Mr. Lacey and Dr. Sampey contributed equally to this work.
Control of fibroblast-like synoviocyte proliferation by macrophage migration inhibitory factor
Article first published online: 10 JAN 2003
Copyright © 2003 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 48, Issue 1, pages 103–109, January 2003
How to Cite
Lacey, D., Sampey, A., Mitchell, R., Bucala, R., Santos, L., Leech, M. and Morand, E. (2003), Control of fibroblast-like synoviocyte proliferation by macrophage migration inhibitory factor. Arthritis & Rheumatism, 48: 103–109. doi: 10.1002/art.10733
- Issue published online: 10 JAN 2003
- Article first published online: 10 JAN 2003
- Manuscript Accepted: 24 SEP 2002
- Manuscript Received: 8 NOV 2001
The hyperplasia of fibroblast-like synoviocytes (FLS) is considered essential to the evolution of joint destruction in rheumatoid arthritis (RA), but the mechanisms underlying FLS proliferation remain poorly understood. Macrophage migration inhibitory factor (MIF) is a cytokine that has recently been shown to exert proinflammatory effects on RA FLS. This study sought to identify the mechanisms of activation of FLS by MIF, and to assess the effects of MIF on synovial cell proliferation.
Human RA FLS were treated with recombinant MIF, interleukin-1β (IL-1β), tumor necrosis factor α (TNFα), and/or anti-MIF monoclonal antibodies (mAb). Proliferation was measured with tritiated thymidine incorporation. Nuclear factor κB (NF-κB) and mitogen-activated protein (MAP) kinase activation were measured with immunohistochemistry and Western blotting, respectively.
FLS proliferation was significantly increased by MIF. IL-1β and TNFα also induced proliferation, but these effects were prevented by neutralization with anti-MIF mAb. Activation of NF-κB was induced by IL-1β, but not by MIF. Anti-MIF mAb had no effect on IL-1β–induced NF-κB nuclear translocation. By contrast, MIF induced phosphorylation of extracellular signal–regulated kinase (ERK) MAP kinase. ERK antagonism, but not NF-κB antagonism, prevented the effect of MIF on FLS proliferation.
These data suggest that MIF may regulate RA synovial hyperplasia by acting directly and via involvement in the effects of IL-1β and TNFα. In addition, the effects of MIF on FLS activation are independent of NF-κB, and dependent on ERK MAP kinase. These data suggest an important therapeutic potential for MIF antagonism in RA.