SAA1 regulates pro-labour mediators in term labour by activating YAP pathway

Abstract

Term labour is associated with activation of inflammation which results in myometrial contractility, cervical ripening and decidual/membrane rupture. Serum amyloid A1 (SAA1) is an acute response protein, whose role and underlying regulatory mechanisms in human labour remain unknown. In this study, we found that the mRNA and protein expression of SAA1 in human myometrium at term was increased in labouring tissues compared to non-labouring tissues. In addition, the expression of SAA1 was significantly increased in human primary myometrial cells treated with the pro-inflammatory cytokines interleukin-1 beta (IL-1β) or tumour necrosis factor-alpha (TNF-α). Knockdown of SAA1 using siRNA (siSAA1) resulted in a significant reduction in the expression and secretion of pro-inflammatory cytokines (IL8, IL6), chemokines (CXCL5, CCL2), adhesion molecules (ICAM1, ICAM5) and contraction-associated factors (COX2, PGE2). Mechanistically, the effects of SAA1 were mediated through activation of the Yes-associated protein (YAP) pathway. There was a decrease in the protein expression of phosphorylated YAP (pYAP) after treatment of siSAA1-transfected human primary myometrial cells with IL-1β or TNF-α. Moreover, enhanced expression of YAP reversed the effect of siSAA1 on pro-labour mediators. In conclusion, these experiments demonstrated that SAA1 accelerates the inflammatory response associated with parturition by activating YAP pathway, which may be a novel understanding of the molecular mechanism of labour onset.

Keywords: Human primary myometrial cells; Inflammatory cytokine; Labour; SAA1; YAP.