title: Therapeutic effects of a novel tylophorine analog, NK-007, on collagen-induced arthritis through suppressing tumor necrosis factor α production and Th17 cell differentiation.
abstract: OBJECTIVE
  To analyze the effects of a novel compound, NK-007, on the prevention and treatment of collagen-induced arthritis (CIA) and the underlying mechanisms.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Nankai University, Tianjin, China.
authors.forename: Ti
authors.initials: T
authors.lastname: Wen
authors.forename: Yangguang
authors.initials: Y
authors.lastname: Li
authors.forename: Meng
authors.initials: M
authors.lastname: Wu
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Sun
authors.forename: Xiucong
authors.initials: X
authors.lastname: Bao
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Lin
authors.forename: Jianlei
authors.initials: J
authors.lastname: Hao
authors.forename: Lin
authors.initials: L
authors.lastname: Han
authors.forename: Guangchao
authors.initials: G
authors.lastname: Cao
authors.forename: Ziwen
authors.initials: Z
authors.lastname: Wang
authors.forename: Yuxiu
authors.initials: Y
authors.lastname: Liu
authors.forename: Zhenzhou
authors.initials: Z
authors.lastname: Wu
authors.forename: Zhangyong
authors.initials: Z
authors.lastname: Hong
authors.forename: Puyue
authors.initials: P
authors.lastname: Wang
authors.forename: Liqing
authors.initials: L
authors.lastname: Zhao
authors.forename: Zhanguo
authors.initials: Z
authors.lastname: Li
authors.forename: Qingmin
authors.initials: Q
authors.lastname: Wang
authors.forename: Zhinan
authors.initials: Z
authors.lastname: Yin
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D002460:Cell Line; D007212:Indolizines / Q000494:pharmacology / Q000627:therapeutic use*; D020381:Interleukin-17 / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D010616:Phenanthrenes / Q000494:pharmacology / Q000627:therapeutic use*; D020871:RNA Stability / Q000187:drug effects / Q000276:immunology; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D007212:Indolizines; D020381:Interleukin-17; C576415:NK-007; D010616:Phenanthrenes; D014409:Tumor Necrosis Factor-alpha