Lipoxin A4 suppresses the development of endometriosis in an ALX receptor-dependent manner via the p38 MAPK pathway

Background and PurposeLipoxins can function as endogenous breaking signals' in inflammation and play important roles in the progression of endometriosis. In this study, we further investigated the molecular mechanism by which lipoxin A(4) (LXA(4)) suppresses the development of endometriosis. Experimental ApproachPrimary endometriotic stromal cells (ESCs) were treated with IL-1, or pre-incubated with LXA(4) before incubation with IL-1. The LXA(4) receptor (ALX receptor) antagonist Boc-2 and gene-silencing approaches were used to study the involvement of the ALX receptor in anti-inflammatory signalling responses in ESCs. An animal model of endometriosis was induced in BALB/c mice by i.p. injection of an endometrium-rich fragment. Key ResultsDecreased levels of LXA(4) and 15-LOX-2 expression but increased expression of AXL receptors were observed in endometriotic tissues. LXA(4) inhibited the release of inflammatory factors and phosphorylation of p38 MAPK in IL-1-induced ESCs, an effect mediated by ALX receptors. LXA(4) inhibited the proliferation of ESCs, as indicated by reduced DNA replication, caused G(0)/G(1) phase cell cycle arrest and down-regulated the expression of proliferating cell nuclear antigen in ESCs. LXA(4) also attenuated the invasive activity of ESCs mainly by suppressing the expression and activity of MMP-9. In vivo, we further confirmed that LXA(4) could inhibit the progression of endometriosis by acting as an anti-inflammatory. Conclusions and ImplicationsLXA(4) exerted anti-inflammatory, anti-proliferative and anti-invasive effects on endometriosis through a mechanism that involved down-regulating the activities of p38 MAPK, which was mediated by ALX receptors.