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 alpha4 mRNA with use of the polymerase chain reaction. Immunohistochemistry showed a decrease of alpha4, alpha v, and beta3, 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 alpha4, alpha v, and beta3.