Department of Vascular Biology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan.
Neurosci Res. 2013 Aug;76(4):195-206. doi: 10.1016/j.neures.2013.05.002. Epub 2013 May 15.
Toll-like receptor (TLR) 4 is a pattern recognition receptor, and recognizes not only bacterial lipopolysaccharide (LPS) but also endogenous danger-associated molecular patterns released from dying or injured cells. It has been reported that TLR4 signaling in astrocytes plays an important role in various neurological diseases. However, details of TLR4 signaling in astrocytes are not fully elucidated. In the present study, we demonstrated that TLR4 signaling, induced by LPS, increases the expression of melanoma differentiation-associated gene 5 (MDA5) and interferon (IFN)-stimulated gene 56 (ISG56) in U373MG human astrocytoma cells. We also found that nuclear factor-κB, p38 mitogen-activated protein kinase and IFN-β are involved in the expression of MDA5 and ISG56 induced by LPS. RNA interference experiments revealed that MDA5 and ISG56 positively regulate the LPS-induced expression of a chemokine CXCL10, but not CCL2. In addition, it was suggested that MDA5 and ISG56 constitute a positive feedback loop. These results suggest that MDA5 and ISG56 may contribute not only to physiological inflammatory reactions but also to the pathogenesis of various neurological diseases elicited by TLR4 in astrocytes, at least in part, by regulating the expression of CXCL10.
Toll 样受体 (TLR) 4 是一种模式识别受体，不仅可以识别细菌脂多糖 (LPS)，还可以识别来自死亡或受损细胞释放的内源性危险相关分子模式。据报道，星形胶质细胞中的 TLR4 信号转导在各种神经疾病中起着重要作用。然而，星形胶质细胞中 TLR4 信号转导的细节尚未完全阐明。在本研究中，我们证明了 LPS 诱导的 TLR4 信号转导增加了 U373MG 人星形细胞瘤细胞中黑色素瘤分化相关基因 5 (MDA5) 和干扰素 (IFN)-刺激基因 56 (ISG56) 的表达。我们还发现核因子-κB、p38 丝裂原活化蛋白激酶和 IFN-β 参与了 LPS 诱导的 MDA5 和 ISG56 的表达。RNA 干扰实验表明，MDA5 和 ISG56 正向调节 LPS 诱导的趋化因子 CXCL10 的表达，但不调节 CCL2 的表达。此外，提示 MDA5 和 ISG56 构成正反馈回路。这些结果表明，MDA5 和 ISG56 不仅可能有助于生理炎症反应，而且可能通过调节 CXCL10 的表达，至少部分参与 TLR4 在星形胶质细胞中引发的各种神经疾病的发病机制。
