A dominant function of IKK/NF-κB signaling in global lipopolysaccharide-induced gene expression
A dominant function of IKK/NF-κB signaling in global lipopolysaccharide-induced gene expression
复制标题
DOI：
10.1074/jbc.m603417200
复制
发表时间：
2006-10-13
影响因子：
4.8
通讯作者：
Wang, Cun-Yu
中科院分区：
文献类型：
--
作者：
Carayol, Nathalie;Chen, Ji;Wang, Cun-Yu
牙龈卟啉单胞菌是牙周炎的病原菌，牙周炎是最常见的炎症性疾病之一。近年来，我们发现牙龈卟啉单胞菌LPS通过I κ B激酶复合物（IKK）激活转录因子核因子-κ B（NF-κ B）。NF-κ B是控制炎症和宿主反应的转录因子。在这项研究中，我们研究了IKK/NF-κ B B的作用，牙龈卟啉单胞菌脂多糖诱导的基因表达的基因组范围内的基础上，使用微阵列和生化方法相结合。在人THP. 1单核细胞系中，发现牙龈卟啉单胞菌LPS共诱导了88个早期应答基因。有趣的是，在IKK/NF-κ B失活的情况下，大多数这些基因的诱导被消除或减弱。在这些IKK/NF-κ B依赖基因中，有20个基因为NF-κ B诱导基因，59个基因为NF-κ B B靶基因。利用转录因子结合分析，我们发现大多数这些推定的NF-κ B B靶基因含有一个或多个NF-κ B结合位点。此外，一些转录因子结合基序在已知和假定的NF-κ B依赖基因的启动子中过度表达，表明这些基因可能以类似的方式进行调控。此外，我们发现牙龈卟啉单胞菌LPS通过IKK/NF-κ B B诱导了一些与代谢和炎症反应相关的转录因子，包括核受体、蛋白激活因子-1和早期生长反应，表明IKK/NF-κ B B可能利用这些转录因子介导继发性反应。综上所述，我们的研究结果表明，IKK/NF-κ B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，这表明IKK/NF-κ B是牙周炎的治疗靶点。
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-kappa B (NF-kappa B) through the I kappa B kinase complex (IKK). NF-kappa B is a transcription factor that controls inflammation and host responses. In this study, we examined the role of IKK/NF-kappa B 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-kappa B. Among those IKK/NF-kappa B-dependent genes, 20 genes were NF-kappa B-inducible genes reported previously, and 59 genes represented putative novel NF-kappa B target genes. Using transcription factor binding analysis, we found that most of these putative NF-kappa B target genes contained one or multiple NF-kappa B-binding sites. Also, some transcription factor-binding motifs were overrepresented in the promoter of both known and putative NF-kappa 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-kappa B, indicating that IKK/NF-kappa B may utilize these transcription factors to mediate secondary responses. Taken together, our results demonstrate that IKK/NF-kappa B signaling plays a dominant role in P. gingivalis LPS-induced early response gene expression, suggesting that IKK/NF-kappa B is a therapeutic target for periodontitis.