Objectives: The interleukin-6 (IL-6)-mediated signaling pathway plays an essential role in the development of rheumatoid arthritis. LMT-28 suppresses the activation of the IL-6-mediated signaling by direct targeting of gp130. Although LMT-28 and metformin both possess anti-inflammatory activity, the beneficial effect of LMT-28 and metformin combination on a collagen-induced arthritis (CIA) model has not yet been investigated. This study aimed to investigate the anti-inflammatory effect and mechanism of a combination of LMT-28 and metformin in a CIA model. Methods: In MH7A cells, cell proliferation and the IL-6-mediated signaling pathway following administration of LMT-28 and metformin combination was analyzed through MTT assay and Western blotting. The level of T helper 17 (Th17) cell differentiation from CD4+ T cells was analyzed in mouse splenocytes and human peripheral blood mononuclear cells. Arthritis score, incidence rate, inflammatory cytokine, and T-cell subsets were measured in CIA mice following administration of LMT-28 and metformin combination. Results: Combination treatment with LMT-28 and metformin diminished proliferation of MH7A cells and IL-6-mediated gp130, STAT3, and ERK signaling more than in individual treatments. Furthermore, the differentiation of CD4+ T cells into Th17 cells was attenuated more by combination treatment with LMT-28 and metformin than individual treatments. The combination of LMT-28 and metformin ameliorated the arthritic score better than individual treatments. The combination significantly reduced tumor necrosis factor and IL-6 levels in the sera and had an anti-inflammatory effect on the distribution of Treg/Th17 cells in the lymph nodes. Conclusion: Combination treatment with LMT-28 and metformin significantly ameliorates arthritic symptoms in CIA by suppressing Th17 differentiation and IL-6 signaling.
Bibliographical noteFunding Information:
This research was supported by the Korean Health Technology R&D Project through the Korean 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 (2018R1A6A1A03025108), and by the Research Fund 2020 of the Catholic University of Korea, and BK21 Plus project of the NRF funded by the Ministry of Education of Korea (22A20130012250). This study was supported by grants from the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF 2018R1A5A2023127). We thank Dr. Stefan Rose-John for providing Hyper-IL-6.
© 2021 S. Karger AG, Basel. Copyright: All rights reserved.
- Collagen-induced arthritis
- Fibroblast-like synoviocytes
- T helper 17
ASJC Scopus subject areas