Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Kaiyu Lei is active.

Publication


Featured researches published by Kaiyu Lei.


PLOS ONE | 2012

Progesterone Acts via the Nuclear Glucocorticoid Receptor to Suppress IL-1β-Induced COX-2 Expression in Human Term Myometrial Cells

Kaiyu Lei; Lin Chen; Ektoras X. Georgiou; Suren R. Sooranna; Shirin Khanjani; Jan J. Brosens; Phillip R. Bennett; Mark R. Johnson

Progesterone is widely used to prolong gestation in women at risk of preterm labour (PTL), and acts at least in part via the inhibition of inflammatory cytokine-induced prostaglandin synthesis. This study investigates the mechanisms responsible for this inhibition in human myometrial cells. We used reporter constructs to demonstrate that interleukin 1beta (IL-1β) inhibits progesterone driven PRE activation via p65 activation and that IL-1β reduced progesterone driven gene expression (FKBP5). Conversely, we found that the activity of a p65-driven NFκB reporter construct was reduced by overexpression of progesterone receptor B (PRB) alone and that this was enhanced by the addition of MPA and that both MPA and progesterone suppressed IL-1β-driven cyclo-oxygenase-2 (COX-2) expression. We found that over-expressed Halo-tagged PRB, but not PRA, bound to p65 and that in IL-1β-treated cells, with no overexpression of either PR or p65, activated p65 bound to PR. However, we found that the ability of MPA to repress IL-1β-driven COX-2 expression was not enhanced by overexpression of either PRB or PRA and that although the combined PR and GR antagonist Ru486 blocked the effects of progesterone and MPA, the specific PR antagonist, Org31710, did not, suggesting that progesterone and MPA act via GR and not PR. Knockdown using siRNA confirmed that both MPA and progesterone acted via GR and not PR or AR to repress IL-1β-driven COX-2 expression. We conclude that progesterone acts via GR to repress IL-1β-driven COX-2 activation and that although the interaction between p65 and PRB may be involved in the repression of progesterone driven gene expression it does not seem to be responsible for progesterone repression of IL-1β-induced COX-2 expression.


The Journal of Clinical Endocrinology and Metabolism | 2011

Uterine stretch and progesterone action

Kaiyu Lei; Li Chen; B. J. Cryar; Renyi Hua; Suren R. Sooranna; Jan J. Brosens; Phillip R. Bennett; Mark R. Johnson

CONTEXT Progesterone administration reduces the risk of preterm labor in high-risk women with singleton pregnancies but has no effect in women with a multiple pregnancy. OBJECTIVE We investigated whether progesterone is able to inhibit stretch-induced gene expression and/or whether stretch in turn inhibits progesterone action, perhaps providing an explanation for the functional progesterone withdrawal associated with human labor. METHODS AND RESULTS In a series of in vitro studies using primary cultures of human myometrial cells, we found that preincubation with progesterone did not block stretch-induced ERK1/2 activation and cyclooxygenase-2 mRNA expression. Furthermore, we found that stretch did not alter the ability of progesterone to: 1) modulate progesterone-responsive gene expression; 2) activate a luciferase-linked progesterone response element; or 3) repress IL-1β-driven cyclooxygenase-2 mRNA expression. We did find that stretch reduced the expression of progesterone receptor mRNA via nuclear factor κB activation but that this did not alter myometrial progesterone response. CONCLUSION These data show that progesterone does not inhibit stretch-induced MAPK activation or gene expression, possibly explaining why progesterone is ineffective in the prevention of preterm labor in multiple pregnancy. Although stretch did reduce progesterone receptor expression in a nuclear factor κB-dependent manner, this was not sufficient to inhibit progesterone action, suggesting that it is not responsible for the functional progesterone withdrawal observed with the onset of human labor.


Endocrinology | 2011

NADPH oxidase-derived reactive oxygen species mediate decidualization of human endometrial stromal cells in response to cyclic AMP signaling.

Marwa Al-Sabbagh; Luca Fusi; Jenny Higham; Yun Lee; Kaiyu Lei; Aylin C. Hanyaloglu; Eric Lam; Mark Christian; Jan J. Brosens

Differentiation of human endometrial stromal cells into specialized decidual cells is critical for embryo implantation and survival of the conceptus. Initiation of this differentiation process is strictly dependent on elevated cAMP levels, but the signal intermediates that control the expression of decidual marker genes, such as prolactin (PRL) and IGFBP1, remain poorly characterized. Here we show that cAMP-dependent decidualization can be attenuated or enhanced upon treatment of primary cultures with a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor (diphenylen iodonium) or activator (apocynin), respectively. Time-course analysis demonstrated that cAMP enhances endogenous reactive oxygen species production, apparent after 12 h of stimulation, which coincides with a dramatic increase in decidual PRL and IGFBP1 expression. Knockdown of the Rho GTPase RAC1, which disables activation of the NADPH oxidase homologs NADPH oxidase (NOX)-1, NOX-2, and NOX-3, had no effect on PRL or IGFBP1 expression. In contrast, silencing of NOX-4, or its cofactor p22(PHOX), inhibited the expression of both decidual markers. Finally, we show that the NOX-4/p22(PHOX) complex regulates the DNA-binding activity of CCAAT/enhancer binding protein-β, a key regulator of human endometrial stromal cell differentiation. Thus, NOX-4 activation and reactive oxygen species signaling play an integral role in initiating the endometrial decidual response in preparation of pregnancy.


Molecular Endocrinology | 2015

Progesterone and the Repression of Myometrial Inflammation: The Roles of MKP-1 and the AP-1 System

Kaiyu Lei; Ektoras X. Georgiou; Li Chen; Angela Yulia; Suren R. Sooranna; Jan J. Brosens; Phillip R. Bennett; Mark R. Johnson

Progesterone (P4) maintains uterine quiescence during pregnancy and its functional withdrawal is associated with increased prostaglandin synthesis and the onset of labor. In primary human myometrial cells, the glucocorticoid receptor (GR) rather than the P4 receptor mediates P4 antagonism of IL-1β-induced cyclooxygenase-2 (COX-2) expression, the rate-limiting enzyme in prostaglandin synthesis. We now report that P4 also acts via GR to induce MAPK phosphatase (MKP)-1 and knockdown of MKP-1 impairs the ability of P4 to repress IL-1β-dependent COX-2 induction. Microarray analysis revealed that P4 repressed preferentially activator protein-1-responsive genes in response to IL-1β. Consistent with these observations, we found that the ability of P4 to reduce c-Jun activation was lost upon GR as well as MKP-1 knockdown. Interestingly, c-Jun levels in human myometrial cells declined upon GR and MKP-1 knockdown, which suggests the presence of an activator protein-1 feedback loop. This is supported by our observation that c-Jun levels declined after an initial rise in primary myometrial cells treated with phorbol 12-myrisatate 13-acetate, a potent activator of c-Jun N-terminal kinase. Finally, we show that MKP-1 is an intermediate in P4-mediated repression of some but not all IL-1β-responsive genes. For example, P4 repression of IL11 and IRAK3 was maintained upon MKP-1 knockdown. Taken together, the data show that P4 acts via GR to drive MKP-1 expression, which in turn inhibits IL-1β-dependent c-Jun activation and COX-2 expression.


Journal of Cellular and Molecular Medicine | 2012

Cyclic AMP increases COX-2 expression via mitogen-activated kinase in human myometrial cells

Li I. Chen; Suren R. Sooranna; Kaiyu Lei; Mandeep K. Kandola; Phillip R. Bennett; Zhiqing Liang; Dimitris K. Grammatopoulos; Mark R. Johnson

Cyclic AMP (cAMP) is the archetypal smooth muscle relaxant, mediating the effects of many hormones and drugs. However, recently PGI2, acting via cAMP/PKA, was found to increase contraction‐associated protein expression in myometrial cells and to promote oxytocin‐driven myometrial contractility. Cyclo‐oxygenase‐2 (COX‐2) is the rate‐limiting enzyme in prostaglandin synthesis, which is critical to the onset and progression of human labour. We have investigated the impact of cAMP on myometrial COX‐2 expression, synthesis and activity. Three cAMP agonists (8‐bromo‐cAMP, forskolin and rolipram) increased COX‐2 mRNA expression and further studies confirmed that this was associated with COX‐2 protein synthesis and activity (increased PGE2 and PGI2 in culture supernatant) in primary cultures of human myometrial cells. These effects were neither reproduced by specific agonists nor inhibited by specific inhibitors of known cAMP‐effectors (PKA, EPAC and AMPK). We then used shRNA to knockdown the same effectors and another recently described cAMP‐effector PDZ‐GEF1‐2, without changing the response to cAMP. We found that MAPK activation mediated the cAMP effects on COX‐2 expression and that PGE2 acts through EP‐2 to activate MAPK and increase COX‐2. These data provide further evidence in support of a dual role for cAMP in the regulation of myometrial function.


Molecular and Cellular Endocrinology | 2014

Cyclic AMP enhances progesterone action in human myometrial cells

Li Chen; Kaiyu Lei; Johann Malawana; Angela Yulia; Suren R. Sooranna; Phillip R. Bennett; Zhiqing Liang; Dimitris K. Grammatopoulos; Mark R. Johnson

Cyclic AMP (cAMP) has been shown to promote progesterone and glucocorticoid action in a variety of cellular settings. In this study, we have used human myometrial cells to investigate whether cAMP potentiates the ability of progesterone to repress IL-1β-driven COX-2 expression. We found that forskolin enhanced progesterone-repression of IL-1β-driven COX-2 expression in association with delayed IL-1β-induced nuclear phospho-p65 entry and reduced NF-κB binding to the COX-2 promoter. Further, forskolin enhanced the progesterone-induced expression of FKBP5 and 11βHSD1, progesterone-driven activity of a progesterone response element (PRE) and progesterone receptor (PR)-B binding to a transfected PRE. In addition, forskolin treatment increased PR-B levels and reduced the PR-A:PR-B ratio while acutely decreasing the association between PR and nuclear receptor co-repressor (NCoR) and reducing NCoR levels after 6h. These findings are of importance in situations where enhancing progesterone activity is desirable, for example in the management of endometrial cancer, the promotion of endometrial receptivity or the maintenance of myometrial quiescence during pregnancy.


Biology of Reproduction | 2018

Progesterone, the maternal immune system and the onset of parturition in the mouse

Lydia F. Edey; Hector Georgiou; Kieran P. O’Dea; Sam Mesiano; Bronwen R. Herbert; Kaiyu Lei; Renyi Hua; Danijela Markovic; Simon N. Waddington; David A. MacIntyre; Philip R. Bennett; Masao Takata; Mark R. Johnson

Abstract The role of progesterone (P4) in the regulation of the local (uterine) and systemic innate immune system, myometrial expression of connexin 43 (Cx-43) and cyclooxygenase 2 (COX-2), and the onset of parturition was examined in (i) naïve mice delivering at term; (ii) E16mice treated with RU486 (P4-antagonist) to induce preterm parturition; and (iii) in mice treated with P4 to prevent term parturition. In naïve mice, myometrial neutrophil and monocyte numbers peaked at E18 and declined with the onset of parturition. In contrast, circulating monocytes did not change and although neutrophils were increased with pregnancy, they did not change across gestation. The myometrial mRNA and protein levels of most chemokines/cytokines, Cx-43, and COX-2 increased with, but not before, parturition. With RU486-induced parturition, myometrial and systemic neutrophil numbers increased before and myometrial monocyte numbers increased with parturition only. Myometrial chemokine/cytokine mRNA abundance increased with parturition, but protein levels peaked earlier at between 4.5 and 9 h post-RU486. Cx-43, but not COX-2, mRNA expression and protein levels increased prior to the onset of parturition. In mice treated with P4, the gestation-linked increase in myometrial monocyte, but not neutrophil, numbers was prevented, and expression of Cx-43 and COX-2 was reduced. On E20 of P4 supplementation,myometrial chemokine/cytokine and leukocyte numbers, but not Cx-43 and COX-2 expression, increased. These data show that during pregnancy P4 controls myometrial monocyte infiltration, cytokine and prolabor factor synthesis via mRNAdependent and independent mechanisms and, with prolonged P4 supplementation, P4 action is repressed resulting in increased myometrial inflammation. Summary Sentence Progesterone independently regulates the maternal immune system and the onset of parturition in the mouse.


Molecular Human Reproduction | 2016

The study of progesterone action in human myometrial explants

Ektoras X. Georgiou; Kaiyu Lei; P.F. Lai; Angela Yulia; Bronwen R. Herbert; Marcos Castellanos; Sean T. May; Suren R. Sooranna; Mark R. Johnson

STUDY HYPOTHESIS Myometrial explants represent a superior model compared with cell culture models for the study of human myometrial progesterone (P4) signalling in parturition. STUDY FINDING Gene expression analysis showed myometrial explants closely resemble the in vivo condition and the anti-inflammatory action of P4 is not lost with labour onset. WHAT IS KNOWN ALREADY Circulating P4 levels decline before the onset of parturition in most animals, but not in humans. This has led to the suggestion that there is a functional withdrawal of P4 action at the myometrial level prior to labour onset. However, to date, no evidence of a loss of P4 function has been provided, with studies hampered by a lack of a physiologically relevant model. STUDY DESIGN, SAMPLES/MATERIALS, METHODS Myometrial biopsies obtained at Caesarean section were dissected into explants after a portion was immediately snap frozen (t = 0). Microarray analysis was used to compare gene expression of t = 0 with paired (i) explants, (ii) passage 4 myometrial cell cultures or (iii) the hTERT myometrial cell line. Western blotting and chemokine/cytokine assays were used to study P4 signalling in myometrial explants. MAIN RESULTS AND THE ROLE OF CHANCE Gene expression comparison of t = 0 to the three models demonstrated that explants more closely resemble the in vivo status. At the protein level, explants maintain both P4 receptor (PR) and glucocorticoid receptor (GR) levels versus t = 0 whereas cells only maintain GR levels. Additionally, treatment with 1 µM P4 led to a reduction in interleukin-1 (IL-1) β-driven cyclooxygenase-2 in explants but not in cells. P4 signalling in explants was PR-mediated and associated with a repression of p65 and c-Jun phosphorylation. Furthermore, the anti-inflammatory action of P4 was maintained after labour onset. LIMITATIONS/REASONS FOR CAUTION There is evidence of basal inflammation in the myometrial explant model. WIDER IMPLICATIONS OF THE FINDINGS Myometrial explants constitute a novel model to study P4 signalling in the myometrium and can be used to further elucidate the mechanisms of P4 action in human labour. LARGE SCALE DATA Data deposited at http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=gvmpggkurbgxfqf&acc=GSE77830. STUDY FUNDING AND COMPETING INTEREST This work was supported by grants from the Joint Research Committee of the Westminster Medical School Research Trust, Borne (No. 1067412-7; a sub-charity of the Chelsea and Westminster Health Charity) and the Imperial NIHR Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS or the Department of Health. The authors have no conflict of interest.


Genomics data | 2015

Expression data from primary culture human myometrial cells

Kaiyu Lei; Suren R. Sooranna; Mark R. Johnson

Inflammation plays a central role in many human diseases. Human parturition also resembles an inflammatory reaction, where progesterone (P4) and progesterone receptors (PRs) have already been demonstrated to suppress contraction-associated gene expression. In our previous studies, we have found that the progesterone actions, including progesterone-induced gene expression and progesterones anti-inflammatory effect, are mediated by PR, GR or both. In this study, we used microarrays (GSE68171) to find P4 and IL-1β responsive genes and IL-1β responsive genes which were repressed by P4. These data may provide a broader view of gene networks and cellular functions regulated by P4 and IL-1β in human myometrial cells. These data will also help us understand the role of PR and GR in human parturition.


Archive | 2010

The effect of cAMP on PRE promoter activity in presence or absence of progesterone

Li Chen; Kaiyu Lei; Suren R. Sooranna; Phillip R. Bennett; Zinging Liang; Dimitris K. Grammatopoulos; Mark R. Johnson

Abstract 367 presented at Poster Session: Basic Parturition/Prematurity II (Friday, 3/26/2010, 10:00 AM - 12:00 PM)Plenary Session: Presidents New Investigator (Thursday, 3/25/2010, 9:00AM 10:00 AM) Scientific Abstracts

Collaboration


Dive into the Kaiyu Lei's collaboration.

Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Li Chen

Third Military Medical University

View shared research outputs
Top Co-Authors

Avatar

Angela Yulia

Imperial College London

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Renyi Hua

Imperial College London

View shared research outputs
Researchain Logo
Decentralizing Knowledge