A Novel Histone Deacetylase 6 Inhibitor, CKD-M808, Regulates the Adhesion and Migration of Fibroblast-like Synoviocytes, and Enhances Suppressive Function of Regulatory T Cells in Rheumatoid Arthritis

Sehui Shon¹, Ji Soo Park¹, Shin Eui Kang¹, Jeong Yeon Kim¹, Dong-Hyeon Suh², Daekwon Bae², Nina Ha², Young Il Choi², Jin Kyun Park^1,3, Eun Young Lee³, Eun Bong Lee³ and Yeong Wook Song^3,4, ¹Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine, Seoul National University, Seoul, Korea, Republic of (South), ²Research Institute of Chong Kun Dang Pharmaceutical Corporation, Yongin, Korea, Republic of (South), ³Division of Rheumatology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea, Republic of (South), ⁴Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Koer, Seoul, Korea, Republic of (South)

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: regulatory cells and rheumatoid arthritis (RA)

Session Information

Date: Sunday, November 5, 2017

Title: Cytokines, Mediators, Cell-Cell Adhesion, Cell Trafficking and Angiogenesis Poster I: The Variable World of Intercellular Signalling

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose:

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by bone and cartilage destruction with leukocyte infiltration and activation at synovial tissue. Recently, upregulated histone deacetylase (HDAC) activity has been reported in peripheral blood mononuclear cells (PBMCs) from RA patients. In addition, it has been reported that HDAC inhibitor (HDACi) improved cancers, neurological diseases and inflammatory diseases by suppressing pro-inflammatory cytokines such as TNF-α and IL-6. Previously, we reported that a novel histone deacetylase 6 inhibitor (HDAC6i), CKD-M808 (M808) decreased clinical score in adjuvant induced arthritis (AIA) rat model. Here, we investigated the effect of M808 on cell adhesion, migration and suppressive function of regulatory T cells (T_reg) derived from RA patients.

Methods:

Fibroblast-like synoviocytes (FLS) were isolated from synovial tissues of RA patients, and treated with HDAC6i such as tubastatin A and M808 under IL-1β stimulation. The expression of α-tubulin, acetylated tubulin, intracellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 were measured in RA FLS by western blotting. The levels of CCL2, CXCL8 and CXCL10 were measured in culture supernatant. Wound healing assay were performed to confirm cell migration ability. The adhesion of U937 or Jurkat cells onto RA FLS was measured by cell adhesion assay. CD4+CD25- T cells (effector T cells, T_eff) were isolated from RA PBMCs, and differentiated into induced T_reg (iT_reg) under differentiating media. After the differentiation, Foxp3 and CTLA-4 were analyzed by flow cytometry. iT_reg were also co-cultured with carboxyfluorescein succinmidyl ester (CFSE)-labeled T_eff derived from healthy donor. The proliferation of T_eff was analyzed by flow cytometry.

Results:

M808 increased the acetylation of tubulin in RA FLS. The number of migrated cell was decreased in M808-treated RA FLS without the change in cell viability. The expression of ICAM-1 and VCAM-1 were decreased in HDAC6i-treated groups in a dose-dependent manner. M808 reduced the levels of chemokines including CCL2, CXCL8 and CXCL10 in RA FLS. In addition, M808 attenuated the adhesion of U937 and Jurkat cells on RA FLS. The suppressive function of iT_reg were significantly increased in M808-treated groups.

Conclusion:

M808 increased the acetylation of tubulin, and decreased the migration of RA FLS. M808 also decreased the expression of ICAM-1, VCAM-1 and chemokines such as CCL2, CXCL8 and CXCL10. The adhesion between RA FLS and U937 or Jurkat cells was decreased in the presence of M808. M808 increased the suppressive function of iT_reg derived from RA PBMCs. The novel HDAC6i, M808, may provide a new therapeutic option in RA patients.

Disclosure: S. Shon, CKD Research Institute, 2; J. S. Park, None; S. E. Kang, None; J. Y. Kim, None; D. H. Suh, CKD Research Institute, 2; D. Bae, CKD Research Institute, 2; N. Ha, CKD Research Institute, 2; Y. I. Choi, CKD Research Institute, 2; J. K. Park, None; E. Y. Lee, None; E. B. Lee, None; Y. W. Song, CKD Research Institute, 2.

To cite this abstract in AMA style:

Shon S, Park JS, Kang SE, Kim JY, Suh DH, Bae D, Ha N, Choi YI, Park JK, Lee EY, Lee EB, Song YW. A Novel Histone Deacetylase 6 Inhibitor, CKD-M808, Regulates the Adhesion and Migration of Fibroblast-like Synoviocytes, and Enhances Suppressive Function of Regulatory T Cells in Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/a-novel-histone-deacetylase-6-inhibitor-ckd-m808-regulates-the-adhesion-and-migration-of-fibroblast-like-synoviocytes-and-enhances-suppressive-function-of-regulatory-t-cells-in-rheumatoid-arth/. Accessed .

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