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Molecular and Cellular Biology, July 2004, p. 6298-6310, Vol. 24, No. 14
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.14.6298-6310.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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

Shigeru Oshima,1,{dagger} Tetsuya Nakamura,1,{dagger} Shin Namiki,1 Eriko Okada,1 Kiichiro Tsuchiya,1 Ryuichi Okamoto,1 Motomi Yamazaki,1 Takanori Yokota,2 Masatoshi Aida,3 Yuki Yamaguchi,3 Takanori Kanai,1 Hiroshi Handa,3 and Mamoru Watanabe1*

Department of Gastroenterology and Hepatology,1 Department of Neurology and Neurological Sciences, Graduate School, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519,2 Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama 226-8501, Japan3

Received 10 September 2003/ Returned for modification 16 January 2004/ Accepted 19 April 2004

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.

* Corresponding author. Mailing address: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. Phone: 81 3 5803 5973. Fax: 81 3 5803 0262. E-mail: mamoru.gast{at}tmd.ac.jp.

{dagger} S.O. and T.N. contributed equally to this work.

Molecular and Cellular Biology, July 2004, p. 6298-6310, Vol. 24, No. 14
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.14.6298-6310.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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