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

Abstract

Background and Purpose Lipoxins 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 A4 (LXA4) suppresses the development of endometriosis. Experimental Approach Primary endometriotic stromal cells (ESCs) were treated with IL‐1β, or pre‐incubated with LXA4 before incubation with IL‐1β. The LXA4 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 Results Decreased levels of LXA4 and 15‐LOX‐2 expression but increased expression of AXL receptors were observed in endometriotic tissues. LXA4 inhibited the release of inflammatory factors and phosphorylation of p38 MAPK in IL‐1β‐induced ESCs, an effect mediated by ALX receptors. LXA4 inhibited the proliferation of ESCs, as indicated by reduced DNA replication, caused G0/G1 phase cell cycle arrest and down‐regulated the expression of proliferating cell nuclear antigen in ESCs. LXA4 also attenuated the invasive activity of ESCs mainly by suppressing the expression and activity of MMP‐9. In vivo, we further confirmed that LXA4 could inhibit the progression of endometriosis by acting as an anti‐inflammatory. Conclusions and Implications LXA4 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.

Effect of interleukin‐1β and lipoxin A4 in human endometriotic stromal cells: Proteomic analysis

“…*P < 0.05, **P < 0.01. microenvironment, Th2 immune response may promote the development of endometriosis. This suggests that LXA 4 not only has anti-inflammatory and anti-invasive effects, as our previous report, 18,23 but also exerts an anti-Th2 immune response effect in ESC.…”

“…23 In brief, ovarian endometriotic cyst tissues were rinsed with phosphate buffer saline (PBS), cut into small pieces, and then incubated with type IV collagenase and deoxyribonuclease I. The cell suspensions were filtered through a stainless steel sieve with 140 μm and 37 μm apertures in sequence.…”

“…23 Briefly, 20 μg total protein for each sample was loaded onto a gel for SDS-PAGE. Proteins were separated and transferred to a PVDF membrane.…”

Lipoxin A4 Reduces Inflammation Through Formyl Peptide Receptor 2/p38 MAPK Signaling Pathway in Subarachnoid Hemorrhage Rats

“…6–8 LXA4 exerted these biological functions through down-regulating the activities of p38 mitogen-activated protein kinase (MAPK), which was mediated by FPR2. 7, 9, 10 Several studies have focused on the neuroprotective effects of LXA4 after stroke. Administration of LXA4 methyl ester was reported to reduce pro-inflammatory cytokines TNF-α and IL-1β and up-regulate anti-inflammatory cytokines IL-10 and TGF-β1 in the ischemic brain.…”

Serum Polyunsaturated Fatty Acids and Endometriosis

“…18 Lipoxin A 4 has been shown to suppress inflammatory cytokine production in endometrium, and recently it has been demonstrated to suppress both the development and the progression of endometriosis in mouse models of endometriosis. 14,[19][20][21][22][23] Although it is possible that increased consumption or circulating levels of EPA may push fatty acid substrates to the production of lipoxin A 4 , further work investigating the metabolism of essential fatty acids to pro-and anti-inflammatory derivatives is needed.…”