Open AccessEffects of a novel tylophorine analog on collagen‐induced arthritis through inhibition of the innate immune response
Author(s) -
You Xin,
Pan Meng,
Gao Wenli,
Shiah HerShyong,
Tao Jian,
Zhang Dongqing,
Koumpouras Fotios,
Wang Shuang,
Zhao Hongyu,
Madri Joseph A.,
Baker David,
Cheng YungChi,
Yin Zhinan
Publication year - 2006
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.21640
Subject(s) - proinflammatory cytokine , arthritis , tumor necrosis factor alpha , innate immune system , inflammation , immune system , cytokine , inflammatory arthritis , monocyte , immunology , in vivo , chemistry , medicine , cancer research , biology , microbiology and biotechnology
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 α (TNFα) and interleukin‐1β (IL‐1β) 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, TNFα, 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. Conclusion Because of its ability to specifically suppress innate immune responses, DCB 3503 may be a novel therapeutic agent for inflammatory arthritis in humans.