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).


METHODS
Controlled experiment.


METHODS
Animal facilities at Stanford University and laboratories of the Instituto Valenciano de Infertilidad and the University of Sydney.


METHODS
Twelve-week-old B6C3F-1 female mice.


METHODS
Intraperitoneal injections of recombinant human IL-1ra during the periimplantation period.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Simón
C
C
Instituto Valenciano de Infertilidad and Department of Pediatrics, Obstetrics, and Gynecology, Valencia University, Spain. ivi@futurnet.es
Valbuena
D
D
Krüssel
J
J
Bernal
A
A
Murphy
C R
CR
Shaw
T
T
Pellicer
A
A
Polan
M L
ML
D000818:Animals; D010064:Embryo Implantation / Q000187:drug effects*; D004624:Embryo Transfer; D004717:Endometrium / Q000187:drug effects*; D004848:Epithelium / Q000187:drug effects; D016326:Extracellular Matrix Proteins / Q000032:analysis; D005260:Female; D005865:Gestational Age; D006801:Humans; D007150:Immunohistochemistry; D053590:Interleukin 1 Receptor Antagonist Protein; D051379:Mice; D008815:Mice, Inbred Strains; D008854:Microscopy, Electron; D011247:Pregnancy; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012795:Sialoglycoproteins / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
D016326:Extracellular Matrix Proteins; C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; D019010:Vascular Cell Adhesion Molecule-1