Medical Research Council, Human Reproductive Sciences Unit, University of Edinburgh, Edinburgh EH16 4TJ, UK.
Mol Hum Reprod. 2010 Mar;16(3):158-69. doi: 10.1093/molehr/gap084. Epub 2009 Oct 3.
Prokineticin-1 (PROK1) is a multifunctional secreted protein which signals via the G-protein coupled receptor, PROKR1. Previous data from our laboratory using a human genome survey microarray showed that PROK1-prokineticin receptor 1 (PROKR1) signalling regulates numerous genes important for establishment of early pregnancy, including the cytokine interleukin (IL)-11. Here, we have shown that PROK1-PROKR1 induces the expression of IL-11 in PROKR1 Ishikawa cells and first trimester decidua via the calcium-calcineurin signalling pathway in a guanine nucleotide-binding protein (G(q/11)), extracellular signal-regulated kinases, Ca(2+) and calcineurin-nuclear factor of activated T cells dependent manner. Conversely, treatment of human decidua with a lentiviral miRNA to abolish endogenous PROK1 expression results in a significant reduction in IL-11 expression and secretion. Importantly, we have also shown a regulatory role for the regulator of calcineurin 1 isoform 4 (RCAN1-4). Overexpression of RCAN1-4 in PROKR1 Ishikawa cells using an adenovirus leads to a reduction in PROK1 induced IL-11 indicating that RCAN1-4 is a negative regulator in the calcineurin-mediated signalling to IL-11. Finally, we have shown the potential for both autocrine and paracrine signalling in the human endometrium by co-localizing IL-11, IL-11Ralpha and PROKR1 within the stromal and glandular epithelial cells of non-pregnant endometrium and first trimester decidua. Overall we have identified and characterized the signalling components of a novel PROK1-PROKR1 signalling pathway regulating IL-11.
促动力素-1（PROK1）是一种多功能分泌蛋白，通过 G 蛋白偶联受体 PROKR1 发出信号。我们实验室之前使用人类基因组调查微阵列获得的数据表明，PROK1-促动力素受体 1（PROKR1）信号调节了许多对早期妊娠建立很重要的基因，包括细胞因子白细胞介素（IL）-11。在这里，我们已经表明，PROK1-PROKR1 通过钙调神经磷酸酶信号通路，以鸟嘌呤核苷酸结合蛋白（G(q/11)）、细胞外信号调节激酶、Ca(2+)和钙调神经磷酸酶-活化 T 细胞核因子依赖的方式，诱导 PROKR1Ishikawa 细胞和早孕蜕膜中 IL-11 的表达。相反，用慢病毒 miRNA 处理人蜕膜以消除内源性 PROK1 表达会导致 IL-11 表达和分泌显著减少。重要的是，我们还表明了钙调神经磷酸酶调节剂 1 同工型 4（RCAN1-4）的调节作用。用腺病毒过表达 PROKR1Ishikawa 细胞中的 RCAN1-4 会导致 PROK1 诱导的 IL-11 减少，表明 RCAN1-4 是钙调神经磷酸酶介导的 IL-11 信号的负调节剂。最后，我们通过在非妊娠子宫内膜和早孕蜕膜的基质和腺上皮细胞中共同定位 IL-11、IL-11Ralpha 和 PROKR1，显示了人子宫内膜中自分泌和旁分泌信号的潜力。总体而言，我们已经鉴定和表征了调节 IL-11 的新型 PROK1-PROKR1 信号通路的信号成分。
