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NF-B Regulates VCAM-1 Expression on Fibroblast-Like Synoviocytes¹

Ping Li^*, Iñaki Sanz, Regis J. O’Keefe and Edward M. Schwarz^2,

^* Department of Microbiology and Immunology, Immunology/Rheumatology Unit, Department of Medicine, and Department of Orthopaedics, University of Rochester Medical Center, Rochester, NY 14642

Expression of VCAM-1 on synovial fibroblasts is a clinical hallmark of rheumatoid arthritis. The interaction of VCAM-1 and its integrin receptor very late Ag-4 is believed to be critically involved in the recruitment and retention of immune cells in the inflamed joints. To study the regulation of VCAM-1 in synovial fibroblasts, fibroblast-like synoviocytes (FLS) were isolated from the knee joints of normal mice and passaged repeatedly to obtain a homogeneous cell population. We have found that VCAM-1 is constitutively expressed on mouse FLS (mFLS) and that its surface expression is further increased after exposure to TNF-. Nuclear translocation of transcription factor NF-B including P50/P50 homodimer and P65/P50 heterodimer was activated by TNF- treatment. In mFLS stably expressing a dominant-negative mutant of the inhibitory protein I-B- (mI-B), which does not undergo proteolytic degradation, NF-B remains in the cytosol and its activation in response to TNF- is abolished. VCAM-1 protein expression after TNF- stimulation was blocked in cells expressing the mI-B. This effect is likely due to the loss of NF-B-mediated transcription of VCAM-1, because the 5-fold increase in mRNA levels in response to TNF- is absent in the mutant cells. To confirm these findings, we transduced mFLS with an adenoviral vector containing the mI-B transgene. VCAM-1 expression was also blocked by mI-B in this system, whereas cells transduced with a control adenoviral vector remained responsive to TNF-. These results indicate that NF-B mediates TNF--induced VCAM-1 expression on mFLS.

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