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Effects of a novel tylophorine analog on collagen-induced arthritis through inhibition of the innate immune response

  1. Xin You1,†,‖,
  2. Meng Pan1,‡,‖,
  3. Wenli Gao1,
  4. Her-Shyong Shiah1,
  5. Jian Tao1,
  6. Dongqing Zhang1,§,
  7. Fotios Koumpouras1,
  8. Shuang Wang1,¶,
  9. Hongyu Zhao1,
  10. Joseph A. Madri1,
  11. David Baker2,
  12. Yung-Chi Cheng1,
  13. Zhinan Yin1,*

Article first published online: 28 FEB 2006

DOI: 10.1002/art.21640

Issue

Arthritis & Rheumatism

Arthritis & Rheumatism

Volume 54, Issue 3, pages 877–886, March 2006

Additional Information

How to Cite

You, X., Pan, M., Gao, W., Shiah, H.-S., Tao, J., Zhang, D., Koumpouras, F., Wang, S., Zhao, H., Madri, J. A., Baker, D., Cheng, Y.-C. and Yin, Z. (2006), Effects of a novel tylophorine analog on collagen-induced arthritis through inhibition of the innate immune response. Arthritis & Rheumatism, 54: 877–886. doi: 10.1002/art.21640

Author Information

  1. 1

    Yale University, New Haven, Connecticut

  2. 2

    University of Tennessee, Knoxville

  1. †

    University of California, San Diego

  2. ‡

    Ruijing Hospital, Shanghai Second Medical University, Shanghai, China

  3. §

    Shanghai Jiao Torg University, Shanghai, China

  4. Columbia University, New York, New York

  1. ‖

    Drs. You and Pan contributed equally to this work.

*Section of Rheumatology, Yale University School of Medicine, Box 208031, The Anylan Center (TAC), Room 517, 300 Cedar Street, New Haven, CT 06520-8031

Publication History

  1. Issue published online: 28 FEB 2006
  2. Article first published online: 28 FEB 2006
  3. Manuscript Accepted: 10 NOV 2005
  4. Manuscript Received: 3 AUG 2005

Funded by

  • Arthritis Foundation Investigator award
  • NIH. Grant Numbers: K01-AR-02188, 1-R01-AI-056219

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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 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.

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