TGF-beta1 inhibits NF-kappaB activity through induction of IkappaB-alpha expression in human salivary gland cells: a possible mechanism of growth suppression by TGF-beta1

Exp Cell Res. 1999 Jul 10;250(1):213-22. doi: 10.1006/excr.1999.4503.


Transforming growth factor (TGF)-beta is the prototype of a large superfamily of signaling molecules involved in the inhibition of proliferation of multiple epithelial cell types. Although accumulated evidence indicates the mechanisms of the antimitogenic effect of TGF-beta in a variety of cell types, the signal transduction mechanism underlying the regulation of NF-kappaB transcription factor by TGF-beta is largely unknown. Because NF-kappaB is not only involved in inflammatory responses but also mediates cell growth, we have investigated the effect of TGF-beta1 on the activity of NF-kappaB and the role of the inhibitory IkappaB-alpha protein in the growth of the human salivary gland cell clones NS-SV-AC, HSGc, and cl-1. NF-kappaB, which is usually maintained in an inactive state by protein-protein interaction with IkappaB, was found to be constitutively active in salivary gland cell lines. Upon treatment of cell clones with TGF-beta1, the NF-kappaB activity in NS-SV-AC and HSGc, but not in cl-1, which lacks the expression of TGF-beta type II receptor, was suppressed. In NS-SV-AC and HSGc, this inhibition was mediated by the induction of IkappaB-alpha at the mRNA and protein levels. The blocking of NF-kappaB subunit with a specific antisense oligonucleotide reduced the growth rate of all of the cell clones, including cl-1. Introduction of a mutated form of IkappaB-alpha cDNA into NS-SV-AC suppressed the growth rate of this cell clone. These results indicate that TGF-beta1 downregulates NF-kappaB activity through the induction of IkappaB-alpha expression in human salivary gland cells and that inhibition of NF-kappaB activity suppresses the growth rate of these cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Cell Division
  • Cell Line, Transformed
  • DNA, Complementary
  • DNA-Binding Proteins / biosynthesis*
  • DNA-Binding Proteins / genetics
  • Down-Regulation
  • Gene Expression
  • Growth Inhibitors / metabolism*
  • Growth Inhibitors / pharmacology
  • Humans
  • I-kappa B Proteins*
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / biosynthesis
  • NF-kappa B / metabolism*
  • NF-kappa B p50 Subunit
  • Oligonucleotides, Antisense / pharmacology
  • RNA, Messenger
  • Salivary Glands / cytology
  • Salivary Glands / metabolism*
  • Transcription Factor RelA
  • Transfection
  • Transforming Growth Factor beta / metabolism*
  • Transforming Growth Factor beta / pharmacology
  • Tumor Cells, Cultured


  • DNA, Complementary
  • DNA-Binding Proteins
  • Growth Inhibitors
  • I-kappa B Proteins
  • NF-kappa B
  • NF-kappa B p50 Subunit
  • NFKBIA protein, human
  • Oligonucleotides, Antisense
  • RNA, Messenger
  • Transcription Factor RelA
  • Transforming Growth Factor beta
  • NF-KappaB Inhibitor alpha