Early regulators in abortion and implications for a preeclampsia model

Abstract 

This paper reports a summary of our comparative analysis of the uterine expression of interleukin-23 (IL-23), IL-27 and TWEAK in the CBA/J female×DBA/2 male mouse mating combination, a model of immune-mediated early pregnancy loss. Compared with the MHC-identical CBA/J×BALB/c mating combination, which yields successful pregnancies, immunohistochemistry and qPCR in uterine tissue showed an immediate post-mating IL-27 hyper-expression after mating with DBA/2 males. Intra-uterine TWEAK expression was present in females mated with DBA/2 or Balb/c males from days 0.5 to 4.5 post-coitum (pc), peaking on day 0.5 pc together with uterine TNFα. In uteri of DBA/2 mated mice, TWEAK declined to almost undetectable levels on days 6.5–9.5 pc, a steeper drop than in BALB/c mated mice where TWEAK remained detectable. In both mating combinations, neutralisation of TWEAK by antibodies increased resorption rates, but surprisingly, so did IL-27 neutralisation. The complement regulator mannan binding lectin-A (MBL-A), but not MBL-C, was present on day 4.5 pc especially after mating with DBA/2 males. High levels of MBL are present in the uterine luminal fluid of sterile women, and possible functions for TWEAK and MBL in human implantation are indicated by their protein and mRNA expression in uterine biopsies from infertile and fertile individuals. Consistent with the results in mice, increased MBL expression is linked with pregnancy failure. Serum and uterine VEGF and VEGF receptor levels are also different between fertile and sterile patients. The implications of these findings for utilising the CBA/J×DBA/2 mating combination as an early onset model of preeclampsia are discussed.

Keywords: Complement, Abortion, Implantation, Interleukins