Tissue inhibitor of metalloproteinases-2 growth-stimulatory activity is mediated by nuclear factor-kappa B in A549 lung epithelial cells

Abstract

Tissue inhibitors of metalloproteinases (TIMPs) are pleiotropic factors that function as key regulators of extracellular matrix remodeling. They exhibit multifunctional roles including cell growth-stimulating activities and protection from apoptosis. In the present study, we showed that human recombinant TIMP-2 (hrTIMP-2) promotes growth of A549 lung cells. This effect was accompanied by increase in nuclear factor-kappa B (NF-κB) activity 24 h after exposure as determined by electrophoretic mobility shift assay (EMSA) analysis. This effect was correlated with downregulation of IκBα and β proteins and later increases in Bcl-3, IκBε, and cyclin D1 proteins. Blocking induction of NF-κB activity using a dominant-negative mutated version of IκBα abrogated NF-κB activation and cell proliferation.