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Prokineticin-1: A Novel Mediator of the Inflammatory Response in Third-Trimester Human Placenta

Department of Reproductive and Developmental Sciences (F.C.D., A.E.K.) and Medical Research Council Human Reproductive Sciences Unit (S.B., M.S., H.N.J.), Centre for Reproductive Biology, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom

Address all correspondence and requests for reprints to: Dr. Henry Jabbour, Medical Research Council Reproductive Sciences Unit, Queens Medical Research Institute, Centre for Reproductive Biology, Edinburgh EH16 4TJ, United Kingdom. E-mail: h.jabbour{at}hrsu.mrc.ac.uk.

Prokineticin-1 (PK1) is a recently described protein with a wide range of functions, including tissue-specific angiogenesis, modulation of inflammatory responses, and regulation of hemopoiesis. The aim of this study was to investigate the localization and expression of PK1 and PK receptor-1 (PKR1), their signaling pathways, and the effect of PK1 on expression of the inflammatory mediators cyclooxygenase (COX)-2 and IL-8 in third-trimester placenta. PK1 and PKR1 were highly expressed in term placenta and immunolocalized to syncytiotrophoblasts, cytotrophoblasts, fetal endothelium, and macrophages. PK1 induced a time-dependent increase in expression of IL-8 and COX-2, which was significantly reduced by inhibitors of Gq, cSrc, epidermal growth factor receptor (EGFR), and MAPK kinase. Treatment of third-trimester placenta with 40 nM PK1 induced a rapid phosphorylation of cSrc, EGFR, and ERK1/2. Phosphorylation of ERK1/2 in response to PK1 was dependent on sequential phosphorylation of cSrc and EGFR. Using double-immunofluorescent immunohistochemistry, PKR1 colocalized with IL-8 and COX-2 in placenta. These data suggest that PK1 may have a novel role as a mediator of the inflammatory response in placenta.