Inhibition of glycogen synthase kinase-3β suppresses inflammatory responses in rheumatoid arthritis fibroblast-like synoviocytes and collagen-induced arthritis

Yong Jin Kwon, Chong Hyeon Yoon, Sang Won Lee, YongBeom Park, Soo Kon Lee, Min Chan Park

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Objectives: 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). Method: 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)240-246
Number of pages7
JournalJoint Bone Spine
Volume81
Issue number3
DOIs
Publication statusPublished - 2014 Jan 1

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Glycogen Synthase Kinase 3
Experimental Arthritis
Rheumatoid Arthritis
Fibroblasts
Therapeutics
Synoviocytes
Lithium Chloride
Protein-Serine-Threonine Kinases
Interleukin-1
Real-Time Polymerase Chain Reaction
Interleukin-6

All Science Journal Classification (ASJC) codes

  • Rheumatology

Cite this

Kwon, Yong Jin ; Yoon, Chong Hyeon ; Lee, Sang Won ; Park, YongBeom ; Lee, Soo Kon ; Park, Min Chan. / Inhibition of glycogen synthase kinase-3β suppresses inflammatory responses in rheumatoid arthritis fibroblast-like synoviocytes and collagen-induced arthritis. In: Joint Bone Spine. 2014 ; Vol. 81, No. 3. pp. 240-246.
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abstract = "Objectives: 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). Method: 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. Conclusion: 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.",
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Inhibition of glycogen synthase kinase-3β suppresses inflammatory responses in rheumatoid arthritis fibroblast-like synoviocytes and collagen-induced arthritis. / Kwon, Yong Jin; Yoon, Chong Hyeon; Lee, Sang Won; Park, YongBeom; Lee, Soo Kon; Park, Min Chan.

In: Joint Bone Spine, Vol. 81, No. 3, 01.01.2014, p. 240-246.

Research output: Contribution to journalArticle

TY - JOUR

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AU - Yoon, Chong Hyeon

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AU - Lee, Soo Kon

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AB - Objectives: 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). Method: 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. Conclusion: 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.

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