Activation of the RON receptor tyrosine kinase by macrophage-stimulating protein inhibits inducible cyclooxygenase-2 expression in murine macrophages
Activation of the RON receptor tyrosine kinase by macrophage-stimulating protein inhibits inducible cyclooxygenase-2 expression in murine macrophages
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DOI：
10.1074/jbc.m206167200
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发表时间：
2002-10-11
影响因子：
4.8
通讯作者：
Wang, MH
中科院分区：
文献类型：
--
作者：
Zhou, YQ;Chen, YQ;Wang, MH
罗恩受体酪氨酸激酶被巨噬细胞刺激蛋白激活，调节巨噬细胞迁移、吞噬作用和一氧化氮产生。本文报道了罗恩对脂多糖（LPS）诱导的小鼠巨噬细胞环氧合酶（考克斯）2表达的抑制作用。在用巨噬细胞刺激蛋白处理的表达RON的巨噬细胞中，LPS诱导的前列腺素E-2（PGE（2））的产生显著减少。抑制伴随着考克斯-2蛋白和mRNA表达的减少。转录研究表明，罗恩激活抑制由考克斯-2基因启动子驱动的LPS诱导的荧光素酶活性。确定罗恩激活是否影响LPS诱导的NF-κ B通路，这对考克斯-2表达很重要。进行蛋白质印迹分析，显示罗恩活化抑制LPS诱导的IkappaB α降解。IkappaB α降解减少是由于IkappaB α（Ser-32）磷酸化抗体测定的Ser-32处IkappaB α磷酸化减少。此外，我们发现LPS诱导的IKK β活性，一种负责IkappaB α磷酸化的酶，在罗恩激活后被抑制。有趣的是，这些抑制作用不受RON介导的磷脂酰肌醇-3激酶的调节。这些结果表明，罗恩活化抑制LPS诱导的巨噬细胞考克斯-2表达。抑制作用是通过损害激活NF-κ B的LPS激活级联酶介导的。考克斯-2表达的抑制可能代表了罗恩在体内抑制LPS诱导的炎症和感染性休克的新机制。
The RON receptor tyrosine kinase is activated by macrophage-stimulating protein, which regulates macrophage migration, phagocytosis, and nitric oxide production. We report here the inhibitory effect of RON on lipopolysaccharide (LPS)-induced cyclooxygenase (Cox)2 expression in mouse macrophages. In RON-expressing macrophages treated with macrophage stimulating protein, LPS-induced prostaglandin E-2 (PGE(2)) production was significantly reduced. The inhibition was accompanied by reduction of Cox-2 protein and mRNA expression. Transcriptional studies indicated that RON activation inhibits LPS-induced luciferase activity driven by the Cox-2 gene promoter. To determine whether RON activation affects LPS-induced NF-kappaB pathway, which is important for Cox-2 expression. Western blot analyses were performed showing that RON activation inhibits LPS-induced IkappaBalpha degradation. The decreased IkappaBalpha degradation was due to reduced IkappaBalpha phosphorylation at Ser-32 as determined by IkappaBalpha (Ser-32) phosphor-antibody. Moreover, we found that LPS-induced IKKbeta activity, an enzyme responsible for phosphorylation of IkappaBalpha, was inhibited upon RON activation. Interestingly, these inhibitory effects were not regulated by RON-mediated phosphatidylinositol-3 kinase. These results suggest that RON activation inhibits LPS-induced macrophage Cox-2 expression. The inhibitory effect is mediated by impairing LPS-activated cascade enzymes that activate NF-kappaB. The inhibition of Cox-2 expression might represent a novel mechanism for the inhibitory functions of RON in vivo against LPS-induced inflammation and septic shock.