Session Type: Poster Session (Sunday)
Session Time: 9:00AM-11:00AM
Background/Purpose: Inhibition of HDAC6 has been proposed beneficial and therapeutic effects in inflammatory diseases. CKD-506, a potent and selective oral HDAC6 inhibitor, has anti-inflammatory and anti-rheumatic effects in arthritis animal models and RA patient samples. Moreover, CKD-506 was generally safe and well tolerated following single and multiple doses in healthy volunteers, and CKD-506 is on clinical investigation to assess the efficacy and safety in patients with rheumatoid arthritis. Herein, we identify the molecular mechanisms of CKD-506 in regulation of inflammation.
Methods: Mouse peritoneal macrophages and Raw264.7 cells were transfected with HDAC6 overexpression vector or pcDNA3.1 vector as control. Cells were cultured in the presence or absence of 0.03~3 μM CKD-506, and the expression and production of inflammatory mediators were determined by RT-PCR and ELISA respectively. For reporter assays, cells were transfected with pNF-kB-luc or pAP-1-luc plasmid and luciferase activity in cell lysates was determined by luminometer. Tubulin acetylation and signaling molecules by CKD-506 in HDAC6 overexpressed cells were checked by immunoblot analysis.
Results: HDAC6 overexpression in both Raw264.7 cells and mouse peritoneal macrophages strongly induced pro-inflammatory mediators such as TNFa, IL-6, IL-1b. However, CKD-506 inhibited the expression and production of TNFa, IL-6, and IL-b at dose dependent manners in HDAC6 overexpressed cells. Moreover, ROS production and NADPH oxidase activity mediated by HDAC6 overexpression were inhibited by CKD-506. In signaling pathway, HDAC6 overexpression strongly induced NF-kB and AP-1 activity and CKD-506 inhibited both signaling pathways. In addition, CKD-506 with methotrexate exhibited better anti-inflammatory effects on macrophages with HDAC6 overexpression.
Conclusion: CKD-506 inhibits inflammatory mediators such as TNFa, IL-6, IL-1b, ROS, and NADPH oxidase activity in HDAC6 overexpressed cells. This anti-inflammatory activities of CKD-506 are mediated through NF-kB and AP-1.
To cite this abstract in AMA style:Shin J, Ha N, Bae D, Suh D, Baek J, Jun J, Lee Y, Choi Y, Ryu K, Youn G, Park J. CKD-506, a Selective Histone Deacetylase (HDAC) 6 Inhibitor, Regulates Inflammatory Responses Through NF-kB and AP-1 Signaling [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/ckd-506-a-selective-histone-deacetylase-hdac-6-inhibitor-regulates-inflammatory-responses-through-nf-kb-and-ap-1-signaling/. Accessed July 4, 2020.
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