Bile acid-mediated induction of cyclooxygenase-2 and Mcl-1 in hepatic stellate cells.
In cholestatic liver diseases, bile acids induce hepatocyte apoptosis and thus cause liver injury, but hepatic stellate cells (HSCs) survive in the presence of bile acids. We attempted to analyze anti-apoptotic signaling pathways in HSCs against bile acid-induced apoptosis. In immortalized human HSCs and primarily cultured rat HSCs, bile acid treatment increased the expression levels of cyclooxygenase-2 (COX-2) and Mcl-1. COX-2 induction was found to be due to transcriptional enhancement dependent on p42/44, p38 MAPK, and JNK activation, whereas Mcl-1 induction resulted from bile acid-mediated protein stabilization in a Raf-1-dependent manner. Moreover, the inhibitions of either COX-2 activity by celecoxib or Mcl-1 induction by siRNA transfection rendered HSCs susceptible to bile acid-induced apoptosis. These results imply that the bile acid-mediated inductions of COX-2 and Mcl-1 may lead to HSC survival in cholestatic liver diseases.
Kim
Kang Mo
KM
Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul 110-744, South Korea.
Yoon
Jung-Hwan
JH
Gwak
Geum-Youn
GY
Kim
Won
W
Lee
Sung Hee
SH
Jang
Ja June
JJ
Lee
Hyo-Suk
HS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002635:Chenodeoxycholic Acid / Q000008:administration & dosage / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D002635:Chenodeoxycholic Acid; D051546:Cyclooxygenase 2