Prostaglandin E2 receptor EP4 agonist induces Bcl-xL and independently activates proliferation signals in mouse primary hepatocytes.
BACKGROUND
To improve the survival rate of fulminant hepatic failure (FHF), we examined the mechanism of the antiapoptotic effect, and the possible proliferative effect, of a specific agonist of prostaglandin E2 receptor EP4 (PGEP4-A) on mouse primary hepatocytes, as a candidate for a new therapeutic agent.


METHODS
The expression of four PGE2 receptor subtypes was detected by a reverse transcriptase polymerase chain reaction (PCR) method. Hepatocytes were stimulated with PGEP4-A, ONO-AE1-437, and changes in the expression levels of Bcl-xL and cyclin D1 and in the phosphorylation of epidermal growth factor receptor (EGF-R) and extracellular-signal related kinase (ERK) were examined by Western blot analysis.


RESULTS
Mouse primary hepatocytes constitutively expressed the mRNAs of all four PGE2 receptor subtypes, including that of PGEP4. PGEP4-A induced not only Bcl-xL protein expression (as we had previously demonstrated in HepG2 cells) but also induced cyclin D1 protein expression in mouse primary hepatocytes as well as the phosphorylation of EGF-R and ERK. The inhibition of ERK phosphorylation by a specific inhibitor, PD98059, did not affect the increase in Bcl-xL expression level.


CONCLUSIONS
PGEP4-A may be a therapeutic agent for FHF because of its antiapoptotic and regenerative effects on hepatocytes.
Kataoka
Kojiro
K
First Department of Internal Medicine, Iwate Medical University, Morioka, Japan.
Takikawa
Yasuhiro
Y
Lin
Shi De
SD
Suzuki
Kazuyuki
K
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D056741:Cyclin D; D016213:Cyclins / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D018078:Receptors, Prostaglandin E / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; D056741:Cyclin D; D016213:Cyclins; D005419:Flavonoids; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D051020:bcl-X Protein; D066246:ErbB Receptors; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one