Oxysterols induce cyclooxygenase‐2 expression in cholangiocytes: Implications for biliary tract carcinogenesis

Cyclooxygenase‐2 (COX‐2), which is expressed by cholangiocytes in biliary tract disorders, has recently been implicated in biliary tract carcinogenesis. The mechanisms responsible for this COX‐2 expression remain unclear. In human diseases, bile contains oxygenated derivatives of cholesterol (oxysterols) which possess diverse biological properties. Therefore, we determined if oxysterols modulate COX‐2 expression. The effect of an oxysterol (22(R)‐hydroxycholesterol, 22‐HC) on COX‐2 expression in KMBC cells, a human cholangiocarcinoma cell line, was examined. 22‐HC enhanced COX‐2 protein expression. This oxysterol activated p42/44 and p38 MAPK, but not JNK 1/2. A p42/44 MAPK inhibitor did not block COX‐2 induction, while p38 MAPK inhibitor effectively attenuated COX‐2 induction. Although COX‐2 mRNA levels were increased by 22‐HC, this increase was not transcriptionally regulated, as 22‐OH did not increase activity in a COX‐2 promoter gene assay. In contrast, COX‐2 mRNA stability was augmented by 22‐HC treatment, and this effect was reversed by a p38 MAPK inhibitor. In conclusion, the results demonstrate that the oxysterol 22‐HC stabilizes COX‐2 mRNA via a p38 MAPK‐dependent mechanism. This enhanced COX‐2 protein expression by oxysterols may participate in the genesis and progression of cholangiocarcinoma. (H EPATOLOGY 2004;39:732–738.)