Interleukin-1 receptor antagonist prevents embryonic implantation by a direct effect on the endometrial epithelium

Objective: To investigate the embryonic and/or endometrial molecular mechanisms underlying the antiimplantation effect of interleukin-1 receptor antagonist (IL-1ra). Design: Controlled experiment. Setting: Animal facilities at Stanford University and laboratories of the Instituto Valenciano de Infertilidad and the University of Sydney. Animal(s): Twelve-week-old B6C3F-1 female mice. Intervention(s): Intraperitoneal injections of recombinant human IL-1ra during the periimplantation period. Main Outcome Measure(s): Implantation sites, embryonic morphology, and viability. Polymerase chain reaction and immunohistochemistry for integrins and extracellular matrices and transmission electron microscopy of endometrium in IL-1ra–treated versus control animals. Result(s): Pregnancy rates in control and IL-1ra–injected animals were 60% and 13%, respectively. At day 8 of pregnancy, flushing of uteri obtained from the treated group resulted in 32 blastocysts. Six pseudopregnant animals received IL-1ra–treated blastocysts (left horn) and control blastocysts (right horn), resulting in one pregnancy, with two embryos and one embryo in the left and right horns, respectively. At day 4 of pregnancy, IL-1ra down-regulated α4 mRNA with use of the polymerase chain reaction. Immunohistochemistry showed a decrease of α4, αv, and β3, and transmission electron microscopy revealed inhibition of transformation of the plasma membrane. Conclusion(s): Impairment of embryonic adhesion with IL-1ra is mediated through a direct effect on transformation of the epithelial plasma membrane at the time of implantation as a result of down-regulation of α4, αv, and β3.