhibitors induced dose-dependent reductions in gene expression and the production of pro-inflammatory mediators. The levels of NF-κB, phosphorylated JNK, c-jun, ATF-2 and p-38 were decreased following treatment with GSK-3β inhibitors. GSK-3β inhibitors treatment attenuated clinical and histological severities of CIA in mice. Infiltration of T-cells, macrophages, and tartrate-resistant acid phosphatase positive cells was decreased in joint sections of CIA mice by GSK-3β inhibitors treatment. Serum levels of IL-1β, IL-6, TNF-α and IFN-γ in CIA mice were also significantly decreased in dose-dependent manners by treatment with GSK-3β inhibitors.
  
  
  CONCLUSIONS
  Treatment with GSK-3β inhibitors suppressed inflammatory responses in RA FLS and CIA mice. These findings suggest that the inhibition of GSK-3β can be used as an effective therapeutic agent for RA.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Yong-Jin
authors.initials: YJ
authors.lastname: Kwon
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Chong-Hyeon
authors.initials: CH
authors.lastname: Yoon
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Sang-Won
authors.initials: SW
authors.lastname: Lee
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Yong-Beom
authors.initials: YB
authors.lastname: Park
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Soo-Kon
authors.initials: SK
authors.lastname: Lee
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea. Electronic address: mcpark@yuhs.ac.
authors.forename: Min-Chan
authors.initials: MC
authors.lastname: Park
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D013583:Synovial Membrane / Q000187:drug effects / Q000473:pathology*
chemical_list: D018501:Antirheumatic Agents; D038362:Glycogen Synthase Kinase 3
keywords: Collagen-induced arthritis; Fibroblast-like synoviocytes; Glycogen synthase kinase-3β; Rheumatoid arthritis