Carayol Nathalie, Chen Ji, Yang Fan, Jin Taocong, Jin Lijian, States David, Wang Cun-Yu
Laboratory of Molecular Signaling and Apoptosis, Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, Michigan 48109, USA.
J Biol Chem. 2006 Oct 13;281(41):31142-51. doi: 10.1074/jbc.M603417200. Epub 2006 Aug 16.
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-kappaB (NF-kappaB) through the IkappaB kinase complex (IKK). NF-kappaB is a transcription factor that controls inflammation and host responses. In this study, we examined the role of IKK/NF-kappaBin 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-kappaB. Among those IKK/NF-kappaB-dependent genes, 20 genes were NF-kappaB-inducible genes reported previously, and 59 genes represented putative novel NF-kappaB target genes. Using transcription factor binding analysis, we found that most of these putative NF-kappaB target genes contained one or multiple NF-kappaB-binding sites. Also, some transcription factor-binding motifs were overrepresented in the promoter of both known and putative NF-kappaB-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-kappaB, indicating that IKK/NF-kappaB may utilize these transcription factors to mediate secondary responses. Taken together, our results demonstrate that IKK/NF-kappaB signaling plays a dominant role in P. gingivalis LPS-induced early response gene expression, suggesting that IKK/NF-kappaB is a therapeutic target for periodontitis.
牙龈卟啉单胞菌是牙周炎的致病病原体，牙周炎是最常见的炎症性疾病之一。最近，我们发现牙龈卟啉单胞菌脂多糖（LPS）通过IκB激酶复合物（IKK）激活转录因子核因子-κB（NF-κB）。NF-κB是一种控制炎症和宿主反应的转录因子。在本研究中，我们使用微阵列和生化方法相结合，在全基因组范围内研究了IKK/NF-κB在牙龈卟啉单胞菌LPS诱导的基因表达中的作用。在人THP-1单核细胞系中，共发现88个早期反应基因由牙龈卟啉单胞菌LPS诱导。有趣的是，在IKK/NF-κB失活的情况下，这些基因中的大多数诱导作用被消除或减弱。在那些依赖IKK/NF-κB的基因中，20个基因是先前报道的NF-κB诱导基因，59个基因代表推定的新型NF-κB靶基因。通过转录因子结合分析，我们发现这些推定的NF-κB靶基因中的大多数含有一个或多个NF-κB结合位点。此外，一些转录因子结合基序在已知的和推定的依赖NF-κB的基因的启动子中过度富集，表明这些基因可能以类似的方式被调控。此外，我们发现牙龈卟啉单胞菌LPS通过IKK/NF-κB诱导了几种与代谢和炎症反应相关的转录因子，包括核受体、蛋白-1激活剂和早期生长反应，这表明IKK/NF-κB可能利用这些转录因子介导次级反应。综上所述，我们的结果表明IKK/NF-κB信号在牙龈卟啉单胞菌LPS诱导的早期反应基因表达中起主导作用，提示IKK/NF-κB是牙周炎的治疗靶点。
