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J. Biol. Chem., Vol. 283, Issue 22, 15309-15318, May 30, 2008

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Requirements for Two Proximal NF-B Binding Sites and IB- in IL-17A-induced Human β-Defensin 2 Expression by Conducting Airway Epithelium^*

From the Center for Comparative Respiratory Biology and Medicine, University of California, Davis, California 95616

Among a panel of 21 cytokines (IL-1, -1β, -2–13, and -15–18; interferon-; granulocyte-macrophage colony-stimulating factor; and tumor necrosis factor ), we have recently observed that IL-17A is the most potent inducer for human β-defensin 2 (hBD-2) in conducting airway epithelial cells (Kao, C. Y., Chen, Y., Thai, P., Wachi, S., Huang, F., Kim, C., Harper, R. W., and Wu, R. (2004) J. Immunol. 173, 3482–3491). The molecular basis of this regulation is not known. In this study, we demonstrated a coordinated degradation of inhibitory B(IB)- followed by a nuclear translocation of p50 and p65 NF-B subunits and their binding to NF-B sites of hBD-2 promoter region. With site-directed mutagenesis, we demonstrated the requirement of two proximal NF-B binding sites (pB1, -205 to -186; pB2, -596 to -572) but not the distal site (dB, -2193 to -2182) in supporting IL-17A-induced hBD-2 promoter activity. These results are consistent with the data of the chromatin immunoprecipitation assay, which showed enhanced p50 binding to these pB sites but not the dB site in cells after IL-17A treatment. We also found that the NF-B binding cofactor, IB-, was up-regulated by IL-17A, and the knockdown of IB- significantly diminished the IL-17A-induced hBD-2 expression. This is the first demonstration of the involvement of two proximal NF-B sites and IB- in the regulation of hBD-2 by IL-17A, two important genes responsible for host defense.

Received for publication, October 5, 2007 , and in revised form, March 11, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HL35635, HL077902, HL077315, and ES00628. This work was also supported by California Tobacco-Related Disease Research Program Grant 16RT-0127. 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.

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¹ To whom correspondence should be addressed: Center for Comparative Respiratory Biology and Medicine Genome and Biomedical Science Facility, Suite 6523, University of California, 451 Health Science Dr., Davis, CA 95616. Tel.: 530-752-2648; Fax: 530-752-8632; E-mail: rwu{at}ucdavis.edu.

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