title: Effects of a novel tylophorine analog on collagen-induced arthritis through inhibition of the innate immune response.
abstract: OBJECTIVE
  To test the effects of a novel tylophorine analog, DCB 3503, on the prevention and treatment of collagen-induced arthritis (CIA) and to elucidate its underlying mechanisms.
  
  
  METHODS
  DBA/1J mice were immunized with type II collagen, and in some cases, lipopolysaccharide (LPS) was used to boost the development of arthritis. DCB 3503 was injected intraperitoneally before or after the onset of CIA. Mice were monitored to assess the effects of DCB 3503 on the clinical severity of the disease, and pathologic changes in the joints were examined histologically. Levels of tumor necrosis factor alpha (TNFalpha) and interleukin-1beta (IL-1beta) in serum and joint tissues were measured by enzyme-linked immunosorbent assay and by cytometric bead array analysis. The effect of DCB 3503 on LPS-induced proinflammatory cytokines from bone marrow-derived dendritic cells was determined by flow cytometry.
  
  
  RESULTS
  DCB 3503 significantly suppressed the development and progression of CIA. Moreover, DCB 3503 completely blocked the LPS-triggered acceleration of joint inflammation and destruction. Consistent with its effects in vivo, DCB 3503 significantly suppressed the synthesis of proinflammatory cytokines in inflamed joints as well as cytokine synthesis by macrophages examined ex vivo. Treatment also reduced the levels of inflammatory cytokines (IL-6, IL-12, TNFalpha, and monocyte chemotactic protein 1) produced by bone marrow-derived dendritic cells in vitro. However, DCB 3503 showed no direct effects on T cell proliferation and B cell antibody response.
  
  
  CONCLUSIONS
  Because of its ability to specifically suppress innate immune responses, DCB 3503 may be a novel therapeutic agent for inflammatory arthritis in humans.
authors.affiliation: Yale University, New Haven, Connecticut 06520-8031, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: You
authors.forename: Meng
authors.initials: M
authors.lastname: Pan
authors.forename: Wenli
authors.initials: W
authors.lastname: Gao
authors.forename: Her-Shyong
authors.initials: HS
authors.lastname: Shiah
authors.forename: Jian
authors.initials: J
authors.lastname: Tao
authors.forename: Dongqing
authors.initials: D
authors.lastname: Zhang
authors.forename: Fotios
authors.initials: F
authors.lastname: Koumpouras
authors.forename: Shuang
authors.initials: S
authors.lastname: Wang
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Madri
authors.forename: David
authors.initials: D
authors.lastname: Baker
authors.forename: Yung-Chi
authors.initials: YC
authors.lastname: Cheng
authors.forename: Zhinan
authors.initials: Z
authors.lastname: Yin
mesh_terms: D000470:Alkaloids / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D018932:Chemokine CCL2 / Q000032:analysis; D024043:Collagen Type II; D003713:Dendritic Cells / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D007212:Indolizines / Q000494:pharmacology* / Q000627:therapeutic use; D007375:Interleukin-1 / Q000032:analysis; D018664:Interleukin-12 / Q000032:analysis; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D010616:Phenanthrenes / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D000470:Alkaloids; D018932:Chemokine CCL2; D024043:Collagen Type II; C509364:DCB 3503; D007212:Indolizines; D007375:Interleukin-1; D010616:Phenanthrenes; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; C004218:tylophorine