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J. Biol. Chem., Vol. 281, Issue 41, 31142-31151, October 13, 2006

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A Dominant Function of IKK/NF-B Signaling in Global Lipopolysaccharide-induced Gene Expression^*

Nathalie Carayol¹, Ji Chen¹, Fan Yang, Taocong Jin^¶, Lijian Jin^||, David States, and Cun-Yu Wang²

From the Laboratory of Molecular Signaling and Apoptosis, Department of Biologic and Materials Sciences, Bioinformatics Training Program and Department of Human Genetics, School of Medicine, and ^¶Molecular Biology Core, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48109 and the ^||Faculty of Dentistry, University of Hong Kong, Hong Kong, China

Porphyromonas gingivalis is an etiologic pathogen of periodontitis that is one of the most common inflammatory diseases. Recently, we found that P. gingivalis LPS activated the transcription factor nuclear factor-B (NF-B) through the IB kinase complex (IKK). NF-B is a transcription factor that controls inflammation and host responses. In this study, we examined the role of IKK/NF-Bin P. gingivalis LPS-induced gene expression on a genome-wide basis using a combination of microarray and biochemical approaches. A total of 88 early response genes were found to be induced by P. gingivalis LPS in a human THP.1 monocytic cell lines. Interestingly, the induction of most of these genes was abolished or attenuated under the inactivation of IKK/NF-B. Among those IKK/NF-B-dependent genes, 20 genes were NF-B-inducible genes reported previously, and 59 genes represented putative novel NF-B target genes. Using transcription factor binding analysis, we found that most of these putative NF-B target genes contained one or multiple NF-B-binding sites. Also, some transcription factor-binding motifs were overrepresented in the promoter of both known and putative NF-B-dependent genes, indicating that these genes may be regulated in a similar fashion. Furthermore, we found that several transcription factors associated with metabolic and inflammatory responses, including nuclear receptors, activator of protein-1, and early growth responses, were induced by P. gingivalis LPS through IKK/NF-B, indicating that IKK/NF-B may utilize these transcription factors to mediate secondary responses. Taken together, our results demonstrate that IKK/NF-B signaling plays a dominant role in P. gingivalis LPS-induced early response gene expression, suggesting that IKK/NF-B is a therapeutic target for periodontitis.

Received for publication, April 10, 2006 , and in revised form, August 16, 2006.

^* This work was supported by NIDCR, National Institutes of Health, Grants R01DE15973 and R01DE16513, an International Association for Dental Research/GlaxoSmithKline Innovation in Oral Care Award (to C.-Y. W.), and National Library of Medicine Grant R01-LM008106 (to D. S.). 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.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Laboratory of Molecular Signaling and Apoptosis, Dept. of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI 48109-1078. Tel.: 734-615-4386; Fax: 734-764-2425; E-mail: cunywang{at}umich.edu.

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