Inhibition of Stat3 activation in the endometrium prevents implantation: a nonsteroidal approach to contraception.
Activation of the receptors for leukemia inhibitory factor (LIF) and IL-11 is essential for embryo attachment and decidualization in mice. Both receptors induce activation of the Stat family of signal transducers via the Jak/Stat pathway. Here, we aimed to establish whether activation of Stat3 in maternal endometrium is essential for successful implantation. Functional blockade of Stat3 before implantation, by injection into the uterine lumen of a cell-permeable Stat3 peptide inhibitor, reduced embryo implantation specifically by 70% (P < 0.001). Stat3 is phosphorylated in the luminal epithelium (LE) in response to LIF, and this phosphorylation was significantly reduced both in vitro and in vivo by the Stat3 inhibitor. The inhibitor also blocked induction by LIF of several LIF-regulated genes in the LE including Irg1, which has been shown previously to be essential for implantation. Successful implantation is therefore dependent on phosphorylation and activation of Stat3 in the endometrium before implantation. This finding provides a target for contraceptive development, based on selective blockade of signal transduction pathways essential for implantation. This study demonstrates that cell-permeable peptide inhibitors can be used effectively to target intracellular signaling pathways in the uterine LE.
Catalano
Rob D
RD
Reproductive Molecular Research Group, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom. rc296@cam.ac.uk
Johnson
Martin H
MH
Campbell
Elizabeth A
EA
Charnock-Jones
D Stephen
DS
Smith
Stephen K
SK
Sharkey
Andrew M
AM
D000818:Animals; D003267:Contraception / Q000379:methods*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010064:Embryo Implantation / Q000502:physiology*; D004717:Endometrium / Q000378:metabolism*; D005260:Female; D015151:Immunoblotting; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D051379:Mice; D008815:Mice, Inbred Strains; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004268:DNA-Binding Proteins; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D011506:Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators