Combination of gp130-targeting and TNF-targeting small molecules in alleviating arthritis through the down-regulation of Th17 differentiation and osteoclastogenesis: A combination of LMT-28 and THP alleviates CIA

Yeon Hwa Park, Hee Jung Kim, Kyeong Lee, Yongseok Choi, Tae Hwe Heo

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

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-1β 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.

Original languageEnglish
Pages (from-to)1030-1036
Number of pages7
JournalBiochemical and biophysical research communications
Volume522
Issue number4
DOIs
Publication statusPublished - 2020 Feb 19

Bibliographical note

Funding Information:
This research was supported by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Ministry of Health and Welfare, Republic of Korea ( HI16C1761 ), the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (grant no. 2018R1A6A1A03025108 and 2018R1A5A2023127 ) and by the Research Fund 2019 of the Catholic University of Korea , and BK21 Plus project of the NRF funded by Ministry of Education of Korea ( 22A20130012250 ). We thank Dr. Stefan Rose-John for providing Hyper-IL-6.

Publisher Copyright:
© 2019 Elsevier Inc.

Keywords

  • Collagen-induced arthritis
  • Fibroblast-like synoviocytes
  • LMT-28
  • Osteoclastogenesis
  • Tetrahydropapaverine
  • Th17

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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