Leptin-induced increase in leukemia inhibitory factor and its receptor by human endometrium is partially mediated by interleukin 1 receptor signaling
Leptin-induced increase in leukemia inhibitory factor and its receptor by human endometrium is partially mediated by interleukin 1 receptor signaling
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DOI：
10.1210/en.2004-0383
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发表时间：
2004-08-01
期刊：
影响因子：
4.8
通讯作者：
Leavis, PC
中科院分区：
文献类型：
--
作者：
Gonzalez, RR;Rueda, BR;Leavis, PC
瘦素和白血病抑制因子（LIF）被认为是着床的重要介质。本研究旨在探讨瘦素是否能直接调节人子宫内膜细胞中LIF及其受体（LIF - R）的表达，以及瘦素诱导的效应是否与白细胞介素 - 1（IL - 1）信号传导相关，或部分受其调节。原代子宫内膜细胞和子宫内膜上皮细胞系（HES和石川细胞）在含有胰岛素（5μg/ml）以及瘦素（3、10和62 nM）或IL - 1β（0.6、3和10 nM）的培养基中培养24 - 48小时，同时设置有或无细胞因子和/或受体拮抗剂的情况。检测指标包括信号转导和转录激活因子3（STAT3）的磷酸化以及LIF、LIF - R、IL - 1β、IL - 1受体拮抗剂（IL - 1Ra）和I型IL - 1受体（IL - 1R tI）的相对水平，通过酶联免疫吸附测定（ELISA）或蛋白质印迹技术测定。瘦素处理可提高磷酸化STAT3、LIF - R和LIF的水平。如先前报道，瘦素还可提高IL - 1配体、受体和拮抗剂的水平。用抗体或特异性瘦素受体（OB - R）抑制剂（瘦素肽拮抗剂 - 2）阻断OB - R可消除瘦素诱导的效应，这表明瘦素与其受体结合可激活Janus激酶2/STAT3信号传导。用IL - 1β处理子宫内膜细胞也会导致LIF - R水平升高。有趣的是，用特异性抗体或IL - 1Ra抑制IL - 1R tI会对瘦素和IL - 1诱导的LIF - R水平变化产生负面影响。子宫内膜LIF表达异常与人的不孕症有关，并且瘦素在体外对LIF、IL - 1及其相应受体的水平有显著影响。因此，很容易推测瘦素在体内的作用可能包括调节其他关键细胞因子，这对着床过程中子宫内膜的容受性至关重要（即LIF和IL - 1）。
Leptin and leukemia inhibitory factor (LIF) have been implicated as important mediators of implantation. The present study was designed to investigate whether leptin can directly regulate the expression of LIF and its receptor (LIF-R) in human endometrial cells and/or whether leptin-induced effects are linked to, or regulated in part by IL-1 signaling. Primary endometrial cells and endometrial epithelial cell lines (HES and Ishikawa cells) were cultured for 24 - 48 h in a medium containing insulin ( 5 mug/ml) and leptin ( 3, 10, and 62 nM) or IL-1beta (0.6, 3, and 10 nM) in the presence or absence of cytokines and/or receptor antagonists. The endpoints included phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the relative levels of LIF, LIF-R, IL-1beta, IL-1 receptor antagonist (IL-1Ra) and IL-1 receptor type I (IL-1R tI) as determined by ELISA or Western blotting techniques. Leptin treatment increases the level of phosphorylated STAT3, LIF-R, and LIF. Leptin also increases the levels of IL-1 ligand, receptor, and antagonist as was previously reported. Blockade of OB-R with antibodies or with a specific OB-R inhibitor ( leptin peptide antagonist-2) abrogated leptin-induced effects, suggesting that leptin binding to its receptor activates Janus kinase 2/STAT3 signaling. Treatment of endometrial cells with IL-1beta also results in elevated levels of LIF-R. Interestingly, the inhibition of IL-1R tI with a specific antibody or with IL-1Ra negatively affects both leptin-induced and IL-1-induced effects on LIF-R levels. Abnormal endometrial LIF expression has been associated with human infertility and leptin has profound effects on the levels of LIF, IL-1, and their cognate receptors in vitro. Thus, it is tempting to speculate that leptin's role in vivo could include the regulation of other key cytokines to be fundamental to endometrial receptivity during implantation (i.e. LIF and IL-1).