NF-κB regulates VCAM-1 expression on fibroblast-like synoviocytes

Ping Li, Iñaki Sanz, Regis J. O'Keefe, Edward M. Schwarz

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58 Scopus citations


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-α. Nuclear translocation of transcription factor NF-κB including P50/P50 homodimer and P65/P50 heterodimer was activated by TNF-α treatment. In mFLS stably expressing a dominant-negative mutant of the inhibitory protein I-κBα- (mI-κB), which does not undergo proteolytic degradation, NF-κB remains in the cytosol and its activation in response to TNF-α is abolished. VCAM-1 protein expression after TNF-α stimulation was blocked in cells expressing the mI-κB. This effect is likely due to the loss of NF-κB-mediated transcription of VCAM-1, because the 5-fold increase in mRNA levels in response to TNF-α is absent in the mutant cells. To confirm these findings, we transduced mFLS with an adenoviral vector containing the mI-κB transgene. VCAM-1 expression was also blocked by mI-κB in this system, whereas cells transduced with a control adenoviral vector remained responsive to TNF-α. These results indicate that NF-κB mediates TNF-α-induced VCAM-1 expression on mFLS.

Original languageEnglish
Pages (from-to)5990-5997
Number of pages8
JournalJournal of Immunology
Issue number11
StatePublished - 2000


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