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activates transcription of NADPH oxidase 1 gene and up-regulates production of superoxide anion by human large intestinal epithelial cells
1 Department of Nutritional Physiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Tokushima Prefecture, Japan
2 Department of Clinical Nutrition, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Tokushima Prefecture, Japan
3 Department of Stress Science, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Tokushima Prefecture, Japan
4 Department of Stress Science, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Tokushima Prefecture, Japan; Japan Science and Technology, Research Institute of Science and Technology for Science, Tokyo, Tokyo, Japan
* To whom correspondence should be addressed. E-mail: rokutan{at}basic.med.tokushima-u.ac.jp.
NADPH oxidase 1 (Nox1), a homologue of gp91phox, is dominantly expressed in large intestinal epithelium, and reactive oxygen species derived from Nox1 are suggested to serve a role in host defense. We report here that interferon (IFN)-
, a crucial trans-activator of the gp91phox gene, also stimulates expression of Nox1 mRNA and protein in large intestinal epithelium (T84 cells), leading to up-regulation of superoxide anion (O2-) generation 4-fold. Introduction of small interfering Nox1 RNA completely blocked this priming. We cloned the -4831 to +195 bp region of the human Nox1 gene. To reveal IFN--responsive cis-elements, transient expression assays were done using a reporter gene driven by serially truncated Nox1 promoters in T84 cells. IFN--responsive elements were located between -4.3 and -2.6 kbp, and one -activated sequence (GAS) element present at -3818 to -3810 bp exhibited this IFN--dependent promoter activity. IFN- caused tyrosine-phosphorylation of signal transducers and activators of transcription 1 (STAT1) and produced a protein-GAS complex that was recognized by anti-STAT1 antibody. The introduction of three-point mutation of GAS, which did not interact with STAT1, completely cancelled the IFN--dependent promoter activity of the -4831 to +195 bp region. A Janus protein tyrosine kinase 2 inhibitor (AG490) blocked the IFN--stimulated tyrosine-phosphorylation of STAT1, promoter activity of the -4831 to +195 bp region, Nox1 mRNA expression, and O2- production, also suggesting a crucial role of STAT1 and GAS in the IFN--stimulated transcription of the Nox1 gene. Our results support a potential contribution of Nox1 to mucosal host defense and inflammation in the colon.
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