Effects of a novel tylophorine analog on collagen-induced arthritis through inhibition of the innate immune response.
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.
You
Xin
X
Yale University, New Haven, Connecticut 06520-8031, USA.
Pan
Meng
M
Gao
Wenli
W
Shiah
Her-Shyong
HS
Tao
Jian
J
Zhang
Dongqing
D
Koumpouras
Fotios
F
Wang
Shuang
S
Zhao
Hongyu
H
Madri
Joseph A
JA
Baker
David
D
Cheng
Yung-Chi
YC
Yin
Zhinan
Z
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
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