Prostanoid stimulation of cytokine production in an amnion-derived cell line: evidence of a feed-forward mechanism with implications for term and preterm labor.
OBJECTIVE
To test the hypothesis that amnion cytokine production might be regulated by prostanoids.


METHODS
Amnion-derived WISH cells were treated with a range of prostanoids and their effects on production of interleukin (IL)-6 and IL-8 were determined by enzyme-linked immunosorbent assay and Northern analysis. The effects of thromboxane inhibitors on cytokine production by term primary amnion explants also were examined.


RESULTS
Prostaglandin (PG)A2, PGD2, PGF2 alpha, PGE2, PGJ2, and the PGI2 analogue carbaprostacyclin (1-1000 nmol/L) exhibited no significant effects on cytokine production. However, the thromboxane A2 (TXA2) agonist U46619 and carbocyclic (c)TXA2 both stimulated WISH cytokine production with similar potencies under basal or cytokine-stimulated conditions. Significant stimulation of IL-6 production was observed at concentrations > or = 8 nmol/L (P < .05 by analysis of variance), whereas IL-8 production was stimulated significantly but to a lesser extent. The effects of U46619 and cTXA2 were rapid; maximal stimulation of cytokine production occurred within 4 to 8 hours of treatment. U46619 augmented IL-1 beta-stimulated IL-6 and IL-8 mRNA expression within 2 hours of treatment. In amnion explants inhibitors of TX synthesis and action abrogated the stimulatory effects of IL-1 beta on cytokine production.


CONCLUSIONS
These results are consistent with the presence of a feed-forward loop in amnion involving TXA2 and cytokines, which could play a significant role in the progression of the inflammatory response involved in the mechanism of infection-driven preterm labor.
Keelan
J A
JA
Department of Pharmacology and Clinical Pharmacology, University of Auckland School of Medicine, New Zealand. j.keelan@auckland.ac.nz
Sato
T A
TA
Gupta
D K
DK
Marvin
K W
KW
Mitchell
M D
MD
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000650:Amnion / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D007743:Labor, Obstetric / Q000502:physiology*; D007752:Obstetric Labor, Premature / Q000209:etiology*; D011247:Pregnancy; D011453:Prostaglandins / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000819:agonists / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology
D016207:Cytokines; D015850:Interleukin-6; D016209:Interleukin-8; D011453:Prostaglandins; C024587:thromboxane A2, carbocyclic; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid