Combination of gp130-targeting and TNF-targeting small molecules in alleviating arthritis through the down-regulation of Th17 differentiation and osteoclastogenesis
- Authors
- Park, Yeon-Hwa; Kim, Hee Jung; Lee, Kyeong; Choi, Yongseok; Heo, Tae-Hwe
- Issue Date
- 19-2월-2020
- Publisher
- ACADEMIC PRESS INC ELSEVIER SCIENCE
- Keywords
- LMT-28; Tetrahydropapaverine; Collagen-induced arthritis; Fibroblast-like synoviocytes; Th17; Osteoclastogenesis
- Citation
- BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, v.522, no.4, pp.1030 - 1036
- Indexed
- SCIE
SCOPUS
- Journal Title
- BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
- Volume
- 522
- Number
- 4
- Start Page
- 1030
- End Page
- 1036
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/57625
- DOI
- 10.1016/j.bbrc.2019.11.183
- ISSN
- 0006-291X
- Abstract
- Rheumatoid arthritis (RA) is a systemic, chronic inflammatory disease that is characterized by T helper 17 (Th17) cell- and osteoclast-induced joint destruction and inflammation. In RA, several cytokines (interleukin (IL)-1, 6,17, and tumor necrosis factor (TNF)) are involved in almost all aspects of articular inflammation and destruction. This study aimed to evaluate the combinatorial effect of TNF and IL-6 inhibitors on the differentiation and activation of Th17 cells and osteoclasts in the context of RA, and to identify the RA-related mechanisms through IL-6 signaling. Tetrahydropapaverine (THP) showed direct binding to TNF in screening-ELISA, and SPR and TNF-neutralization assays. In a previous study, the therapeutic effect of gp130-targeting LMT-28 was confirmed in RA. Combinatorial treatment with LMT-28 and THP reduced the arthritis index and showed protective effects against bone and cartilage destruction in CIA mice. The secretion levels of TNF, IL-6, and IL-1 beta significantly decreased upon combinatorial treatment with LMT-28 and THP. Further, the LMT-28 and THP combination suppressed the differentiation and activation of Th17 cells in mouse splenocytes and human PBMCs. In human RA-FLS, the LMT-28 and THP combination inhibited cell proliferation and downregulated IL-6 and/or TNF-mediated signaling relative to that observed upon independent treatment with LMT-28 or THP. Furthermore, the combination of LMT-28 and THP significantly inhibited the differentiation of mouse bone marrow monocytes (BMMs) into osteoclasts. In conclusion, the LMT-28 and THP combination can attenuate RA through the inhibition of Th17 differentiation and osteoclastogenesis, and suppression of IL-6 or TNF-induced signaling pathways. This combinatorial therapy could be used as a new strategy for the treatment of RA. (C) 2019 Elsevier Inc. All rights reserved.
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