Prokineticin-1 (PROK1) modulates interleukin (IL)-11 expression via prokineticin receptor 1 (PROKR1) and the calcineurin/NFAT signalling pathway.
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.
Medical Research Council, Human Reproductive Sciences Unit, University of Edinburgh, Edinburgh EH16 4TJ, UK.
Ian H
IH
Cook
Jemma
J
Evans
David
D
Maldonado-Pérez
Hilary O
HO
Critchley
Kurt J
KJ
Sales
Henry N
HN
Jabbour
D019703:Calcineurin / Q000378:metabolism / Q000502:physiology*; D065095:Calcineurin Inhibitors; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000494:pharmacology; D003656:Decidua / Q000378:metabolism; D004533:Egtazic Acid / Q000494:pharmacology; D004717:Endometrium / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D017370:Interleukin-11 / Q000235:genetics / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*
D065095:Calcineurin Inhibitors; D005419:Flavonoids; D017370:Interleukin-11; D050778:NFATC Transcription Factors; C470837:PROKR1 protein, human; D010456:Peptides, Cyclic; D043562:Receptors, G-Protein-Coupled; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived; C475455:YM-254890; D004533:Egtazic Acid; D016572:Cyclosporine; D019703:Calcineurin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one