Wu Rongfeng, Zhou Weidong, Chen Shuo, Shi Yan, Su Lin, Zhu Maobi, Chen Qionghua, Chen Qingxi
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China.
Br J Pharmacol. 2014 Nov;171(21):4927-40. doi: 10.1111/bph.12816.
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.
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.
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.
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.
脂氧素可作为炎症中的内源性“终止信号”，并在子宫内膜异位症进展中发挥重要作用。在本研究中，我们进一步探究了脂氧素A4（LXA4）抑制子宫内膜异位症发展的分子机制。
用白细胞介素-1β（IL-1β）处理原代子宫内膜异位间质细胞（ESC），或在与IL-1β孵育前先用LXA4预孵育。采用LXA4受体（ALX受体）拮抗剂Boc-2和基因沉默方法，研究ALX受体在ESC抗炎信号反应中的作用。通过腹腔注射富含子宫内膜的片段，在BALB/c小鼠中诱导建立子宫内膜异位症动物模型。
在子宫内膜异位组织中观察到LXA4和15-脂氧合酶-2（15-LOX-2）表达水平降低，但AXL受体表达增加。LXA4抑制IL-1β诱导的ESC中炎症因子的释放和p38丝裂原活化蛋白激酶（p38 MAPK）的磷酸化，这一作用由ALX受体介导。LXA4抑制ESC的增殖，表现为DNA复制减少，导致G0/G1期细胞周期阻滞，并下调ESC中增殖细胞核抗原的表达。LXA4还主要通过抑制基质金属蛋白酶-9（MMP-9）的表达和活性来减弱ESC的侵袭活性。在体内，我们进一步证实LXA4可作为抗炎因子抑制子宫内膜异位症的进展。
LXA4通过下调由ALX受体介导的p38 MAPK活性，对子宫内膜异位症发挥抗炎、抗增殖和抗侵袭作用。
