Role for NF-kappa B in mediating the effects of hyperoxia on IGF binding protein 2 promoter activity in lung alveolar epithelial cells

The surface of the pulmonary alveolus is a major target for oxidant injury, and its proper repair following injury is dependent on the proliferative r esponse of the stem cells of the alveolar epithelium, the type 2 cells. In previous studies on the mechanisms controlling this response, we have docum ented involvement of several components of the IGF system, and mainly of th e IGF binding protein-2 (IGFBP-2). We have provided evidence that this bind ing protein was associated with inhibition of DNA synthesis of type 2 cells exposed to oxidants and that its expression was regulated mostly at the le vel of transcription. In the present study, we focused on the factors invol ved in this regulation. From examination of the IGFBP-2 gene promoter seque nce which revealed the presence of four potential binding sites for transcr iption factors of the NF-kappa B/Rel family, we hypothesized that NF-kappa B might be involved in the transcriptional activation of IGFBP-2 in oxidant -exposed cells. Data reported herein demonstrated that NF-kappa B activated IGFBP-2 promoter in transient transfection assays, and that exposure of ce lls to hyperoxia was associated with accumulation of the active form of NF- kappa B, Using gel shift analysis, we documented in O-2-treated cells an in creased binding to the four NF-kappa B binding sites, We also showed that a ccumulation of NF-kappa B was associated with a decrease in the inhibitory molecule I kappa B-alpha, Based on the current knowledge on NF-kappa B regu lation, it is likely that in a number of situations associated with injury of lung alveolar epithelial cells signaling events involving accumulation o f NF-kappa B converge to activate IGFBP-2 and to block entry into S phase. (C) 1999 Elsevier Science B.V. All rights reserved.