Interferon Regulatory Factor 1 (IRF-1) and IRF-2 Distinctively Up-Regulate Gene Expression and Production of Interleukin-7 in Human Intestinal Epithelial Cells

• DOI: 10.1128/mcb.24.14.6298-6310.2004
• Publication Date: 2004-06-29T22:39:25Z
• Authors: Shigeru Oshima; Tetsuya Nakamura; Shin Namiki; Eriko Okada; Kiichiro Tsuchiya; Ryuichi Okamoto; Motomi Yamazaki; Takanori Yokota; Masatoshi Aida; Yuki Yamaguchi; Takanori Kanai; Hiroshi Handa; Mamoru Watanabe
• Keywords: 0303 health sciences; Base Sequence; Interleukin-7; Molecular Sequence Data; 610; Epithelial Cells; Regulatory Sequences, Nucleic Acid; Phosphoproteins; 630; DNA-Binding Proteins; Interferon-gamma; 03 medical and health sciences; Gene Expression Regulation; Genes, Reporter; Cell Line, Tumor; Animals; Humans; Intestinal Mucosa; RNA, Small Interfering; 5' Untranslated Regions; Interferon Regulatory Factor-2; Interferon Regulatory Factor-1; Interleukin-1; Protein Binding

Intestinal epithelial cell-derived interleukin (IL)-7 functions as a pleiotropic and nonredundant cytokine in the human intestinal mucosa; however, the molecular basis of its production has remained totally unknown. We here showed that human intestinal epithelial cells both constitutively and when induced by gamma interferon (IFN-gamma) produced IL-7, while several other factors we tested had no effect. Transcriptional regulation via an IFN regulatory factor element (IRF-E) on the 5' flanking region, which lacks canonical core promoter sequences, was pivotal for both modes of IL-7 expression. IRF-1 and IRF-2, the latter of which is generally known as a transcriptional repressor, were shown to interact with IRF-E and transactivate IL-7 gene expression in an IFN-gamma-inducible and constitutive manner, respectively. Indeed, tetracycline-inducible expression experiments revealed that both of these IRF proteins up-regulated IL-7 protein production, and their exclusive roles were further confirmed by small interfering RNA-mediated gene silencing systems. Moreover, these IRFs displayed distinct properties concerning the profile of IL-7 transcripts upon activation and expression patterns within human colonic epithelial tissues. These results suggest that the functional interplay between IRF-1 and IRF-2 serves as an elaborate and cooperative mechanism for timely as well as continuous regulation of IL-7 production that is essential for local immune regulation within human intestinal mucosa.