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.
Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City 84132.
R M
RM
Silver
W S
WS
Lohner
R A
RA
Daynes
M D
MD
Mitchell
D W
DW
Branch
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