Induction of cyclooxygenase-2 gene by Candida albicans through EGFR, ERK, and p38 pathways in human urinary epithelium.

Abstract

In the present data, we found that Candida albicans (C. albicans) caused bladder epithelial cell morphology alteration, cell damage, and inflammatory responses, including cyclooxygenase-2 (COX-2) gene and protein expression as well as prostaglandin E2 accumulation. In addition, the molecular pathway underlying C. albicans-induced urothelial COX-2 gene expression was examined. Among MAPK pathways, phosphorylation of ERK1/2, p38, and JNK each increased following C. albicans infection for 12h. However, C. albicans-induced COX-2 protein expression was inhibited by specific inhibitors of ERK and p38 (U0126 and SB203580) but not by JNK inhibitor SP600125. Additional evidence came from the increased amount of phosphorylated RSK that is the mutual downstream molecule of ERK1/2 and p38. Furthermore, phosphorylation of RSK protein was reduced by the ERK and p38 inhibitor, suggesting that the urothelial COX-2 gene was induced majorly though the ERK/p38-RSK pathway by C. albicans infection. We also found transcription factor CREB-1 showed increased binding to the COX-2 gene promoter by chromatin immunoprecipitation assay. Next, we used receptor inhibitors including Toll-like receptor (TLR)-Myd88 inhibitor ST2825, Dectin-Syk inhibitor Syk inhibitor, and epidermal growth factor receptor (EGFR) inhibitor PD168393 to identify which one was the main target associated with C. albicans binding. The results revealed that it was EGFR, recognized by C. albicans, that mostly mediated the ERK/p38-RSK pathway activation to induce COX-2 gene expression, but this was not the case for TLRs and Dectin receptors. In summary, these results demonstrated the EGFR-ERK/p38-RSK-CREB-1 pathway was involved significantly in the C. albicans-induced COX-2 expression in human urothelium.