Miyazawa K, Mori A, Miyata H, Akahane M, Ajisawa Y, Okudaira H
Central Research Laboratories, Kissei Pharmaceutical Co., Ltd., Nagano-Pref. 399-8304, Japan.
J Biol Chem. 1998 Sep 18;273(38):24832-8. doi: 10.1074/jbc.273.38.24832.
Involvement of p38 mitogen-activated protein (MAP) kinase in interleukin (IL)-6 gene expression of human fibroblast-like synoviocytes (FLSs) was assessed. p38 MAP kinase was constitutively expressed in human FLSs and activated in response to IL-1beta. A pyridinylimidazole compound, SB203580, inhibited p38 MAP kinase activity in vivo, since the activity of MAPKAP kinase-2 (a substrate of p38 MAP kinase) in IL-1beta-stimulated FLSs was totally suppressed by it. SB203580 concentration-dependently inhibited protein production and gene expression of IL-6 by human FLSs. The effect of SB203580 was dependent on de novo protein synthesis. SB203580 significantly reduced the stability of IL-6 mRNA without affecting the rate of IL-6 gene transcription. Here, we provide evidence that p38 MAP kinase is activated in response to IL-1beta in human FLSs and is involved in IL-6 synthesis by stabilizing IL-6 mRNA.
评估了p38丝裂原活化蛋白（MAP）激酶在人成纤维样滑膜细胞（FLS）白细胞介素（IL）-6基因表达中的作用。p38 MAP激酶在人FLS中组成性表达，并在白细胞介素-1β刺激下被激活。一种吡啶基咪唑化合物SB203580在体内抑制p38 MAP激酶活性，因为在白细胞介素-1β刺激的FLS中，MAPKAP激酶-2（p38 MAP激酶的一种底物）的活性被其完全抑制。SB203580浓度依赖性地抑制人FLS中IL-6的蛋白质产生和基因表达。SB203580的作用依赖于从头合成蛋白质。SB203580显著降低了IL-6 mRNA的稳定性，而不影响IL-6基因转录速率。在此，我们提供证据表明，p38 MAP激酶在人FLS中对白细胞介素-1β作出反应而被激活，并通过稳定IL-6 mRNA参与IL-6的合成。
