The American Journal of Pathology, Vol. 179, No. 6, December 2011 Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. DOI: 10.1016/j.ajpath.2011.08.029 Biomarkers, Genomics, Proteomics, and Gene Regulation
Prokineticin 1 Induces Inflammatory Response in Human Myometrium
A Potential Role in Initiating Term and Preterm Parturition
Marta R. Gorowiec,*† Rob D. Catalano,* Human parturition is a pro-inflammatory event associated Jane E. Norman,† Fiona C. Denison,† and with the influx of leukocytes, such as neutrophils and 1,2 Henry N. Jabbour* macrophages, to the uterus. Indeed, 40% to 60% of genes up-regulated in the myometrium and cervix at la- From the Medical Research Council Human Reproductive bor are involved in inflammation and chemotaxis.3 Re- Sciences Unit * and Reproductive and Developmental cruited leukocytes secrete cytokines, including IL-1, † Sciences, The Queen’s Medical Research Institute, Edinburgh, 4 IL-6, and IL-8, and prostaglandins E2 (PGE2) and F2␣ United Kingdom (PGF2␣). These cytokines and prostaglandins can stimu- late production of matrix metalloproteinases that are in- volved in membrane rupture5 and can also promote cer- vical ripening.6 However, during labor, the greatest influx The infiltration of human myometrium and cervix of leukocytes is observed in the myometrium.1 Cytokines, with leukocytes and the formation of a pro-inflam- such as IL-1, released by leukocytes, promote the syn- matory environment within the uterus have been thesis of prostaglandin synthase 2 (PTGS2)–dependent associated with the initiation of both term and pre- prostaglandins (PGE2 and PGF2␣), which are important term parturition. The mechanism regulating the on- regulators of myometrial contractility.7,8 More important, set of this pro-inflammatory cascade is not fully independently of prostaglandins, IL-1 also regulates elucidated. We demonstrate that prokineticin 1 basal and store-operated calcium entry in myometrial (PROK1) is up-regulated in human myometrium smooth muscle cells, which is important for contractions and placenta during labor. The expression of of individual smooth muscle cells.9 PROK1 receptor remains unchanged during labor The same pro-inflammatory events can be initiated and is abundantly expressed in the myometrium. before 37 weeks of gestation and lead to premature onset Gene array analysis identified 65 genes up-regu- of parturition and preterm birth. Nearly 11% of all single- lated by PROK1 in human myometrium, mainly cy- ton deliveries are preterm, and this constitutes the big- tokines and chemokines, including IL-1, chemo- gest cause of neonatal morbidity and mortality.10,11 Al- kine C-C motif ligand 3, and colony-stimulating though several factors, such as smoking, alcohol, factor 3. In addition, we demonstrate that PROK1 advanced maternal age, and structural abnormalities of 12,13 increases the expression of chemokine C-C motif the cervix, can contribute to preterm initiation of la- ligand 20, IL-6, IL-8, prostaglandin synthase 2, and bor, bacterial infection in the uteroplacental unit is be- lieved to be a major cause. Such infections are detected prostaglandin E2 and F2␣ secretion. The treatment of myometrial explants with 100 ng/mL of lipopoly- in 79% of births at 23 weeks and in 11% of births at 31 to 14,15 saccharide up-regulates the expression of PROK1, 34 weeks. In most cases of preterm birth, even in the PROK1 receptor, and inflammatory mediators. The infection of myometrial explants with lentiviral mi- Supported by the Medical Research Council, Piggy Bank Kids. croRNA targeting PROK1, preceding treatment with Accepted for publication August 18, 2011. lipopolysaccharide, reduces the expression of in- M.R.G. and R.D.C. contributed eq