Omega-3 polyunsaturated fatty acids reduce preterm labor by inhibiting trophoblast cathepsin S and inflammasome activation

Abstract

Preterm labor is associated with inflammation and infection. The mechanisms underlying the role of omega-3 fatty acid in inflammasome activation and prevention of preterm labor remain unknown. We hypothesized that omega-3 fatty acid can reduce the rate of preterm birth induced by infection and trophoblast inflammation. In the present study, we found that inflammasome-related molecules and IL-1β in trophoblasts were activated by TNF-α derived from lipopolysaccharide (LPS)-stimulated THP-1 cell-conditioned medium (CM) and recombinant TNF-α protein. The results demonstrated that stimulation with TNF-α caused lysosomal rupture in trophoblasts, which accelerated cathepsin S (CTSS) diffusion from lysosomes to the cytosol and activated NLRP1 (nacht domain-leucine-rich repeat, and pyd-containing protein 1) and absent in melanoma 2 (AIM2) inflammasomes, thereby increasing IL-1β secretion. Moreover, in response to LPS challenge, TNF-α increased trophoblast cell death and decreased cell viability through inflammasome and CTSS activation. Stearidonic acid (SDA; 18:4n-3) and docosahexaenoic acid (DHA; 22:6n-3) inhibited inflammasome-related molecule synthesis and CTSS and caspase-1 activation, which further reduced the preterm delivery rate of pregnant mice induced by LPS (92.9 compared with 69.7% (DHA); 92.9 compared with 53.5% (SDA)). Higher expression of TNF-α, IL-1β, prostaglandin E2, and CTSS, but lower resolvin D1 expression, was observed in preterm pregnant mice than in controls. Similarly, resolvin D1 was highly expressed in women with term delivery compared with women with preterm delivery. Thus, SDA and DHA may attenuate macrophage-derived TNF-α inducing CTSS and inflammasome activation, IL-1β secretion, and placental trophoblast cell death. These functions are implicated in the preventive effects of SDA and DHA on preterm labor.

Keywords: docosahexaenoic acid; inflammasome; preterm; stearidonic acid; trophoblast.