Pellino 1 is a novel regulator of TNF and TLR signalling in human myometrial and amnion cells

Preterm birth is the primary cause of neonatal deaths and morbidities. Pathological processes causally linked to preterm birth are inflammation and infection. Pellino-1 (Peli1) has previously been found to regulate the inflammatory response in non-gestational tissues in response to toll-like receptor (TLR) ligands and pro-inflammatory cytokines. The aims of this study were to determine the effect of labor on Peli1 expression in myometrium and fetal membranes, and the effect of Peli1 silencing by siRNA (siPELI1) on the production of pro-inflammatory and pro-labor mediators. The expression of Peli1 was found to be higher in myometrium and fetal membranes with term labor, compared to non-laboring samples. Peli1 mRNA and protein expression was also higher in amnion from women with preterm histological chorioamnionitis. In human primary myometrial cells, siPELI1 transfected cells showed a decrease in pro-inflammatory cytokine IL6, chemokines (CXCL8, CCL2) and adhesion molecule ICAM1 when in the presence of pro-inflammatory cytokine TNF, TLR2/6 ligand fsl-1, TLR5 ligand flagellin, and TLR3 ligand poly(I:C). Similarly in primary amnion cells, siPELI1 transfected cells decreased IL1B-induced expression and secretion of IL6 and CXCL8. In siPELI1 transfected myometrial cells, there was a decrease in prostaglandin PGF2α and its receptor, PTGFR mRNA expression when treated with TNF. There was a decrease in NF-κB RELA transcriptional activity in siPELI1 transfected cells in the presence of TNF, fsl-1 and flagellin, but not poly(I:C). Our study suggests a novel role for Peli1 in regulating pro-inflammatory and pro-labor mediators through TNF and TLR signalling.