Signal pathways JNK and NF-kappaB, identified by global gene expression profiling, are involved in regulation of TNFalpha-induced mPGES-1 and COX-2 expression in gingival fibroblasts.
Signal pathways JNK and NF-kappaB, identified by global gene expression profiling, are involved in regulation of TNFalpha-induced mPGES-1 and COX-2 expression in gingival fibroblasts.
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DOI：
10.1186/1471-2164-11-241
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发表时间：
2010-04-15
期刊：
影响因子：
4.4
通讯作者：
Yucel-Lindberg T
中科院分区：
文献类型：
--
作者：
Båge T;Lindberg J;Lundeberg J;Modéer T;Yucel-Lindberg T
前列腺素 E2 (PGE2) 与多种慢性炎症性疾病有关，包括牙周炎，牙周炎会导致牙龈组织和支撑牙齿的牙槽骨丧失。我们之前已经证明肿瘤坏死因子α（TNFα）诱导牙龈成纤维细胞合成PGE2。在本研究中，我们旨在研究 TNFα 刺激的原代人牙龈成纤维细胞的整体基因表达谱，重点关注与 PGE2 合成酶前列腺素 E 合酶 (PGES) 以及上游酶环加氧酶-2 (COX-2) 和 PGE2 产生相关的信号通路。微阵列和蛋白质印迹分析表明，炎症诱导的微粒体前列腺素E合酶-1（mPGES-1）的mRNA和蛋白表达被细胞因子TNFα上调，伴随着COX-2表达增强和PGE2产生增加。相反，同工酶微粒体前列腺素E合酶-2 (mPGES-2)和胞质前列腺素E合酶(cPGES)的表达不受TNFα处理的影响。在包括时间点 1、3 和 6 小时的时程因子设计中使用寡核苷酸微阵列分析，鉴定出响应 TNFα 治疗的差异表达基因。微阵列数据的富集分析表明有两种正向调节的信号转导途径：c-Jun N 末端激酶 (JNK) 和核因子-κB (NF-κB)。为了评估它们对 mPGES-1 和 COX-2 表达调节的参与，我们使用了特定的抑制剂以及磷酸化分析。 JNK (T183/Y185) 和 NF-κB p65 (S536) 的磷酸化分析显示，TNFα 治疗后磷酸化增加，而 JNK (SP600125) 和 NF-κB (Bay 11-7082、Ro 106-9920) 的特异性抑制剂可降低磷酸化。 JNK 和 NF-κB 抑制剂还降低了 TNFα 刺激的 mPGES-1 和 COX-2 的上调以及 PGE2 的产生。在全局基因表达谱中，微阵列数据的富集分析确定了两条信号转导途径JNK和NF-κB受到细胞因子TNFα的正向调节。抑制这些 TNFα 激活的信号通路可减少牙龈成纤维细胞中 mPGES-1 和 COX-2 及其最终产物 PGE2 的表达。信号通路 JNK 和 NF-κB 参与 TNFα 诱导的 PGE2 调节，可能表明这两条通路可能是慢性炎症性疾病牙周炎的有吸引力的靶点。
Prostaglandin E2 (PGE2) is involved in several chronic inflammatory diseases including periodontitis, which causes loss of the gingival tissue and alveolar bone supporting the teeth. We have previously shown that tumor necrosis factor α (TNFα) induces PGE2 synthesis in gingival fibroblasts. In this study we aimed to investigate the global gene expression profile of TNFα-stimulated primary human gingival fibroblasts, focusing on signal pathways related to the PGE2-synthesizing enzymes prostaglandin E synthases (PGES), as well as the upstream enzyme cyclooxygenase-2 (COX-2) and PGE2 production. Microarray and western blot analyses showed that the mRNA and protein expression of the inflammatory induced microsomal prostaglandin E synthase-1 (mPGES-1) was up-regulated by the cytokine TNFα, accompanied by enhanced expression of COX-2 and increased production of PGE2. In contrast, the expression of the isoenzymes microsomal prostaglandin E synthase-2 (mPGES-2) and cytosolic prostaglandin E synthase (cPGES) was unaffected by TNFα treatment. Using oligonucleotide microarray analysis in a time-course factorial design including time points 1, 3 and 6 h, differentially expressed genes in response to TNFα treatment were identified. Enrichment analysis of microarray data indicated two positively regulated signal transduction pathways: c-Jun N-terminal kinase (JNK) and Nuclear Factor-κB (NF-κB). To evaluate their involvement in the regulation of mPGES-1 and COX-2 expression, we used specific inhibitors as well as phosphorylation analysis. Phosphorylation analysis of JNK (T183/Y185) and NF-κB p65 (S536) showed increased phosphorylation in response to TNFα treatment, which was decreased by specific inhibitors of JNK (SP600125) and NF-κB (Bay 11-7082, Ro 106-9920). Inhibitors of JNK and NF-κB also decreased the TNFα-stimulated up-regulation of mPGES-1 and COX-2 as well as PGE2 production. In the global gene expression profile, the enrichment analysis of microarray data identified the two signal transduction pathways JNK and NF-κB as positively regulated by the cytokine TNFα. Inhibition of these TNFα-activated signal pathways reduced the expression of mPGES-1 and COX-2 as well as their end product PGE2 in gingival fibroblasts. The involvement of the signal pathways JNK and NF-κB in the regulation of PGE2 induced by TNFα may suggest these two pathways as possible attractive targets in the chronic inflammatory disease periodontitis.
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DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
Bennett, BL;Sasaki, DT;Anderson, DW
通讯作者：
Anderson, DW
影响因子：
2.7
作者：
Beikler T;Peters U;Prior K;Eisenacher M;Flemmig TF
通讯作者：
Flemmig TF
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
3.6
作者：
Chen, CC;Sun, YT;Chang, YJ
通讯作者：
Chang, YJ
NCBI GEO：开采数以百万计的表达概况 - 数据库和工具更新。
影响因子：
14.9
作者：
Barrett, Tanya;Troup, Dennis B.;Wilhite, Stephen E.;Ledoux, Pierre;Rudnev, Dmitry;Evangelista, Carlos;Kim, Irene F.;Soboleva, Alexandra;Tomashevsky, Maxim;Edgar, Ron
通讯作者：
Edgar, Ron