A dominant function of IKK/NF-κB signaling in global lipopolysaccharide-induced gene expression

Abstract

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-κB (NF-κB) through the IκB kinase complex (IKK). NF-κB is a transcription factor that controls inflammation and host responses. In this study, we examined the role of IKK/NF-κB in 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-κB. Among those IKK/NF-κB-dependent genes, 20 genes were NF-κB-inducible genes reported previously, and 59 genes represented putative novel NF-κB target genes. Using transcription factor binding analysis, we found that most of these putative NF-κB target genes contained one or multiple NF-κB-binding sites. Also, some transcription factor-binding motifs were overrepresented in the promoter of both known and putative NF-κB-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-κB, indicating that IKK/NF-κB may utilize these transcription factors to mediate secondary responses. Taken together, our results demonstrate that IKK/NF-κB signaling plays a dominant role in P. gingivalis LPS-induced early response gene expression, suggesting that IKK/NF-κB is a therapeutic target for periodontitis. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.