Lipopolysaccharide-induced fetal death: the role of tumor-necrosis factor alpha.
Lipopolysaccharide (LPS) administration has been known to cause murine fetal death for over 50 years, but the responsible mechanism(s) remains unclear. We used the LPS-hyporesponsive murine strain, C3H/HeJ, to 1) establish whether LPS-induced fetal death is due to a maternal or fetal response to LPS and 2) to investigate the involvement of tumor necrosis factor alpha (TNF alpha) in fetal death caused by LPS. C3H/HeJ (LPS-hyporesponsive) or C3H/HeN (LPS-responsive) females were mated with C57B1/6 or C3H/HeN males (both LPS-responsive). Administration of 10 micrograms LPS caused fetal death in C3H/HeN mothers. However, up to 1000 micrograms LPS did not result in the death of LPS-responsive fetuses when administered to C3H/HeJ mothers. Systemic administration of TNF alpha was able to cause fetal death in both C3H/HeN and C3H/HeJ strains of mice. Pretreatment of pregnant C3H/HeN mice with anti-TNF alpha antibodies significantly reduced fetal death caused by LPS administration. The administration of a sublethal dose of TNF alpha plus 10 micrograms LPS to pregnant C3H/HeJ mice restored abortifacient activity. These results indicate that LPS-induced fetal death is due to a maternal response as opposed to a direct fetal response to LPS and that TNF alpha appears to be an important mediator of fetal death caused by LPS.
Silver
R M
RM
Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City 84132.
Lohner
W S
WS
Daynes
R A
RA
Mitchell
M D
MD
Branch
D W
DW
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D004926:Escherichia coli; D005260:Female; D005313:Fetal Death / Q000139:chemically induced*; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology / Q000502:physiology*
D000906:Antibodies; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha