Therapeutic effects of a novel tylophorine analog, NK-007, on collagen-induced arthritis through suppressing tumor necrosis factor α production and Th17 cell differentiation
Article first published online: 27 AUG 2012
Copyright © 2012 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 64, Issue 9, pages 2896–2906, September 2012
How to Cite
Wen, T., Li, Y., Wu, M., Sun, X., Bao, X., Lin, Y., Hao, J., Han, L., Cao, G., Wang, Z., Liu, Y., Wu, Z., Hong, Z., Wang, P., Zhao, L., Li, Z., Wang, Q. and Yin, Z. (2012), Therapeutic effects of a novel tylophorine analog, NK-007, on collagen-induced arthritis through suppressing tumor necrosis factor α production and Th17 cell differentiation. Arthritis & Rheumatism, 64: 2896–2906. doi: 10.1002/art.34528
- Issue published online: 27 AUG 2012
- Article first published online: 27 AUG 2012
- Accepted manuscript online: 10 MAY 2012 01:41PM EST
- Manuscript Accepted: 26 APR 2012
- Manuscript Received: 9 FEB 2012
- National Basic Research Program of China. Grant Number: 2010CB529104
- National Natural Science Foundation of China. Grant Number: 30890143
- International Science and Technology Cooperation Program of China. Grant Number: 2010DFB34000
To analyze the effects of a novel compound, NK-007, on the prevention and treatment of collagen-induced arthritis (CIA) and the underlying mechanisms.
We determined the effect of NK-007 on lipopolysaccharide (LPS)–triggered tumor necrosis factor α (TNFα) production by murine splenocytes and a macrophage cell line (RAW 264.7) by enzyme-linked immunosorbent assay, intracellular cytokine staining, and Western blotting. The LPS-boosted CIA model was adopted, and NK-007 or vehicle was administered at different time points after immunization. Mice were monitored for clinical severity of arthritis, and joint tissues were used for histologic examination, cytokine detection, and immunohistochemical staining. Finally, stability of TNFα production and Th17 cell differentiation were studied using quantitative polymerase chain reaction and flow cytometry.
NK-007 significantly suppressed LPS-induced TNFα production in vitro. Administration of NK-007 completely blocked CIA development and delayed its progression. Furthermore, treatment with NK-007 at the onset of arthritis significantly inhibited the progress of joint inflammation. Administration of NK-007 also suppressed production of TNFα, interleukin-6 (IL-6), and IL-17A in the joint and reduced percentages of IL-17+ cells among CD4+ and γ/δ T cells in draining lymph nodes. We further demonstrated that NK-007 acted on the stability of TNFα messenger RNA and reduced Th17 cell differentiation. In addition, it significantly inhibited levels of IL-6 and IL-17A in human coculture assay.
For its effects on the development and progression of CIA and for its therapeutic effect on CIA, NK-007 has great potential to be a therapeutic agent for human rheumatoid arthritis.