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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-B

Eicosanoid and Lipid Research Division and Centre for Experimental Gynecology and Breast Research, Department of Gynecology, University Medical Centre Benjamin Franklin, Free University of Berlin, Berlin, Germany

Candidiasis, in its mucocutaneous form as well as in an invasive form, is frequently associated with high morbidity. PGE₂, 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 PGE₂, 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-B promoter construct and dominant negative plasmid of IB kinase showed that COX-2 transcription is mediated through p38^MAPK and NF-B pathways. That NF-B up-regulates p38^MAPK is novel and is in contradiction to earlier reports in which NF-B was shown to inhibit p38^MAPK. In conclusion, multiple converging signaling pathways, involving TLRs followed by PKC, p38^MAPK, and/or NF-B, are triggered by C. albicans in activation of COX-2 gene.

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