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Abstract Number: 117

The Indole Derivative NecroX Blocks Th17 Cell Differentiation and Fibroblast-like Synoviocytes-mediated Th1/Th17 Responses in Rheumatoid Arthritis

Hyun Jung Yoo1, Shin Eui Kang 2, Ji Hye Lee 3, Ra Ham Kim 4 and Yeong-Wook Song 5, 1Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine, Seoul National University, Seoul, Repulbic of Korea, Seoul, Republic of Korea, 2Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine, Seoul National University, Seoul, Republic of Korea, Seoul, Republic of Korea, 3Division of Rheumatology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea., Seoul, Republic of Korea, 4Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine, Seoul National University, Seoul, Republic of Korea, Seoul, Republic of Korea, 5Seoul National University Hospital, Seoul, Republic of Korea

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: Rheumatoid arthritis (RA), small molecules and inflammatory cytokines, Synovial Immune Biology, Th17

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Session Information

Date: Sunday, November 10, 2019

Title: T Cell Biology & Targets in Autoimmune & Inflammatory Disease Poster

Session Type: Poster Session (Sunday)

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

Background/Purpose: Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of synovium, which causes progressive joint destruction and reduction in quality of life. T-helper-17 (Th17) cells have been implicated to play a crucial role in the development and progression of persistent inflammation. In addition, Th17 cells from patients with early RA induce a pro-inflammatory feedback loop upon RA fibroblast-like synoviocytes (RA-FLS) interaction, including autocrine interleukin (IL)-17A production. NecroX is an inhibitor of necrosis/necroptosis and has been shown to scavenge mitochondrial reactive oxygen and nitrogen species in inflammatory cells, and preventing necrotic cell death against various kinds of oxidative stresses. We aimed to investigate the effects of NecroX on Th17 cell differentiation and T cell – RA-FLS interaction and the production of immune mediators in these interactions.

Methods: RA-FLS were cultured from synovial specimens obtained from RA patients undergoing joint replacement therapy. Inflammatory cytokines/chemokines level was measured by ELISA. Human CD4+ T cells were isolated by magnetic-activated cell sorting from healthy controls and RA patients. Activated naïve CD4+ T cells were pretreated with or without NecroX for Th17 differentiation. The location of phosphorylated signal transducer and activator of transcription 3 (pSTAT3) was detected by immunofluorescence microscope. Human CD4+ T cells were cultured with or without NecroX or co-cultured with RA-FLS by transwell culture system. Th1 or Th17 phenotype was measured by flow cytometry and culture supernatant was collected for analyses of IFN-gamma and IL-17A by ELISA.

Results: NecroX reduced the TNF-alpha induced production of IL-6, CXCL10, MMP-1, 3, 9 and 13 in RA-FLS. When peripheral CD4+ T cells were cultured under Th17 condition, NecroX decreased the population of IL-17+ and CD4+ T cells, and production of IL-17A in dose-dependent manner and also prevented the nuclear translocation of pSTAT3. When RA-FLS were co-cultured with CD4+ T cells, NecroX-7 inhibited RA-FLS-mediated Th1 and Th17 cell expansion both in cell-cell contact-dependent and inflammatory cytokine-dependent manners.

Conclusion: NecroX could be an immune regulator of inflammatory arthritis by suppressing Th17 cell differentiation and RA-FLS activation and inhibiting the pro-inflammatory feedback loop between Th17 cell and RA-FLS. These observations suggest that NecroX might be useful for the development of anti-inflammatory agents.


Disclosure: H. Yoo, None; S. Kang, None; J. Lee, None; R. Kim, None; Y. Song, Astellas Pharma, Inc., 9.

To cite this abstract in AMA style:

Yoo H, Kang S, Lee J, Kim R, Song Y. The Indole Derivative NecroX Blocks Th17 Cell Differentiation and Fibroblast-like Synoviocytes-mediated Th1/Th17 Responses in Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/the-indole-derivative-necrox-blocks-th17-cell-differentiation-and-fibroblast-like-synoviocytes-mediated-th1-th17-responses-in-rheumatoid-arthritis/. Accessed .
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-indole-derivative-necrox-blocks-th17-cell-differentiation-and-fibroblast-like-synoviocytes-mediated-th1-th17-responses-in-rheumatoid-arthritis/

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