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

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-kappaB) activity 24h after exposure as determined by electrophoretic mobility shift assay (EMSA) analysis. This effect was correlated with downregulation of IkappaBalpha and beta proteins and later increases in Bcl-3, IkappaB, and cyclin D1 proteins. Blocking induction of NF-kappaB activity using a dominant-negative mutated version of IkappaBalpha abrogated NF-kappaB activation and cell proliferation.