Therapeutic effects of a novel Tylophorine analog NK-007 on collagen-induced arthritis through suppressing TNF-(alpha) production and Th17 differentiation

Arthritis & Rheumatism, 05/11/2012

Wen T et al. – For its effects on the development, progression and therapeutic effect on collagen–induced arthritis, NK–007 has a great potential to be a therapeutic agent for human RA.

Methods

  • The effect of NK–007 on lipopolysaccharides (LPS)–triggered tumor necrosis factor– α (TNF–α) production by murine splenocytes and macrophage cell line (Raw 264.7) was determined by ELISA, intracellular cytokine staining as well as Western Blot.
  • LPS–boosted CIA model was adopted and NK–007 or vehicle was administered at different time points post immunization and the mice were monitored for the clinical severity, the joint tissues were used for histological examination, cytokine detection and immunohistochemical staining.
  • Finally, stability of TNF–α and Th17 differentiation were studied using qPCR and flow cytometry.

Results

  • NK–007 significantly suppressed LPS–induced TNF–α production in vitro.
  • Administration of NK–007 completely blocked CIA development and 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 TNF–α, IL–6 and IL–17A in joint, and reduced IL–17 positive cells in CD4+ and γδ T cells in draining lymph nodes.
  • The authors further demonstrated that NK–007 acted on the stability of TNF–α mRNA, and reduced Th17 differentiation.
  • In addition, it significantly inhibited IL–6 and IL–17A level in human co–culture assay.

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