Leukaemia inhibitory factor and interleukin 11 levels in uterine flushings of infertile patients with endometriosis

Mikołajczyk, Mateusz; Wirstlein, Przemysław; Skrzypczak, Jana

doi:10.1093/humrep/del225

Cited by 62 publications

(56 citation statements)

References 25 publications

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“…These results give evidence of the transcriptional dysfunction of the NFKB during the late secretory phase in the eutopic endometrium from women with endometriosis, similar to that observed in recurrent abortion cases in which deregulation of IL6, IL1B, IL11 and LIF, cytokines related to or dependent on this system, were observed (Von Wolff et al 2000, Dimitriadis et al 2006, Mikolajczyk et al 2006. IL6 participates in endometrial function by acting as a mediator in the maternal-embryo peri-implantational communication, endometrial immune-tolerance and on inflammatory events in the implantation site (Sengupta et al 2003).…”

Section: Discussionsupporting

confidence: 75%

Nuclear factor κB pathway and interleukin-6 are affected in eutopic endometrium of women with endometriosis

Ponce¹,

Torres²,

Galleguillos³

et al. 2009

Reproduction

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In order to investigate the role of the nuclear factor kB (NFKB) pathway on gene expression in the eutopic endometrium in endometriosis, and in particular of interleukin-6 (IL6), we evaluated RELA, IkB kinase (CHUK), NFKBIA and IL6 expressions and NFKB DNA binding in eutopic endometrium from women with endometriosis. Eutopic endometrium was obtained from 37 women with endometriosis and 42 fertile women during laparoscopy. We analysed RELA, CHUK, NFKBIA and IL6 mRNA levels (RT-PCR); RELA, CHUK and NFKBIA proteins and p-NFKBIA/NFKBIA ratio (western blot); and NFKB binding (DNA shift assay) and IL6 concentration (ELISA) in endometrial explants. Our results indicate that mRNA and cytoplasmic proteins of RELA and CHUK exhibit constant levels in normal endometrium during the menstrual cycle. A dramatic increase (P!0.05) in NFKBIA mRNA expression, RELA nuclear presence and the mRNA and the protein of IL6 during late secretory phase was also observed in this tissue. By contrast, in eutopic endometrium from endometriosis patients, a decrease (P!0.05) in IL6 mRNA and protein (61%), NFKBIA mRNA (46%), p-NFKBIA/NFKBIA ratio (42%), RELA nuclear stromal (68%) and CHUK (48%) proteins were found exclusively during the late secretory phase compared with normal endometrium. In conclusion, the canonical activation of NFKB pathway is deregulated and may have reduced transcriptional function affecting NFKBIA and IL6 expression, genes related local proinflammatory processes. These molecular alterations observed during the late secretory phase in eutopic endometrium from endometriosis patients constitute a NFKB system dysfunction, suggesting that NFKB could be an important factor in endometriosis aetiology.

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Section: Discussionsupporting

confidence: 75%

Nuclear factor κB pathway and interleukin-6 are affected in eutopic endometrium of women with endometriosis

Ponce¹,

Torres²,

Galleguillos³

et al. 2009

Reproduction

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“…Embryos remained unattached or became degenerated in the uterine cavity of pregnant ewes, whose uteri lacked endometrial epithelial glands and their secretions (Gray et al 2002). In humans also, infertility in some cases was found to be associated with altered levels of proteins such as leukemia inhibitory factor, proprotein convertase, and mucin-1 in the UF (Aplin et al 1996, Mikolajczyk et al 2006, Heng et al 2011. Thus, investigations of the UF in the receptive phase assume significance as these may lead to the identification of the biomarkers of endometrial function.…”

Section: Discussionmentioning

confidence: 99%

“…However, it has become apparent now that uterine glands and their secretions continue playing an active role in terms of nutrition till the first trimester of pregnancy in humans (Burton et al 2002). Levels of leukemia inhibitory factor, mucin-1, glycodelin, vascular endothelial growth factor, and proprotein convertase 5/6 in the UF were found to be suboptimal in women with infertility (Mackenna et al 1993, Aplin et al 1996, Mikolajczyk et al 2006, Heng et al 2011. These studies showed the utility of UF analysis in gauging endometrial function.…”

Section: Introductionmentioning

confidence: 97%

Uterine secretome and its modulation in rat (Rattus norvegicus)

et al. 2013

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The present study identifies uterine fluid (UF) proteins that display differential abundance during the embryo-permissive phase in nonconception and conception cycles in rats. UF samples were collected from nonpregnant rats in the proestrous (nZ17) and metestrous (nZ18) phases and also from pregnant (nZ17) and pseudopregnant (nZ17) rats on day 4 post coitus. UF protein profile in the metestrous phase was compared with that in the proestrous phase. Similarly, UF protein profile of the pregnant rats was compared with that of the pseudopregnant rats. Two-dimensional PAGE, followed by densitometric analysis of the paired protein spots, revealed differential abundance of 44 proteins in the metestrous phase, compared with that in the proestrous phase. Of these, 29 proteins were identified by matrix-assisted laser desorption/ionization time-of-flight or liquid chromatography-tandem mass spectrometry. Functional groups such as proteases, protease inhibitors, and oxidoreductases were enriched in differentially abundant proteins. Total protease activity in UF was found to be significantly (P!0.05; t-test) higher in the proestrous phase, compared with that in the metestrous phase. Furthermore, 41 UF proteins were found to be differentially abundant in pregnant rats, compared with pseudopregnant rats. Of these, 11 proteins could be identified. Immunoblotting analysis confirmed significantly higher (P!0.05; t-test) abundance of b-actin, Rho-specific guanine nucleotide dissociation inhibitor alpha (Rho-GDIa), and peroxiredoxin-2 and -6 in the metestrous phase, compared with that in the proestrous phase. Compared with pseudopregnant rats, pregnant rats had significantly higher (P!0.05; t-test) levels of UF b-actin and Rho-GDIa. Furthermore, these proteins could be detected in the culture supernatants of endometrial epithelial cell lines, thereby providing an evidence of their secretion from endometrial epithelial cells. Data obtained from the study expand our knowledge on the uterine milieu that favours embryo implantation.

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“…Depleted LIF secretion and/or mutations of the LIF gene are believed to be involved in infertility in humans [15][16][17][18]. However, women with no impairment of LIF also show infertility [19,20].In the murine uterus, peak LIF expression is observed primarily in the GE and LE at estrus and at D4 [21,22]. LIF binds the LIF receptor, a heterodimer of LIF receptor β (LIFRβ) and gp130, and signals are transmitted via the Jak-Stat3 pathway [23].…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Embryo Implantation is Blocked by Intraperitoneal Injection with Anti-LIF Antibody in Mice

Terakawa

Wakitani

Sugiyama

et al. 2011

Journal of Reproduction and Development

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Abstract. Leukemia inhibitory factor (LIF) is essential for embryo implantation in mice and plays an important role in other mammals including humans. Intraperitoneal (ip) injections with anti-LIF antibody (7.5 µg/g body weight, 3 times) between D3 (D1 = day of vaginal plug detection) and D4 effectively blocked embryo implantation; complete inhibition was achieved in C57BL/6J mice, and implantation was dramatically reduced in ICR mice (reduced to 27%). Normal rabbit IgG used as the control did not disturb embryo implantation. Anti-LIF antibody was localized not only in the stroma, but also in the luminal epithelium and the glandular lumen after ip injections. Growth-arrested blastocysts were recovered from the uterus without any implantation sites in both strains. Blastocysts made contact with the LE on the antimesometrial side; however, uterine stromal cells did not undergo secondary decidual reaction, and the uterine lumen was open, even at D7. Several regions of decidualization in ICR mice treated with anti-LIF antibody were smaller than those of the control, and development of blastocysts was delayed. The expression of LIF-regulated genes, such as immune-responsive gene-1 and insulin-like growth factor binding protein-3, was significantly decreased in C57BL/6J mice treated with anti-LIF antibody compared with the control, but not in ICR mice. The present study demonstrated that simple ip injections of an antibody are sufficient to block one of the important factors involved in embryo implantation in mice, and this method should also be easily applicable to the investigation of other factors involved in implantation.Key words: Anti-LIF antibody, Embryo implantation, Intraperitoneal injection, Leukemia inhibitory factor, Mice (J. Reprod. Dev. 57 : [700][701][702][703][704][705][706][707] 2011) E mbryo implantation is an important event in early pregnancy. Synchronization between active blastocysts and maternal tissues is essential for successful implantation. In addition to the secretory molecules regulated by progesterone and estrogen, appropriate modulation of the extracellular matrix is also essential for accommodation of the embryo [1,2].In mice, blastocysts nidate on the receptive endometrium in response to transient estrogen stimulation at D4 (D1, the first day of pregnancy, is defined as the day when a vaginal plug is first observed) [3]. Estrogen triggers the secretion of leukemia inhibitory factor (LIF), a member of the interleukin (IL)-6 family of cytokines (such as IL-11, oncostatin M, ciliary neurotrophic factor and cardiotrophin-1), mainly from the uterine glandular epithelium (GE) [4,5]. Targeted mutation of the Lif gene in mice has been shown to result in infertility [6]. In female LIF-deficient mice, blastocysts make contact with the luminal epithelium (LE) at D4, but subsequent processes, such as closure of the uterine lumen, stromal decidualization and apoptosis of the LE at the site of attachment of the blastocyst, do not occur [7]. However, implantation can be rescued by exogenous LIF, a...

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Leukaemia inhibitory factor and interleukin 11 levels in uterine flushings of infertile patients with endometriosis

Abstract: There is no receptivity defect with regard to LIF and IL-11 secretions by eutopic endometrium in infertile women with endometriosis.

Cited by 62 publications

References 25 publications

Nuclear factor κB pathway and interleukin-6 are affected in eutopic endometrium of women with endometriosis

Nuclear factor κB pathway and interleukin-6 are affected in eutopic endometrium of women with endometriosis

Uterine secretome and its modulation in rat (Rattus norvegicus)

Embryo Implantation is Blocked by Intraperitoneal Injection with Anti-LIF Antibody in Mice

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