TGF-beta 1 inhibits NF-kappa B activity through induction of I kappa B-alpha expression in human salivary gland cells: A possible mechanism of growthsuppression by TGF-1 beta

Transforming growth factor (TGF)-beta is the prototype of a large superfami ly of signaling molecules involved in the inhibition of proliferation of mu ltiple epithelial cell types. Although accumulated evidence indicates the m echanisms of the antimitogenic effect of TGF-beta in a variety of cell type s, the signal transduction mechanism underlying the regulation of NF-kappa B transcription factor by TGF-beta is largely unknown. Because NF-kappa B i s not only involved in inflammatory responses but also mediates cell growth , we have investigated the effect of TGF-beta 1 on the activity of NF-kappa B and the role of the inhibitory I kappa B-alpha protein in the growth of the human salivary gland cell clones NS-SV-AC, HSGc, and cl-1. NF-kappa B, which is usually maintained in an inactive state by protein-protein interac tion with I kappa B, was found to be constitutively active in salivary glan d cell lines. Upon treatment of cell clones with TGF-beta 1, the NF-kappa B 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 i nhibition was mediated by the induction of I kappa B-alpha at the mRNA and protein levels. The blocking of NF-kappa B subunit with a specific antisens e oligonucleotide reduced the growth rate of all of the cell clones, includ ing cl-1. Introduction of a mutated form of I kappa B-alpha cDNA into NS-SV -AC suppressed the growth rate of this cell clone, These results indicate t hat TGF-beta 1 downregulates NF-kappa B activity through the induction of I kappa B-alpha expression in human salivary gland cells and that inhibition of NF-kappa B activity suppresses the growth rate of these cells. (C) 1999 Academic Press.