Effect of phosphodiesterase 4 inhibitors on NFAT-dependent cyclooxygenase-2 expression in human T lymphocytes
Effect of phosphodiesterase 4 inhibitors on NFAT-dependent cyclooxygenase-2 expression in human T lymphocytes
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DOI：
10.1016/j.cellsig.2004.04.002
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发表时间：
2004-12-01
影响因子：
4.8
通讯作者：
Fresno, M
中科院分区：
文献类型：
--
作者：
Jimenez, JL;Iñiguez, MA;Fresno, M
环氧化酶-2（考克斯-2）的转录诱导在T细胞受体触发后早期发生，并在炎症中具有功能意义。在这里，我们表明，磷酸二酯酶（PDE）-4抑制剂块考克斯-2诱导和前列腺素的合成在活化的T细胞。PDE 4抑制剂对考克斯-2的抑制作用主要发生在转录水平。在考克斯-2启动子中激活的T细胞核因子（NFAT）的两个反应元件是这些药物抑制所必需的。PDE 4抑制剂在T细胞活化时不影响NFAT核转位;相反，它们阻止NFAT与DNA结合并诱导GAL 4-NFAT的反式激活功能。这些作用似乎是cAMP/PKA独立的，因为它们不被渗透性类似物dBcAMP或毛喉素模拟，也不能被PKA抑制剂H89或KT-5720逆转。这些结果可以解释PDE 4抑制剂通过阻断NFAT介导的促炎基因（如考克斯-2）的反式激活而产生的某些抗炎特性。(C)2004年爱思唯尔公司All rights reserved.
Transcriptional induction of cyclooxygenase-2 (COX-2) occurs early after T cell receptor triggering and has functional implications in inflammation. Here, we show that phosphodiesterase (PDE)-4 inhibitors block COX-2 induction and prostaglandin synthesis in activated T cells. COX-2 inhibition by PDE4 inhibitors occurs mainly at the transcriptional level. Two response elements for the nuclear factor of activated T cells (NFAT) in the COX-2 promoter were required for inhibition by these drugs. PDE4 inhibitors did not affect NFAT nuclear translocation upon T cell activation; rather they prevented NFAT binding to DNA and induction of the transactivation function of GAL4-NFAT. These effects seem to be cAMP/PKA independent as they were not mimicked by the permeable analog dBcAMP or by forskolin, neither can be reverted by the PKA inhibitors H89 or KT-5720. These results may explain some of the anti-inflammatory properties of PDE4 inhibitors through the blockade of NFAT-mediated transactivation of pro-inflammatory genes such as COX-2. (C) 2004 Elsevier Inc. All rights reserved.