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J. Biol. Chem., Vol. 281, Issue 9, 5657-5667, March 3, 2006

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NF-B Regulates Phagocytic NADPH Oxidase by Inducing the Expression of gp91^phox*

From the Division of Neurobiology, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021

The superoxide-generating phagocytic NADPH oxidase is an important component of the innate immune response against microbial agents, and is involved in shaping the cellular response to a variety of physiological and pathological signals. One of the downstream targets of NADPH oxidase-derived radicals is the ubiquitous transcription factor NF-B, which controls the expression of a large array of genes involved in immune function and cell survival. Here we show that NF-B itself is a key factor in controlling NADPH oxidase expression and function. In monocytic and microglial cell lines, the expression of the NADPH oxidase subunit gp91^phox was induced by lipopolysaccharide/interferon treatment and was inhibited in cells constitutively expressing IB. Furthermore, inducible reactive oxygen species production was inhibited in IB overexpressing cells. gp91^phox expression was very low in RelA^-/- fibroblasts and could be induced by reconstituting these cells with p65/RelA. Thus, gp91^phox expression is dependent on the presence of p65/RelA. We also found that gp91^phox transcription is dependent on NF-B and we identified two potential cis-acting elements in the murine gp91^phox promoter that control NF-B-dependent regulation. The findings raise the possibility of a positive feedback loop in which NF-B activation by oxidative stress leads to further radical production via NADPH oxidase.

Received for publication, June 7, 2005 , and in revised form, December 28, 2005.

^* This work was supported by National Institutes of Health Grants HL077308 (to J. A.) and HL018974 (to C. I.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1 and Fig. S1.

¹ To whom correspondence should be addressed: 411 East 69th St. KB410, New York, NY 10021. Tel.: 212-570-2900; Fax: 212-988-3672; E-mail: joa2006{at}med.cornell.edu.

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