PROBLEM: Fetal loss syndrome (abortion/resorption) occurring on or after gestation day (gd) 9.5 in CBA/J×DBA/2 matings is dependent upon presence of TNF-α + IFN-γ, which act by increasing expression of fgl2 prothrombinase at the feto-maternal interface. The magnitude by which the abortion rate can be boosted by an injection of these cytokines on gd 7.5 depends on endogenous rate of loss, and appears to depend on microbial flora. Is cytokine-triggered abortion dependent upon a third signaling pathway that senses ‘danger'?
METHODS: Female CBA/J were mated to DBA/2 males and, C57Bl/6 and C57Bl/6 TNFαR1−/−Mak were mated to C57Bl/6 control or TNFαR1−/−Mak males. LPS from Escherichia coli and Salmonella enteritidis, or the combination of TNF-α + IFN-γ, was injected to stimulate abortions. The effect of anti-MD-1, which interferes with expression of CD14 and, hence, with signaling by LPS via the CD14-tlr4 complex, on TNF-α + IFN-γ was tested. The presence of MD-1 in the uterus was evaluated by in situ hybridization, and effect of lipopolysaccharide (LPS) on mice lacking TNF-αR1 was tested.
RESULTS: Anti-MD-1 completely abrogated TNF-α + IFN-γ -induced abortions. MD-1 was expressed on trophoblast and in deciduas on gd 8.5 but LPS could not abort mice that lacked the type 1 receptor for TNF-α. Pregnant CBA/J females had classical resorptions (abortions) countable on gd 13.5–14.5 in response to LPS from E. coli or S. enteritidis, but C57Bl/6 strain mice resorbed only in response to the latter, and E. coli LPS appeared to induce ‘occult’ losses. ‘Occult’ loss did not require TNF-α R1.
CONCLUSIONS: TNF-α + IFN-γ could not induce murine abortions without co-presence of a ‘danger’ signal such as LPS acting via CD14 on toll receptors, and LPS could not act without co-signaling by TNF-α. Classical resorptions/abortions and ‘occult’ losses have a different mechanism in these models as reflected in type of endotoxin and requirement for TNF-αR1 signaling.