Interleukin-1β-induced cyclooxygenase-2 expression requires activation of both c-Jun NH2-terminal kinase and p38 MAPK signal pathways in rat renal mesangial cells
Interleukin-1β-induced cyclooxygenase-2 expression requires activation of both c-Jun NH2-terminal kinase and p38 MAPK signal pathways in rat renal mesangial cells
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DOI：
10.1074/jbc.273.44.28670
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发表时间：
1998-10-30
影响因子：
4.8
通讯作者：
Morrison, AR
中科院分区：
文献类型：
--
作者：
Guan, ZH;Buckman, SY;Morrison, AR
炎症细胞因子白细胞介素-1 β (IL-1 β)诱导环氧化酶-a （Cox-a）的表达，同时从肾小球系膜细胞释放前列腺素。我们之前报道过IL-1 β可以快速激活c-Jun nh2末端/应激激活蛋白激酶（JNK/SAPK）和p38丝裂原激活蛋白激酶（MAPK），还可以诱导Cox-a表达和前列腺素E-2 （PGE(2)）的产生。目前的研究表明，JNK1或p54的显性阴性形式JNK2/SAPK β的过表达会降低IL-1 β刺激的Cox-a表达和PGE(2)的产生。同样，p38 MAPK激酶死亡形式的过表达也抑制IL-1 β诱导的Cox-a表达和PGE(2)的产生。这些结果表明，在IL-1 β激活后，Cox-a的表达需要激活JMK/SAPK和p38 MAPK。此外，我们的实验证实IL-1 β激活肾系膜细胞的MAP激酶激酶4 (MKK4)/SEK1， MKK3和MKK6。MKK4/SEK1显性阴性形式的过表达降低IL-1 β诱导的Cox-2表达，同时抑制JNK/SAPK和p38 MAPK磷酸化。激酶死亡形式的过表达MKK3或MKK6表明，这两种突变激酶均抑制IL-1 β诱导的p38 MAPK磷酸化和Cox-a表达，但不抑制JNK/SAPK磷酸化和活化。本研究表明，IL-1 β诱导的Cox-a表达和PGE(2)合成需要JNK/SAPK和p38 MAPK信号级联的激活。
The inflammatory cytokine interleukin-1 beta (IL-1 beta) induces cyclooxygenase-a (Cox-a) expression with a concomitant release of prostaglandins from glomerular mesangial cells. We reported previously that IL-1 beta rapidly activates the c-Jun NH2-terminal/stress-activated protein kinases (JNK/SAPK) and p38 mitogen-activated protein kinase (MAPK) and also induces Cox-a expression and prostaglandin E-2 (PGE(2)) production. The current study demonstrates that overexpression of the dominant negative form of JNK1 or p54 JNK2/SAPK beta reduces Cox-a expression and PGE(2) production stimulated by IL-1 beta. Similarly, overexpression of the kinase-dead form of p38 MAPK also inhibits IL-1 beta-induced Cox-a expression and PGE(2) production. These results suggest that activation of both JMK/SAPK and p38 MAPK is required for Cox-a expression after IL-1 beta activation. Furthermore, our experiments confirm that IL-1 beta activates MAP kinase kinase-4 (MKK4)/SEK1, MKK3, and MKK6 in renal mesangial cells. Overexpression of the dominant negative form of MKK4/SEK1 decreases IL-1 beta- induced Cox-2 expression with inhibition of both JNK/SAPK and p38 MAPK phosphorylation. Overexpression of the kinase-dead form of MKK3 or MKK6 demonstrated that either of these two mutant kinases inhibited IL-1 beta-induced p38 MAPK phosphorylation and Cox-a expression but not JNK/SAPK phosphorylation and activation. This study suggests that the activation of both JNK/SAPK and p38 MAPK signaling cascades is required for IL-1 beta-induced Cox-a expression and PGE(2) synthesis.