Inhibition of Stat3 activation in the endometrium prevents implantation: A nonsteroidal approach to contraception

Catalano, Rob D.; Johnson, Martin H.; Campbell, Elizabeth A.; Charnock-Jones, D. Stephen; Smith, Stephen K.; Sharkey, Andrew

doi:10.1073/pnas.0502343102

Cited by 110 publications

(70 citation statements)

References 43 publications

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“…Since p-STAT3 expression in the LE 12 h post injection was absent in control and inhibited uteri, STAT3 activation is tightly regulated early on day 4. Studies using a peptide inhibitor of STAT3 or a STAT3 decoy in vivo reduced embryo implantation by 70% (Catalano et al 2005, Nakamura et al 2006; further demonstrating that STAT3 is a key regulator of uterine maturation. Moreover, STAT3 also transduces the response to other IL6 family cytokines such as IL11, which is also involved in later events of implantation.…”

Section: Discussionmentioning

confidence: 99%

Determining the LIF-sensitive period for implantation using a LIF-receptor antagonist

Mohamet

Heath²,

Kimber³

2009

Reproduction

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Uteri of Lif null mice do not support embryo implantation. Since deletion of some genes often prevents the survival of null mice to adulthood, we have used a proven inhibitor of leukaemia inhibitory factor (LIF) signalling to identify the precise window of time during which LIF is required in vivo, and assessed the cellular expression of several LIF-associated targets. On day 4 of pregnancy, mice were injected with hLIF-05 (inhibitor) into the uterine lumen, with corresponding volumes of PBS (vehicle) injected into the contralateral horn. On days 5 and 6, the number of implantation sites was recorded and the uteri processed for immunohistochemistry. Blockade of LIF on day 4 reduced embryo implantation by 50% (P%0.0001) and was effective maximally between 0930 and 1230 h. Antagonism of LIF signalling was evidenced by a lack of phosphorylated STAT3 in the luminal epithelium (LE). Amphiregulin was absent from the LE on day 4 evening and H-type-1 antigen expression was retained in the LE on day 5 in inhibited uteri. Interleukin-1a and oncostatin M expression were reduced in the stroma on day 6, following LIF inhibition. Unexpectedly, PTGS2 expression in stroma was unaffected by LIF inhibition in vivo, in contrast to Lif null mice. In summary, this suggests that LIF signalling is effective for implantation during a discrete time window on day 4 and antagonism of LIF signalling recapitulates many features exhibited in Lif null uteri. The data presented validates the use of antagonists to investigate tissue specific and temporal cytokine signalling in reproductive function.

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Section: Discussionmentioning

confidence: 99%

Determining the LIF-sensitive period for implantation using a LIF-receptor antagonist

Mohamet

Heath²,

Kimber³

2009

Reproduction

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“…indicating that STAT3 activation in endometrium was associated with endometrial receptivity to implantation in rodents (Liu & Ogle 2002, Catalano et al 2005, Nakamura et al 2006). It appears therefore apparently contradictory that the relative abundance of transcripts for JAK1 and STAT3 were higher in anti-progestin (mifepristone)-treated endometrium in the present study.…”

Section: Implantation-stage Endometrial Transcript Profilesmentioning

confidence: 99%

Effect of low-dose mifepristone administration on day 2 after ovulation on transcript profiles in implantation-stage endometrium of rhesus monkeys

Ghosh¹,

Sharkey²,

Charnock-Jones³

et al. 2009

Reproduction

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Progesterone is essential for endometrial receptivity in primates. In studies previously performed using global gene profiling based on microarray technology, attempts have been made to identify changes in gene expression between early luteal-phase and mid-luteal-phase endometria. However, the issue of the putative impact of preimplantation embryo-derived signal in the process of endometrial receptivity was missing in the previous studies. In the present study, an attempt has been made to delineate the transcripts profile in implantation-stage endometrium under combinatorial regulation of progesterone and embryo-derived signal in the rhesus monkey. To this effect, we have compared transcript profiles for 409 known genes between control receptive stage (nZ13), and mifepristone-induced desynchronized and non-receptive stage (nZ12) monkey endometrial samples collected on days 4 (nZ12) and 6 (nZ13) after ovulation from mated, potential conception cycles, using cDNA arrays containing sequence-verified clones. Statistical analysis of correlation of estimated transcript abundance between arrays and qRT-PCR for nine selected gene products yielded significant (P!0.05) concordance. Of 409 genes, a total of 40 gene transcripts were seen to be affected, nine gene transcripts in endometrial samples were found to progressively increase between days 4 and 6 following mifepristone treatment, while an additional five genes showed differential expression profile depending on the day after treatment. Additionally, different sets of 12 and 14 gene products showed changes in days 4 and 6 post-ovulation samples respectively. A new cohort of 28 gene products in implantation-stage endometrium was seen to be affected by luteal-phase mifepristone.

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“…LIF mRNA is also expressed in the subluminal stroma at the implantation site [10]. Secreted LIF activates signal transducer and activator of transcription 3 (STAT3) via heterodimerization of LIF receptor and gp130 and induces various factors, such as cochlin, insulin-like growth factor binding protein 3 (IGFBP3) and immunoresponsive gene 1 (IRG1), in luminal epithelial cells (LE) [9,[11][12][13][14][15]. LIF can be substituted for E2 action in terminating artificial delayed implantation and reinitiation of embryo implantation in mice [5].…”

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confidence: 99%

Upregulation of Indian Hedgehog Gene in the Uterine Epithelium by Leukemia Inhibitory Factor During Mouse Implantation

Wakitani

Hondo

Phichitraslip

et al. 2008

Journal of Reproduction and Development

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Abstract. Leukemia inhibitory factor (LIF) and Indian hedgehog (Ihh) are essential for embryo implantation in mice and are regulated by the actions of 17β-estradiol (E2) and progesterone, respectively. The present study examined the effect of LIF on Ihh and Ihh-related factors in the uterine luminal epithelium during the implantation period using a DNA microarray. Expression of Ihh mRNA reached its peak on the forth day of pregnancy, and progesterone receptor (Pgr) mRNA decreased on the fifth day of pregnancy in wildtype mice. On the other hand, these changes in expression were not seen in LIF-/-mice. Ihh and Pgr mRNA were upregulated by LIF injection in delayed implantation mice. This upregulation of Pgr was transient and preceded an increase of Ihh mRNA. Ihh mRNA also increased after E2 injection in delayed implantation mice of the LIF-/-genotype. E2 did not affect transcription of Pgr mRNA in the uterine luminal epithelium of delayed implantation LIF-/-mice. Using an antibody against the C-terminal epitope of Ihh, unprocessed Ihh proteins, but not C-terminal peptides, by autoproteolytic cleavage of Ihh were detected by western blot analysis. Unprocessed Ihh did not show quantitative changes between the wildtype and LIF-/-mice during the implantation period. Transcription of hedgehog acyltransferase was not influenced by LIF and E2 injection. In conclusion, LIF, which has a crucial role in E2 action for initiation of implantation, caused transient induction of Pgr mRNA and subsequent upregulation of Ihh mRNA, which mediates progesterone-Pgr actions for successful implantation.

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Inhibition of Stat3 activation in the endometrium prevents implantation: A nonsteroidal approach to contraception

Cited by 110 publications

References 43 publications

Determining the LIF-sensitive period for implantation using a LIF-receptor antagonist

Determining the LIF-sensitive period for implantation using a LIF-receptor antagonist

Effect of low-dose mifepristone administration on day 2 after ovulation on transcript profiles in implantation-stage endometrium of rhesus monkeys

Upregulation of Indian Hedgehog Gene in the Uterine Epithelium by Leukemia Inhibitory Factor During Mouse Implantation

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