A role for lipoxin A ₄ as anti‐inflammatory and proresolution mediator in human parturition

Abstract

The purpose of this study was to investigate the role of lipoxin A(4), an anti-inflammatory and proresolution modulator, during human parturition. We measured serum levels of lipoxin A(4) and myometrial protein release using ELISA, quantified lipoxin receptor (FPR2/ALX) mRNA expression using qRT-PCR, and localized protein expression using immunohistochemstry in myometrial biopsies from pregnant women. In addition, we compared the effects of lipoxin A(4) (100 nM) with vehicle on basal and LPS-stimulated expression of proinflammatory cytokines from samples of myometrium from pregnant women. Mean ± SE circulating level of lipoxin A(4) was 5.89 ± 0.63 nM at 24-wk gestation, with a further modest increase during pregnancy (P<0.05), but no differences in gestation matched women before and after labor (P>0.05). Levels of lipoxin A(4) in nonpregnant women were 0.48 ± 0.04 nM, significantly lower than in pregnant women (P<0.001). FPR2/ALX localized to myocytes and neutrophils, with a 9-fold increase in mRNA expression in labor (P<0.001). Lipoxin A(4) significantly reduced LPS-induced but not basal expression of the proinflammatory cytokines IL-6 and IL-8 in cultured myometrium (P<0.05), compared to vehicle-treated controls. We demonstrate for the first time a potential role for lipoxin A(4) and its receptor in the resolution of the inflammatory events of both physiological and pathological labor.

Molecular regulators of resolution of inflammation: potential therapeutic targets in the reproductive system

“…LOX enzymes are also detected in the theca and granulosa layers of rat pre-ovulatory ovarian follicles (Kurusu et al 2009). Direct evidence for altered resolution mediator signalling in pregnancy is provided by a recent report that LXA 4 levels are significantly elevated in serum from pregnant compared with non-pregnant women (Maldonado-Pérez et al 2010).…”

“…These cells are thought to play a role in the systemic shift towards immunosuppression and tolerance observed during pregnancy, which may be an epiphenomenon reflecting local uterine cytokine signalling. In this context, the elevated LXA 4 levels described in pregnant serum may well result from significant local uterine production (Maldonado-Pérez et al 2010). IL4, IL13 and IL10 expression at the maternal-foetal interface reflects the M2 gene expression profile of first trimester decidual macrophages (Gustafsson et al 2008).…”

“…Thus, it appears that central to the process of labour is an immune switch, from anti-inflammatory pathways actively maintaining uterine quiescence towards local and systemic pro-inflammatory activation. A further increase in serum LXA 4 levels observed as term approaches (Maldonado-Pérez et al 2010) may therefore represent a homoeostatic adjustment maintaining uterine quiescence in the face of increased inflammatory activation. This would ultimately be overwhelmed by the inflammatory cascade, ensuring rapid and complete parturition following eventual, irreversible onset of labour.…”

“…LXA 4 treatment inhibits pro-inflammatory cytokine production by term myometrial explants in response to LPS (Maldonado-Pérez et al 2010). Levels of resolution mediators may themselves be reduced during labour.…”

Renin–angiotensin–aldosterone system in insulin resistance and metabolic syndrome

“…LXA 4 exhibited estrogenic activity in vivo, increasing uterine wet weight and modulating 17β-estradiol regulated gene expression [59] . These studies [59][60][61][62] suggest that LXA 4 mediates anti-inflammatory actions of estrogen. Since LXA 4 induces the production and release of eNO [63][64][65] , this implies that estrogen induced LXA 4 synthesis, which, in turn, enhances eNO generation.…”