Department of Pathophysiology, Norman Bethune College of Medicine, Jilin University, Changchun, China.
Int Immunopharmacol. 2013 Nov;17(3):785-92. doi: 10.1016/j.intimp.2013.09.001. Epub 2013 Sep 23.
Our previous results showed that JLU1124 is a potent p38 mitogen-activated protein kinase (MAPK) inhibitor. Compared to the classic p38 MAPK inhibitor SB203580, JLU1124 inhibits p38 phosphorylation at low concentrations without cytotoxicity on cells. p38 MAPK is a known target for inflammation treatment. Thus, we became interested in whether JLU1124 has anti-inflammatory effects. We used LPS stimulated RAW264.7 macrophages as a model of inflammation to evaluate the anti-inflammatory effects of JLU1124. Our results showed that p38 phosphorylation, the production of nitric oxide (NO), interleukin (IL)-6 and tumor necrosis factor (TNF)-α, the mRNA and protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 were enhanced by lipopolysaccharide (LPS). At concentrations of less than 10 μmol/L, JLU1124 inhibits p38 phosphorylation in a dose-dependent manner and significantly suppresses LPS-induced production of NO, IL-6 and TNF-α, and decreases the expressions of iNOS and COX-2 in RAW264.7 macrophages which indicate that JLU1124 has anti-inflammatory effects. However, JLU1124 has no significant effect on the phosphorylation of extracellular signal-regulated kinase1/2 and c-Jun NH2-terminal kinase which was involved in inflammation. Furthermore, our results showed that JLU1124 inhibits NF-κB inhibitor (IκB)α phosphorylation, nuclear translocation and transcriptional activity of NF-κB induced by LPS which may be through suppression of Akt phosphorylation. In conclusion, our study indicates that JLU1124 efficiently inhibits p38 phosphorylation and has anti-inflammatory effects in LPS-treated RAW264.7 macrophages. The anti-inflammatory mechanism of JLU1124 is mainly through decreasing Akt phosphorylation and inhibiting IκBα phosphorylation, thus suppressing NF-κB activation and nuclear translocation.
我们之前的研究结果表明，JLU1124 是一种有效的 p38 丝裂原活化蛋白激酶（MAPK）抑制剂。与经典的 p38 MAPK 抑制剂 SB203580 相比，JLU1124 在低浓度下抑制 p38 磷酸化，而对细胞无细胞毒性。p38 MAPK 是炎症治疗的已知靶点。因此，我们对 JLU1124 是否具有抗炎作用产生了兴趣。我们使用 LPS 刺激的 RAW264.7 巨噬细胞作为炎症模型来评估 JLU1124 的抗炎作用。我们的结果表明，p38 磷酸化、一氧化氮（NO）、白细胞介素（IL）-6 和肿瘤坏死因子（TNF）-α的产生、诱导型一氧化氮合酶（iNOS）和环氧化酶（COX）-2 的 mRNA 和蛋白水平在脂多糖（LPS）的作用下均升高。在低于 10μmol/L 的浓度下，JLU1124 呈剂量依赖性抑制 p38 磷酸化，并显著抑制 LPS 诱导的 NO、IL-6 和 TNF-α的产生，降低 RAW264.7 巨噬细胞中 iNOS 和 COX-2 的表达，表明 JLU1124 具有抗炎作用。然而，JLU1124 对参与炎症的细胞外信号调节激酶 1/2（ERK1/2）和 c-Jun NH2-末端激酶（JNK）的磷酸化没有显著影响。此外，我们的结果表明，JLU1124 抑制 LPS 诱导的 NF-κB 抑制剂（IκB）α磷酸化、核转位和转录活性，这可能是通过抑制 Akt 磷酸化实现的。总之，我们的研究表明，JLU1124 可有效抑制 LPS 处理的 RAW264.7 巨噬细胞中 p38 的磷酸化，具有抗炎作用。JLU1124 的抗炎机制主要是通过降低 Akt 磷酸化和抑制 IκBα磷酸化，从而抑制 NF-κB 激活和核转位。
