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Abstract Number: 2464

Anti-Arthritic Effect of Tubastatin A, a Novel Histone Deacetylases-6 Inhibitor, Is Mediated By Stabilization of IkB Via Suppression of Ubiquitin-Proteasome Pathway

Eun Chung Hong1, Hemin Jeong2, Jiwon Hwang2, Eun-Kyung Bae1, Hyungjin Kim2, Joong Kyong Ahn3, Hoon-Suk Cha2, Eun-mi Koh4 and Jaejoon Lee4, 1Samsung Biomedical Research Institute, Seoul, South Korea, 2Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea, 3Sungkyunkwan univ. school of medicine, Seoul, South Korea, 4Division of Rheumatology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Fibroblasts, histone acetylation, IL-6, rheumatoid arthritis (RA) and tumor necrosis factor (TNF)

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Session Information

Title: Rheumatoid Arthritis - Human Etiology and Pathogenesis

Session Type: Abstract Submissions (ACR)

Background/Purpose: Histone deacetylase-6 (HDAC-6) functions as a non-epigenetic deacetylase for non-histone substrates and regulates microtubule-mediates processes such as cell migration, cell cycle arrest, and angiogenesis. We have previously demonstrated that Tubastatin A suppresses synovial inflammation and joint destruction in a collagen antibody-induced arthritis mouse model. However, the exact mechanism through which Tubastatin A exerts its anti-arthritic effect is not fully understood. The aim of the study is to investigate whether ubiquitin-proteasome pathway is involved in the anti-arthritic mechanism of Tubastatin A.

Methods: Fibroblast-like synoviocytes (FLS) were treated with TNF-α in a time-dependent manner (control, 5, 15, 30 minutes) and the phosphorylation activity of NF-κB and IκB was measured using Western blot analysis. FLS were stimulated with TNF-α after treatment with different doses of proteasome inhibitor (MG-132) or Tubastatin A, and the expression of IL-6 were measured using ELISA. FLS were stimulated with TNF-α after treatment with different doses of Tubastatin A and phosphorylation of nuclear NF-κB and of cytosolic IκB were measured using Western blot analysis. FLS were stimulated with TNF-α in a time dependent manner (15, 30, 45, 60 min) after pretreatment with Tubastatin A or control and expression of phosphorylated IκB was measured using Western blot analysis. FLS were treated with TNF-α after treatment with different doses of Tubastatin A, and cytosolic proteasome activity was measured using 20S Proteasome Activity Assay Kit.

Results: The phosphorylation of NF-κB and IκB were increased after stimulation of TNF-α at 5 minutes. After stimulation with TNF-α, the expression of IL-6 was attenuated in FLS treated with Tubastatin A or MG-132 compared with controls. At 3µM of Tubastatin A, the phosphorylation of NF-κB induced by TNF-α was suppressed, and phosphorylated IκB in cytosol was increased. Furthermore, the total cytosolic IκB remained the same. Phosphorylated IκB appeared in the cytosol 30 min after incubation with TNF-α after treatment with Tubastatin A, but no effect was seen when treated with TNF-α alone. After stimulation with TNF-α, the cytosolic proteasome activity was significantly decreased after treatment of Tubastatin A or MG-132 compared with controls.

Conclusion: Our study demonstrates that Tubastatin A exerts its anti-arthritic effect, at least in part, through preventing degradation of IκB by attenuating ubiquitin-proteasome pathway, and thus inactivating nuclear translocation of NF-κB.


Disclosure:

E. C. Hong,
None;

H. Jeong,
None;

J. Hwang,
None;

E. K. Bae,
None;

H. Kim,
None;

J. K. Ahn,
None;

H. S. Cha,
None;

E. M. Koh,
None;

J. Lee,
None.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/anti-arthritic-effect-of-tubastatin-a-a-novel-histone-deacetylases-6-inhibitor-is-mediated-by-stabilization-of-ikb-via-suppression-of-ubiquitin-proteasome-pathway/

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