Differential regulation of vascular cell adhesion molecule 1 gene expression by specific NF-κB subunits in endothelial and epithelial cells

Hong Bing Shu, Adam B. Agranoff, Elizabeth G. Nabel, Kwanyee Leung, Colin S. Duckett, Andrew S. Neish, Tucker Collins, Gary J. Nabel

Research output: Contribution to journalArticle

Abstract

Vascular cell adhesion molecule 1 (VCAM-1) is expressed in both endothelial and epithelial cell types, where it contributes to lymphocyte migration to sites of inflammation. Its expression is regulated by cytokines, in part through two κB-like regulatory elements. Because NF-κB can be composed of multiple alternative subunits with differential effects on gene expression, the role of different specific NF-κB family members subunits in VCAM-1 regulation is unknown. In this report, we define the contribution of different NF-κB family members to VCAM-1 gene regulation. We show that both κB sites in the VCAM-1 enhancer are required to optimally stimulate gene expression, but the enhancer is differentially regulated by specific combinations of NF-κB subunits. At low concentrations, RelA(p65) acted in concert with the ∼50-kDa product of p105S NF-κB, NF-κB1(p50), to stimulate transcription, and at high concentrations, RelA(p65) alone stimulated the VCAM-1 promoter. In contrast, NF-κB2 inhibited functional activation of the VCAM reporter by p65. Consistent with this finding, an additional binding complex was detected by using recombinant NF-κB2(p49)/RelA(p65) with radiolabeled VCAM κB site probes. Interestingly, the human immunodeficiency virus enhancer responded differently to stimulation by NF-κB subunits, with optimal response to p49(100)/p65. Analysis of NF-κB mRNA in human umbilical vein endothelial cells revealed that nfkb1, nfkb2, and relA NF-κB but not c-rel were induced by tumor necrosis factor alpha and lipopolysaccharide, which also induce VCAM-1. These data suggest that specific subunits of NF-κB regulate VCAM-1 and differentially activate other genes in these cells.

Original languageEnglish (US)
Pages (from-to)6283-6289
Number of pages7
JournalMolecular and Cellular Biology
Volume13
Issue number10
StatePublished - Oct 1993
Externally publishedYes

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ASJC Scopus subject areas

  • Cell Biology
  • Genetics
  • Molecular Biology

Cite this

Shu, H. B., Agranoff, A. B., Nabel, E. G., Leung, K., Duckett, C. S., Neish, A. S., Collins, T., & Nabel, G. J. (1993). Differential regulation of vascular cell adhesion molecule 1 gene expression by specific NF-κB subunits in endothelial and epithelial cells. Molecular and Cellular Biology, 13(10), 6283-6289.