PGF2? modulates the output of chemokines and pro-inflammatory cytokines in myometrial cells from term pregnant women through divergent signaling pathways.

ABSTRACT: Prostaglandin F2? (PGF2?) plays a critical role in the initiation and process of parturition. Since human labor has been described as an inflammatory event, we investigated the role of PGF2? in the inflammatory process using cultured human uterine smooth muscle cells (HUSMCs) isolated from term pregnant women as a model. Using a multiplex assay, HUSMCs treated with PGF2? changed their output of a number of cytokines and chemokines, with a distinct response pattern that differed between HUSMCs isolated from the upper and lower segment region of the uterus. Confirmatory enzyme-linked immunosorbent assays (ELISAs) showed that PGF2? stimulated increased output of interleukin (IL) 1?, IL6, IL8 (CXCL8) and monocyte chemotactic protein-1 (MCP1, also known as chemokine (c-c motif) ligand 2, CCL2) by HUSMCs isolated from both upper and lower uterine segments. In contrast, PGF2? inhibited tumor necrosis factor ? (TNF?) release by HUMSCs from the lower uterine segment while the output of TNF? was undetectable in the upper segment. Small interfering (si) RNA mediated knockdown of the PGF2? receptor prevented the changes in cytokine and chemokine output by the HUSMCs. Since the PGF2? receptor (PTGFR) couples via the Gq protein and subsequently activates the phospholipase C (PLC) and protein kinase C (PKC) signaling pathways, we examined the role of these pathways in PGF2? modulation of the cytokines. Inhibition of PLC and PKC reversed the effects of PGF2?. PGF2? activated multiple signaling pathways including extracellular signal-regulated kinases (ERK) 1/2, phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), P38, calcineurin/nuclear factor of activated T-cells (NFAT) and NF-?B signaling. Inhibition of ERK reversed PGF2?-induced IL1?, IL6 and CCL2 output, while inhibition of PI3K blocked the effect of PGF2? on IL6, CXCL8 and CCL2 output and inhibition of NF-?B reversed PGF2?-induced IL1? and CCL2 output. NFAT was involved in PGF2? modulation of CCL2 and TNF? output. In conclusion, our results support a role of PGF2? in creating an inflammatory environment during the late stage of human pregnancy.

SUBMITTER: Xu C 

PROVIDER: S-EPMC4487446 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature