Candida albicans induces selectively transcriptional activation of cyclooxygenase-2 in HeLa cells:: Pivotal roles of toll-like receptors, p38 mitogen-activated protein kinase, and NF-κB
Candida albicans induces selectively transcriptional activation of cyclooxygenase-2 in HeLa cells:: Pivotal roles of toll-like receptors, p38 mitogen-activated protein kinase, and NF-κB
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DOI：
10.4049/jimmunol.171.6.3047
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发表时间：
2003-09-15
影响因子：
4.4
通讯作者：
Nigam, S
中科院分区：
文献类型：
--
作者：
Deva, R;Shankaranarayanan, P;Nigam, S
念珠菌病，无论是皮肤粘膜形式还是侵袭性形式，通常与高发病率有关。PGE(2)是由环氧化酶（cox） 1和cox 2的酶活性产生的，已被证明可以触发白色念珠菌的形态发生。在本研究中，我们研究了白色念珠菌是否改变了HeLa细胞中COX-2的表达。RT-PCR和Western blot分析显示COX-2 mRNA表达和COX-2蛋白水平具有时间依赖性的双相行为。COX-1蛋白未受影响。针对toll样受体（TLR） 2和4的抗体中和抑制了念珠菌诱导的PGE的产生(2)，这表明TLR在哺乳动物细胞感染白色念珠菌后的识别和信号传导中起着重要作用。瞬时转染COX-2启动子-荧光素酶构建体和多种丝裂原活化蛋白激酶（MAPK）抑制剂，如蛋白激酶C （PKC）抑制剂GF203190X、p38（MAPK）抑制剂SB203109和细胞外调节激酶1和2抑制剂PD98509，表明白色念珠菌通过p38（MAPK）和PKC途径选择性上调COX-2，而不上调COX-1。未观察到其他应激激酶，如c-Jun nh2末端激酶和细胞外调节激酶1和2的参与。瞬时转染NF-kappaB启动子构建体和ikappabβ激酶显性负质粒表明，COX-2的转录通过p38（MAPK）和NF-kappaB途径介导。NF-kappaB上调p38（MAPK）是一个新发现，这与NF-kappaB抑制p38（MAPK）的早期报道相矛盾。综上所述，白色念珠菌在激活COX-2基因时触发了多种趋同信号通路，包括TLRs、PKC、p38（MAPK）和/或NF-kappaB。免疫学杂志，2003。
Candidiasis, in its mucocutaneous form as well as in an invasive form, is frequently associated with high morbidity. PGE(2), which is generated by enzymatic activity of cyclooxygenases (COXs) 1 and 2, has been shown to trigger morphogenesis in Candida albicans. In the present study, we investigated whether C. albicans altered COX-2 expression in HeLa cells. RT-PCR and Western blot analyses revealed a time-dependent biphasic behavior of COX-2 mRNA expression and COX-2 protein level. COX-1 protein remained unaffected. Neutralization with Abs against Toll-like receptors (TLR) 2 and 4 inhibited the Candida-induced production of PGE(2), suggesting a vital role for TLRs in the recognition and signaling in mammalian cells upon infection with C albicans. Transient transfections with COX-2 promoter-luciferase construct and various inhibitors of mitogen-activated protein kinases (MAPK), such as protein kinase C (PKC) inhibitor GF203190X, p38(MAPK) inhibitor SB203109, and extracellular-regulated kinases 1 and 2 inhibitor PD98509 showed that C albicans up-regulates selectively COX-2, but not COX-1, through p38(MAPK) and PKC pathways. No involvement of other stress kinases, e.g., c-Jun NH2-terminal kinase and extracellular-regulated kinases 1 and 2, was observed. Transient transfection of NF-kappaB promoter construct and dominant negative plasmid of IkappaBbeta kinase showed that COX-2 transcription is mediated through p38(MAPK) and NF-kappaB pathways. That NF-kappaB up-regulates p38(MAPK) is novel and is in contradiction to earlier reports in which NF-kappaB was shown to inhibit p38(MAPK). In conclusion, multiple converging signaling pathways, involving TLRs followed by PKC, p38(MAPK), and/or NF-kappaB, are triggered by C albicans in activation of COX-2 gene. The Journal of Immunology, 2003.