Department of Life Science, Ewha Womans University, Seoul, 120-750, Korea.
The Research Center for Cellular Homeostasis, Ewha Womans University, Seoul, 120-750, Korea.
Sci Rep. 2017 Jul 28;7(1):6807. doi: 10.1038/s41598-017-07316-3.
Toll-like receptor 2 (TLR2) mediates the innate immune response to bacterial lipopeptides and peptidoglycans by stimulating the production of inflammatory cytokines. However, the mechanisms by which TLR2 signaling regulates type I interferon (IFN)-β production are poorly understood. Here, we identified Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) as a negative regulator of TLR2-induced IFN-β production. Pharmacological inhibition or reduced expression of SHP2 potentiated TLR2 agonist-mediated IFN-β transcription and STAT1 activation, whereas overexpression of SHP2 impaired IFN-β transcription and STAT1 activation. SHP2 physically associated with the glycogen synthase kinase 3β (Gsk3β) in an agonist-dependent manner. Gsk3β positively regulates transcription of IFN-β following TLR2 stimulation by inhibiting the phosphorylation of SHP2. SHP2 inhibited the transcriptional activity of IRF-1 and IRF-8 at the IFN-β promoter. Remarkably, IRF-1 and IRF-8 are recruited to the IFN-β promoter in a SHP2 phosphatase activity-dependent manner. These findings provide insight into the mechanisms by which SHP2 and Gsk3β work together to modulate TLR2-mediated IFN-β production in macrophages.
Toll 样受体 2（TLR2）通过刺激炎症细胞因子的产生，介导对细菌脂肽和肽聚糖的固有免疫反应。然而，TLR2 信号转导如何调节 I 型干扰素（IFN）-β产生的机制还知之甚少。在这里，我们确定 SH2 结构域含有蛋白酪氨酸磷酸酶 2（SHP2）是 TLR2 诱导的 IFN-β 产生的负调控因子。SHP2 的药理学抑制或表达减少增强了 TLR2 激动剂介导的 IFN-β 转录和 STAT1 激活，而 SHP2 的过表达则损害了 IFN-β 转录和 STAT1 激活。SHP2 以激动剂依赖性方式与糖原合酶激酶 3β（Gsk3β）发生物理关联。Gsk3β 通过抑制 SHP2 的磷酸化来正向调节 TLR2 刺激后的 IFN-β 转录。SHP2 在 IFN-β 启动子上抑制 IRF-1 和 IRF-8 的转录活性。值得注意的是，IRF-1 和 IRF-8 以 SHP2 磷酸酶活性依赖性方式募集到 IFN-β 启动子。这些发现为 SHP2 和 Gsk3β 如何协同作用来调节巨噬细胞中 TLR2 介导的 IFN-β 产生的机制提供了深入了解。
