Prostaglandin E receptors in bile ducts of hepatolithiasis patients and the pathobiological significance for cholangitis.
OBJECTIVE
In hepatolithiasis, chronic proliferative cholangitis may influence the progression of the disease. Prostaglandin (PG) E(2) experimentally causes morphologic changes to intrahepatic bile ducts, analogous to the changes found in cholangitis. This study was designed to gain an understanding of the involvement of PGE(2) and PGE receptor (EP) subtypes in the development of cholangitis.


METHODS
The expression levels of secretory-type group IIA phospholipase A(2) (sPLA(2)-IIA) and cyclooxygenase (COX)-2 as well as EP subtypes were determined in the bile ducts with change of cholangitis. In in vitro experiments, growth promotion and mucin secretagogue properties of biliary epithelial cells in response to EP-selective agonists or antagonists were studied.


RESULTS
The messenger RNA (mRNA) level of sPLA(2)-IIA and the protein and mRNA levels of COX-2 were significantly increased in the bile ducts of patients with hepatolithiasis compared with the levels of the bile ducts of control subjects. These changes were associated with a concomitant increase in PGE(2) and total mucin concentrations in the bile. The mRNAs of EP subtypes EP(2), EP(3), and EP(4) but not EP(1) were amplified in the bile ducts. Treatment with an EP(4)-selective agonist (ONO-AE1-329) caused a dose-dependent increase in DNA synthesis, colony number, and mucin secretion in the cells. Conversely, treatment with an EP(4)-selective antagonist (ONO-AE3-208) abolished the biological effects of PGE(2) on the cells.


CONCLUSIONS
In hepatolithiasis, an enhanced synthesis of sPLA(2)-/COX-2-derived PGE(2) and its actions mediated via the EP(4) receptor in the bile ducts may be of pathobiological significance for chronic proliferative cholangitis.
Shoda
Junichi
J
Department of Gastroenterology, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan. shodaj@md.tsukuba.ac.jp
Ueda
Tetsuya
T
Kawamoto
Toru
T
Todoroki
Takesi
T
Asano
Toru
T
Sugimoto
Yukihiko
Y
Ichikawa
Atsushi
A
Maruyama
Takayuki
T
Nimura
Yuji
Y
Tanaka
Naomi
N
D000368:Aged; D001653:Bile Ducts, Intrahepatic / Q000166:cytology / Q000378:metabolism* / Q000473:pathology*; D015415:Biomarkers / Q000032:analysis; D002761:Cholangitis / Q000378:metabolism*; D042883:Choledocholithiasis / Q000378:metabolism*; D002908:Chronic Disease; D000242:Cyclic AMP / Q000378:metabolism; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D042882:Gallstones / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D007527:Isoenzymes / Q000378:metabolism; D007564:Japan; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009077:Mucins / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D010741:Phospholipases A / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011448:Prostaglandin Antagonists / Q000008:administration & dosage; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000378:metabolism*; D012720:Severity of Illness Index
D015415:Biomarkers; D007527:Isoenzymes; D008565:Membrane Proteins; D009077:Mucins; D011448:Prostaglandin Antagonists; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D000242:Cyclic AMP; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D015232:Dinoprostone