Prokineticin 1 modulates IL-8 expression via the calcineurin/NFAT signaling pathway.
Prokineticins and their receptors are expressed in various cellular compartments in human endometrium, with prokineticin 1 (PROK1) showing a dynamic pattern of expression across the menstrual cycle and during pregnancy. Previous studies suggest that PROK1 can play an important role in implantation and early pregnancy by inducing vascular remodeling and increasing vascular permeability. Here we demonstrate that PROK1 induces the expression of IL-8, a chemokine with angiogenic properties, in endometrial epithelial Ishikawa cells stably expressing prokineticin receptor 1 and in human first trimester decidua. We also show that IL-8 promoter activity is induced by PROK1 and that this requires the presence of AP1 and NFAT motifs. The role of calcineurin/NFAT signaling pathway is confirmed by the use of specific chemical inhibitors. Additionally, PROK1 induces the expression of the regulator of calcineurin 1 isoform 4 (RCAN1-4) via the calcineurin/NFAT pathway. A modulatory role for RCAN1-4 is demonstrated by RCAN1-4 overexpression which results in the inhibition of PROK1-induced IL-8 expression whereas reduction in RCAN1-4 endogenous expression results in an increase in PROK1-induced IL-8 production. Our findings show that in endometrial cells PROK1 can activate the calcineurin/NFAT pathway to induce IL-8 expression and that this is negatively modulated by the induction of expression of RCAN1-4.
Maldonado-Pérez
David
D
Human Reproductive Sciences Unit, Medical Research Council, Edinburgh EH16 4TJ, UK.
Brown
Pamela
P
Morgan
Kevin
K
Millar
Robert P
RP
Thompson
E Aubrey
EA
Jabbour
Henry N
HN
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D019703:Calcineurin / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D003656:Decidua / Q000166:cytology / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism*; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D016209:Interleukin-8; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D050778:NFATC Transcription Factors; C108612:RCAN1 protein, human; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived; D019703:Calcineurin