In this study we show that GATA-6 is a novel repressor of TN-C gene expression. We demonstrated that overexpression of GATA-6 in fibroblasts inhibited basal levels, as well as markedly decreased IL-4- and TGF-beta-induced TN-C mRNA and protein levels. A GATA-6 response element was mapped to position -467 to -460 of the TN-C promoter. In addition, we showed that GATA-6 binds this site both in vitro and in vivo.