Yra-1909 suppresses Production of Pro-Inflammatory Mediators and MMPs through Downregulating Akt, p38, JNK and NF-κb Activation in Rheumatoid Arthritis Fibroblast-like Synoviocytes

Hyun Jung Yoo^1,2, Jeong Yeon Kim¹, Shin Eui Kang¹, Ji Seok Yoo³, Yong Nam Lee³, Dong Goo Lee³, Ji Soo Park¹, Eun Bong Lee⁴, Eun Young Lee⁴ and Yeong Wook Song^2,5, ¹Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea, Seoul, Korea, Republic of (South), ²Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea, Seoul, Korea, Republic of (South), ³Central R&D Institute, Yungjin Pharm Co., Ltd., Suwon, Korea, Suwon, Korea, Republic of (South), ⁴Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea, Republic of (South), ⁵Department 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)

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: cytokines, drug treatment, pathogenesis, rheumatoid arthritis, synovium and signal transduction

Session Information

Date: Monday, November 6, 2017

Session Title: Rheumatoid Arthritis – Human Etiology and Pathogenesis Poster II

Session Type: ACR Poster Session B

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

Background/Purpose: Rheumatoid arthritis (RA) is characterized by hyperplastic synovial pannus tissue, which mediates destruction of cartilage and bone. Fibroblast-like synoviocyte (FLS) are a key component of the invasive pannus and have a major role in the initiation and perpetuation of destructive joint inflammation. Stauntonia hexalphylla (Lardizabalaceae) is widely distributed in Korea, Japan and China, and is a popular herbal supplement in Korean and Chinese folk medicine owing to its analgesic, sedative, and diuretic properties. However, the exact pharmacological effects of S. hexaphylla extract, particularly its effect on inflammation, are not known. We investigated the suppressive effects of S. hexaphyllaextract, YRA-1909 on the aggressiveness of lipopolysaccharide (LPS) – induced RA-FLS.

Methods: RA-FLS were cultured from synovial specimens obtained from RA patients undergoing joint replacement therapy. Inflammatory cytokines/chemokines level was measured by multiplex cytokine ELISA. Matrix metalloproteinase-2 (MMP-2) activity was measured using gelatin zymography. The expression of p-ERK1/2, p-p38, p-JNK and p-Akt was detected by Western blot analysis. The location of NF-κB p65 and expression of pro-inflammatory mediators in RA-FLS was detected by immunofluorescence microscope.

Results: YRA-1909 inhibited the production of pro-inflammatory cytokines, chemokines and matrix metalloproteinases (MMPs) including tumor necrosis factor-α, interleukin-6 (IL-6), IL-17A, CXCL8, CXCL10, MMP-1, 2, 3, 9 and 13 in RA-FLSs. Moreover, YRA-1909 suppressed LPS-induced MMP-2 enzyme activity and expression of MMP-2 and MMP-9 in RA-FLSs. YRA-1909 inhibited LPS-induced nuclear factor kappa B (NF-κB) activation by reducing the phosphorylation of p65 at Ser468 and Ser536. YRA-1909 also suppressed nucleus translocation of p65. Furthermore, YRA-1909 suppressed LPS-induced phosphorylation Akt and mitogen-activated protein kinases (MAPKs), including JNK1/2, and p38 signaling.

Conclusion: YRA-1909 reduces production of inflammatory cytokines/chemokines via inhibition of MMP-2 activity and MAPKs-NF-κB signaling pathway in activated RA-FLS. These observations suggest that YRA-1909 might be useful for the development of new anti-inflammatory agents.

Disclosure: H. J. Yoo, None; J. Y. Kim, None; S. E. Kang, None; J. S. Yoo, None; Y. N. Lee, None; D. G. Lee, None; J. S. Park, None; E. B. Lee, None; E. Y. Lee, None; Y. W. Song, None.

To cite this abstract in AMA style:

Yoo HJ, Kim JY, Kang SE, Yoo JS, Lee YN, Lee DG, Park JS, Lee EB, Lee EY, Song YW. Yra-1909 suppresses Production of Pro-Inflammatory Mediators and MMPs through Downregulating Akt, p38, JNK and NF-κb Activation in Rheumatoid Arthritis Fibroblast-like Synoviocytes [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/yra-1909-suppresses-production-of-pro-inflammatory-mediators-and-mmps-through-downregulating-akt-p38-jnk-and-nf-%ce%bab-activation-in-rheumatoid-arthritis-fibroblast-like-synoviocytes/. Accessed May 18, 2022.

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