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Mol. Hum. Reprod. Advance Access published online on October 3, 2009
Molecular Human Reproduction, doi:10.1093/molehr/gap084
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© The Author 2009. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Prokineticin (PROK1) modulates interleukin (IL)-11 expression via prokineticin receptor (PROKR1) and the calcineurin/NFAT signalling pathway

Ian H. Cook1, Jemma Evans1, David Maldonado-Pérez1,2, Hilary O. Critchley2, Kurt J. Sales1 and Henry N. Jabbour1,{dagger}

1Medical Research Council Human Reproductive Sciences Unit and University of Edinburgh, Edinburgh, EH16 4TJ, UK 2Department of Reproductive and Developmental Sciences, University of Edinburgh, Edinburgh, EH16 4TJ, UK

{dagger} To whom correspondence should be addressed: Human Reproductive Sciences Unit, Medical Research Council, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ. Tel.: 44-131-2426220; Fax: 44-131-2426231; Email: h.jabbour{at}hrsu.mrc.ac.uk

Prokineticin-1 (PROK1) is a multifunctional secreted protein which signals via the G-protein coupled receptor (GPCR), PROKR1. Previous data from our laboratory using a human genome survey microarray showed that PROK1-PROKR1 signalling regulates numerous genes important for establishment of early pregnancy, including the cytokine 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 (Gq/11), extracellular signal-regulated kinases (ERK), Ca2+ and calcineurin-nuclear factor of activated T cells (NFAT) 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-11R{alpha} and PROKR1 within the stromal and glandular epithelial cells of non pregnant endometrium and first trimester decidua. Overall we have identified and characterised the signalling components of a novel PROK1-PROKR1 signalling pathway regulating IL-11.

Key Words: Endometrium/Interleukin-11/Prokineticin-1/RCAN1-4

Submitted on May 5, 2009; resubmitted on September 16, 2009; accepted on September 29, 2009.


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