TRANSCRIPTIONAL REGULATION OF THE HUMAN POLYMERIC IMMUNOGLOBULIN RECEPTOR GENE BY INTERFERON-GAMMA

IgA is transported into external secretions by the polymeric Ig recept or (pIgR). Interferon-gamma (IFN-gamma), a major regulator of pIgR exp ression, has been shown to increase pIgR mRNA levels in HT-29 human co lon carcinoma cells. To determine the molecular mechanisms of pIgR reg ulation, genomic DNA containing the 5'-flanking region of the human pI gR gene was isolated and a single start site of transcription in human intestinal epithelial cells was identified. Using chimeric reporter p lasmids containing flanking regions of the pIgR gene, a segment of the pIgR promoter which is necessary and sufficient for induction of tran scription by IFN-gamma in HT-29 cells was identified. Significantly, t he pIgR promoter contains three motifs homologous to the interferon-st imulated response element (ISRE), two in the 5'-flanking region and on e in exon 1 of the pIgR gene. The upstream ISREs bind nuclear protein( s) which are constitutively expressed by HT-29 cells, while the exon 1 ISRE binds interferon regulatory factor-1 (IRF-1), following stimulat ion with IFN-gamma. Furthermore, induction of the IRF-1 promoter by IF N-gamma correlates with induction of the pIgR promoter by IFN-gamma. I t has previously been demonstrated that induction of pIgR mRNA by IFN- gamma requires tie novo protein synthesis. It is now shown that IRF-1 is not detected in nuclear extracts from HT-29 cells stimulated with I FN-gamma in the presence of cycloheximide, suggesting that de novo syn thesis of IRF-1 is required for induction of pIgR transcription by IFN -gamma. (C) 1997 Elsevier Science Ltd.