Blocking LIF action in the uterus by using a PEGylated antagonist prevents implantation: A nonhormonal contraceptive strategy
Blastocyst implantation is a critical stage in the establishment of pregnancy. Leukemia inhibitory factor (LIF) is essential for mouse blastocyst implantation and also plays a role in human pregnancy. We examined the effect of a potent LIF antagonist (LA) on mouse implantation. In mice, LIF expressi...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2007-12, Vol.104 (49), p.19357-19362 |
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| creator | White, Christine A Zhang, Jian-Guo Salamonsen, Lois A Baca, Manuel Fairlie, W. Douglas Metcalf, Donald Nicola, Nicos A Robb, Lorraine Dimitriadis, Evdokia |
| description | Blastocyst implantation is a critical stage in the establishment of pregnancy. Leukemia inhibitory factor (LIF) is essential for mouse blastocyst implantation and also plays a role in human pregnancy. We examined the effect of a potent LIF antagonist (LA) on mouse implantation. In mice, LIF expression peaks on day 3.5 of pregnancy (D3.5) (D0.5 = day of mating plug detection) in the uterine glandular epithelium. LA (7 mg/kg per day) administered from D2.5 to D4.5 via four hourly i.p. injections plus continuous administration via miniosmotic pump resulted in complete implantation failure. To improve its pharmacokinetic properties, we conjugated LA to polyethylene glycol (PEG), achieving a significant increase in serum levels. PEGylated LA (PEGLA) (37.5 mg/kg per day) administered via three i.p. injections between D2.5 and D3.5 also resulted in complete implantation failure. PEGLA immunolocalized to the uterine luminal epithelium at the time of blastocyst implantation. Both LA and PEGLA reduced phosphorylation of the downstream signaling molecule STAT3 in luminal epithelial cells on D3.5. The effects of PEGLA were found to be endometrial, with no embryo-lethal effects observed. These data demonstrate that administration of a PEGylated LIF antagonist is an effective method of targeting LIF signaling in the endometrium and a promising novel approach in the development of nonhormonal contraceptives for women. |
| doi_str_mv | 10.1073/pnas.0710110104 |
| format | Article |
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Douglas ; Metcalf, Donald ; Nicola, Nicos A ; Robb, Lorraine ; Dimitriadis, Evdokia</creator><creatorcontrib>White, Christine A ; Zhang, Jian-Guo ; Salamonsen, Lois A ; Baca, Manuel ; Fairlie, W. Douglas ; Metcalf, Donald ; Nicola, Nicos A ; Robb, Lorraine ; Dimitriadis, Evdokia</creatorcontrib><description>Blastocyst implantation is a critical stage in the establishment of pregnancy. Leukemia inhibitory factor (LIF) is essential for mouse blastocyst implantation and also plays a role in human pregnancy. We examined the effect of a potent LIF antagonist (LA) on mouse implantation. In mice, LIF expression peaks on day 3.5 of pregnancy (D3.5) (D0.5 = day of mating plug detection) in the uterine glandular epithelium. LA (7 mg/kg per day) administered from D2.5 to D4.5 via four hourly i.p. injections plus continuous administration via miniosmotic pump resulted in complete implantation failure. To improve its pharmacokinetic properties, we conjugated LA to polyethylene glycol (PEG), achieving a significant increase in serum levels. PEGylated LA (PEGLA) (37.5 mg/kg per day) administered via three i.p. injections between D2.5 and D3.5 also resulted in complete implantation failure. PEGLA immunolocalized to the uterine luminal epithelium at the time of blastocyst implantation. Both LA and PEGLA reduced phosphorylation of the downstream signaling molecule STAT3 in luminal epithelial cells on D3.5. The effects of PEGLA were found to be endometrial, with no embryo-lethal effects observed. These data demonstrate that administration of a PEGylated LIF antagonist is an effective method of targeting LIF signaling in the endometrium and a promising novel approach in the development of nonhormonal contraceptives for women.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.0710110104</identifier><identifier>PMID: 18042698</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; Biological Sciences ; Blastocyst ; Blastocyst - drug effects ; Cells ; Contraception - methods ; Contraceptive Agents, Female - chemistry ; Contraceptive Agents, Female - pharmacology ; Cytokines ; Embryo implantation ; Embryo Implantation - drug effects ; Epithelium ; Female ; Gene expression ; Intrauterine administration ; Intravenous injections ; Leukemia Inhibitory Factor - antagonists & inhibitors ; Leukemia Inhibitory Factor - blood ; Leukemia Inhibitory Factor - chemistry ; Leukemia Inhibitory Factor - pharmacology ; Medical research ; Mice ; Mice, Inbred C57BL ; Phosphorylation - drug effects ; Polyethylene glycol ; Polyethylene Glycols - chemistry ; Polyethylene Glycols - pharmacology ; Pregnancy ; Pumps ; Reproductive system ; Rodents ; STAT3 Transcription Factor - metabolism ; Uterus ; Uterus - cytology ; Uterus - drug effects ; Uterus - metabolism</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2007-12, Vol.104 (49), p.19357-19362</ispartof><rights>Copyright 2007 The National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Dec 4, 2007</rights><rights>2007 by The National Academy of Sciences of the USA 2007</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c620t-f40863c68df97528d220ac30da1b419d71a9d17b5e0c6d3dfcafca0c550f918c3</citedby><cites>FETCH-LOGICAL-c620t-f40863c68df97528d220ac30da1b419d71a9d17b5e0c6d3dfcafca0c550f918c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/104/49.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/25450714$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/25450714$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27924,27925,53791,53793,58017,58250</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18042698$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>White, Christine A</creatorcontrib><creatorcontrib>Zhang, Jian-Guo</creatorcontrib><creatorcontrib>Salamonsen, Lois A</creatorcontrib><creatorcontrib>Baca, Manuel</creatorcontrib><creatorcontrib>Fairlie, W. Douglas</creatorcontrib><creatorcontrib>Metcalf, Donald</creatorcontrib><creatorcontrib>Nicola, Nicos A</creatorcontrib><creatorcontrib>Robb, Lorraine</creatorcontrib><creatorcontrib>Dimitriadis, Evdokia</creatorcontrib><title>Blocking LIF action in the uterus by using a PEGylated antagonist prevents implantation: A nonhormonal contraceptive strategy</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Blastocyst implantation is a critical stage in the establishment of pregnancy. Leukemia inhibitory factor (LIF) is essential for mouse blastocyst implantation and also plays a role in human pregnancy. We examined the effect of a potent LIF antagonist (LA) on mouse implantation. In mice, LIF expression peaks on day 3.5 of pregnancy (D3.5) (D0.5 = day of mating plug detection) in the uterine glandular epithelium. LA (7 mg/kg per day) administered from D2.5 to D4.5 via four hourly i.p. injections plus continuous administration via miniosmotic pump resulted in complete implantation failure. To improve its pharmacokinetic properties, we conjugated LA to polyethylene glycol (PEG), achieving a significant increase in serum levels. PEGylated LA (PEGLA) (37.5 mg/kg per day) administered via three i.p. injections between D2.5 and D3.5 also resulted in complete implantation failure. PEGLA immunolocalized to the uterine luminal epithelium at the time of blastocyst implantation. Both LA and PEGLA reduced phosphorylation of the downstream signaling molecule STAT3 in luminal epithelial cells on D3.5. The effects of PEGLA were found to be endometrial, with no embryo-lethal effects observed. These data demonstrate that administration of a PEGylated LIF antagonist is an effective method of targeting LIF signaling in the endometrium and a promising novel approach in the development of nonhormonal contraceptives for women.</description><subject>Animals</subject><subject>Biological Sciences</subject><subject>Blastocyst</subject><subject>Blastocyst - drug effects</subject><subject>Cells</subject><subject>Contraception - methods</subject><subject>Contraceptive Agents, Female - chemistry</subject><subject>Contraceptive Agents, Female - pharmacology</subject><subject>Cytokines</subject><subject>Embryo implantation</subject><subject>Embryo Implantation - drug effects</subject><subject>Epithelium</subject><subject>Female</subject><subject>Gene expression</subject><subject>Intrauterine administration</subject><subject>Intravenous injections</subject><subject>Leukemia Inhibitory Factor - antagonists & inhibitors</subject><subject>Leukemia Inhibitory Factor - blood</subject><subject>Leukemia Inhibitory Factor - chemistry</subject><subject>Leukemia Inhibitory Factor - pharmacology</subject><subject>Medical research</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Phosphorylation - drug effects</subject><subject>Polyethylene glycol</subject><subject>Polyethylene Glycols - chemistry</subject><subject>Polyethylene Glycols - pharmacology</subject><subject>Pregnancy</subject><subject>Pumps</subject><subject>Reproductive system</subject><subject>Rodents</subject><subject>STAT3 Transcription Factor - metabolism</subject><subject>Uterus</subject><subject>Uterus - cytology</subject><subject>Uterus - drug effects</subject><subject>Uterus - metabolism</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc9rFDEUxwdR7Fo9e1KDB8HDtC8_ZibxINTS1sKCgvYcspnMbtbZZEwyi3vwfzfjLl31IjxIyPu8L9-Xb1E8x3CGoaHng1PxDBoMOBewB8UMg8BlzQQ8LGYApCk5I-ykeBLjGgBExeFxcYI5MFILPit-fui9_mbdEs1vr5HSyXqHrENpZdCYTBgjWuzQGCdCoc9XN7teJdMi5ZJaemdjQkMwW-NSRHYz9NP7pPEOXSDn3cqHjXeqR9q7FJQ2Q7Jbg2K-J7PcPS0edaqP5tnhPC3urq--Xn4s559ubi8v5qWuCaSyY8BrqmvedqKpCG8JAaUptAovGBZtg5VocbOoDOi6pW2nVS7QVQWdwFzT0-L9XncYFxvTajOZ6eUQ7EaFnfTKyr87zq7k0m8lwYwTwbLAm4NA8N9HE5Pc2KhNn_c1fowSC1ZjTEUGX_8Drv0Y8g9ESQBTqASf1M73kA4-xmC6eycY5JSrnHKVx1zzxMs_FzjyhyAz8PYATJNHOSaZyO5o1chu7PtkfqTMov-wGXmxR9Yx-XDPkIpV2dXk59W-3ykv1TLYKO--_F4QOKWcAf0FaO_M8Q</recordid><startdate>20071204</startdate><enddate>20071204</enddate><creator>White, Christine A</creator><creator>Zhang, Jian-Guo</creator><creator>Salamonsen, Lois A</creator><creator>Baca, Manuel</creator><creator>Fairlie, W. Douglas</creator><creator>Metcalf, Donald</creator><creator>Nicola, Nicos A</creator><creator>Robb, Lorraine</creator><creator>Dimitriadis, Evdokia</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7QO</scope><scope>5PM</scope></search><sort><creationdate>20071204</creationdate><title>Blocking LIF action in the uterus by using a PEGylated antagonist prevents implantation: A nonhormonal contraceptive strategy</title><author>White, Christine A ; Zhang, Jian-Guo ; Salamonsen, Lois A ; Baca, Manuel ; Fairlie, W. 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Douglas</au><au>Metcalf, Donald</au><au>Nicola, Nicos A</au><au>Robb, Lorraine</au><au>Dimitriadis, Evdokia</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Blocking LIF action in the uterus by using a PEGylated antagonist prevents implantation: A nonhormonal contraceptive strategy</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2007-12-04</date><risdate>2007</risdate><volume>104</volume><issue>49</issue><spage>19357</spage><epage>19362</epage><pages>19357-19362</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Blastocyst implantation is a critical stage in the establishment of pregnancy. Leukemia inhibitory factor (LIF) is essential for mouse blastocyst implantation and also plays a role in human pregnancy. We examined the effect of a potent LIF antagonist (LA) on mouse implantation. In mice, LIF expression peaks on day 3.5 of pregnancy (D3.5) (D0.5 = day of mating plug detection) in the uterine glandular epithelium. LA (7 mg/kg per day) administered from D2.5 to D4.5 via four hourly i.p. injections plus continuous administration via miniosmotic pump resulted in complete implantation failure. To improve its pharmacokinetic properties, we conjugated LA to polyethylene glycol (PEG), achieving a significant increase in serum levels. PEGylated LA (PEGLA) (37.5 mg/kg per day) administered via three i.p. injections between D2.5 and D3.5 also resulted in complete implantation failure. PEGLA immunolocalized to the uterine luminal epithelium at the time of blastocyst implantation. Both LA and PEGLA reduced phosphorylation of the downstream signaling molecule STAT3 in luminal epithelial cells on D3.5. The effects of PEGLA were found to be endometrial, with no embryo-lethal effects observed. These data demonstrate that administration of a PEGylated LIF antagonist is an effective method of targeting LIF signaling in the endometrium and a promising novel approach in the development of nonhormonal contraceptives for women.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>18042698</pmid><doi>10.1073/pnas.0710110104</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Biological Sciences Blastocyst Blastocyst - drug effects Cells Contraception - methods Contraceptive Agents, Female - chemistry Contraceptive Agents, Female - pharmacology Cytokines Embryo implantation Embryo Implantation - drug effects Epithelium Female Gene expression Intrauterine administration Intravenous injections Leukemia Inhibitory Factor - antagonists & inhibitors Leukemia Inhibitory Factor - blood Leukemia Inhibitory Factor - chemistry Leukemia Inhibitory Factor - pharmacology Medical research Mice Mice, Inbred C57BL Phosphorylation - drug effects Polyethylene glycol Polyethylene Glycols - chemistry Polyethylene Glycols - pharmacology Pregnancy Pumps Reproductive system Rodents STAT3 Transcription Factor - metabolism Uterus Uterus - cytology Uterus - drug effects Uterus - metabolism |
| title | Blocking LIF action in the uterus by using a PEGylated antagonist prevents implantation: A nonhormonal contraceptive strategy |
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