Prevention of human recombinant interleukin-1 beta (rhIL-1 beta) embryolethality with progesterone or indomethacin.
OBJECTIVE
Bropirimine and tilorone were found in earlier studies to be embryolethal when administered to Crl:TUC(SD)spf (TUC) rats on gestation day 10. Progesterone or indomethacin could, at least partially, prevent this effect. The immunomodulators appeared to mimic the luteolytic effects of PGF2 alpha, resulting in a shutdown in progesterone release by the corpora lutea, followed by a disruption in maternal support to the pregnant uterus and embryolethality. Since bropirimine has been shown to induce interleukin-1, and since this cytokine has been found to increase PGF2 alpha levels in human decidual cells, the decision was made to investigate whether human interleukin-1 beta might act in an analogous manner to bropirimine and tilorone.


METHODS
Bropirimine (400 mg/kg, p.o.) or rhIL-1 beta (20, 30, or 40 micrograms/kg, s.c.) was administered on gestation day 10 to Crl:CD[BR] (CD) or TUC rats, alone and in combination with progesterone (2 mg/kg/day, s.c.) or indomethacin (0.6 mg/day, s.c., days 9-11). On gestation day 14 the dams were killed and their uterine contents examined.


RESULTS
rhIL-1 beta (30-40 micrograms/kg) was embryolethal when administered to CD or TUC rats on gestation day 10. Progesterone or indomethacin coadministration prevented, at least partially, the embryolethality seen when rhIL-1 beta was administered (30 micrograms/kg) to TUC rats.


CONCLUSIONS
Evidence was obtained in support of the hypothesis that interleukin-1 is involved in the embryolethal actions of the immunomodulators bropirimine and tilorone.
Marks
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Hypersensitivity Diseases Research, Upjohn Company, Kalamazoo, MI 49001, USA.
Tracy
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D000276:Adjuvants, Immunologic / Q000633:toxicity; D000818:Animals; D003596:Cytosine / Q000031:analogs & derivatives / Q000633:toxicity; D004347:Drug Interactions; D005260:Female; D005313:Fetal Death / Q000139:chemically induced* / Q000517:prevention & control*; D007213:Indomethacin / Q000627:therapeutic use*; D007369:Interferon Inducers / Q000633:toxicity; D007375:Interleukin-1 / Q000633:toxicity*; D051379:Mice; D011247:Pregnancy; D011374:Progesterone / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000633:toxicity; D013994:Tilorone / Q000633:toxicity
D000276:Adjuvants, Immunologic; D007369:Interferon Inducers; D007375:Interleukin-1; D011994:Recombinant Proteins; D011374:Progesterone; D003596:Cytosine; C033560:bropirimine; D013994:Tilorone; D007213:Indomethacin