Regulation of prostaglandin production in an immortalized human myometrial cell line by cytokines and non-steroidal anti-inflammatory drugs.
OBJECTIVE
To test the effect of selective and non-selective inhibitors of prostaglandin H synthase-2 (PGHS-II) on basal and cytokine-stimulated prostaglandin (PG) production by the immortalized human myometrial cell line, UTLRp16.


METHODS
UTLRp16 cells were treated with interleukin (IL)-1beta (0.1, 1, 10ng/ml) and tumor necrosis factor (TNF)-alpha (1, 3, 10ng/ml) in the presence or absence of indomethacin, etodolac, 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl) phenyl-2 (5H)-furanone (DFU) or nimesulide for 16h (1.6-1000nM). PG production was then measured by radioimmunoassay.


RESULTS
IL-1beta and TNF-alpha both stimulated production of PGE(2) and 6-keto-PGF(1alpha) in a concentration-dependent manner. DFU showed the most PGHS-II selectivity with IL-beta-stimulated PG production, with a IC(50)(basal)/IC(50)(stimulated) ratio of 177.8, followed by nimesulide (122.5), etodolac (23.5) and indomethacin (2.7). DFU was not as selective in TNF-alpha stimulated cells (ratio 99.5).


CONCLUSIONS
PGHS-II-selective inhibitors may be effective in the prevention of cytokine-driven myometrial PG production associated with preterm labor.
Sato
Timothy A
TA
The Division of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, Liggins Institute, University of Auckland, Private Bag 92019, Auckland, New Zealand. t.sato@auckland.ac.nz
Keelan
Jeffrey A
JA
Mitchell
Murray D
MD
D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002461:Cell Line, Transformed; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017308:Etodolac / Q000494:pharmacology; D005260:Female; D005663:Furans / Q000494:pharmacology; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D011453:Prostaglandins / Q000096:biosynthesis*; D013449:Sulfonamides / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C106876:5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D004791:Enzyme Inhibitors; D005663:Furans; D007375:Interleukin-1; D011453:Prostaglandins; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D017308:Etodolac; D015121:6-Ketoprostaglandin F1 alpha; D015232:Dinoprostone; C012655:nimesulide; D007213:Indomethacin