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  • Title: NF-kappa B regulates VCAM-1 expression on fibroblast-like synoviocytes.
    Author: Li P, Sanz I, O'Keefe RJ, Schwarz EM.
    Journal: J Immunol; 2000 Jun 01; 164(11):5990-7. PubMed ID: 10820282.
    Abstract:
    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-alpha. Nuclear translocation of transcription factor NF-kappa B including P50/P50 homodimer and P65/P50 heterodimer was activated by TNF-alpha treatment. In mFLS stably expressing a dominant-negative mutant of the inhibitory protein I-kappa B alpha- (mI-kappa B), which does not undergo proteolytic degradation, NF-kappa B remains in the cytosol and its activation in response to TNF-alpha is abolished. VCAM-1 protein expression after TNF-alpha stimulation was blocked in cells expressing the mI-kappa B. This effect is likely due to the loss of NF-kappa B-mediated transcription of VCAM-1, because the 5-fold increase in mRNA levels in response to TNF-alpha is absent in the mutant cells. To confirm these findings, we transduced mFLS with an adenoviral vector containing the mI-kappa B transgene. VCAM-1 expression was also blocked by mI-kappa B in this system, whereas cells transduced with a control adenoviral vector remained responsive to TNF-alpha. These results indicate that NF-kappa B mediates TNF-alpha-induced VCAM-1 expression on mFLS.
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