Prokineticin-I (PROKI) modulates interleukin (IL)-I I expression via prokineticin receptor I (PROKRI) and the calcineurin/NFAT signalling pathway

摘要

Prokineticin-I (PROKI) is a multifunctional secreted protein which signals via the G-protein coupled receptor, PROKRI. Previous data from our laboratory using a human genome survey microarray showed that PROKI -prokineticin receptor I (PROKRI) signalling regulates numerous genes important for establishment of early pregnancy, including the cytokine interleukin (IL)-I I. Here, we have shown that PROKI -PROKRI induces the expression of IL-I I in PROKRI Ishikawa cells and first trimester decidua via the calcium-calci-neurin signalling pathway in a guanine nucleotide-binding protein (G_(q/II)), 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 PROKI expression results in a significant reduction in IL-I I expression and secretion. Importantly, we have also shown a regulatory role for the regulator of calcineurin I isoform 4 (RCANI-4). Overexpression of RCANI-4 in PROKRI Ishikawa cells using an adenovirus leads to a reduction in PROKI induced IL-I I indicating that RCANI-4 is a negative regulator in the calcineurin-mediated signalling to IL-I I. Finally, we have shown the potential for both autocrine and paracrine signalling in the human endometrium by co-localizing IL-I I, IL-I I Ralpha and PROKRI 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 PROKI-PROKRI signalling pathway regulating IL-I I.