The immunoproteasome inhibitor ONX‐0914 regulates inflammation and expression of contraction associated proteins in myometrium. Issue 8 (28th June 2018)

• Record Type: Journal Article
• Authors: Liong, Stella; Lim, Ratana; Nguyen‐Ngo, Caitlyn; Barker, Gillian; Parkington, Helena C.; Lappas, Martha
• Is Part Of: European journal of immunology. Volume 48:Issue 8(2018)
• Page Start: 1350
• Page End: 1363
• Publication Date: 2018-06-28
• Subjects: Human labor -- Immunoproteasome -- Inflammation -- LMP7 -- Myometrium; Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201747458
• Languages: English
• ISSNs: 0014-2980

Abstract

Abstract: There are currently no effective treatments to prevent spontaneous preterm labor. The precise upstream biochemical pathways that regulate the transition between uterine quiescence during pregnancy and contractility during labor remain unclear. It is well known however that intrauterine inflammation, including infection, is commonly associated with preterm labor. In this study, we identified the immunoproteasome subunit low‐molecular‐mass protein (LMP)7 mRNA expression to be significantly upregulated in laboring human myometrium. Silencing LMP7 using siRNA‐targeted knockdown of LMP7 and its inhibitor ONX‐0914 in human myometrial cells and tissues decreased proinflammatory cytokines (IL‐6), cell chemotaxis (CXCL8, CCL2 expression, and THP‐1 migration), cell to cell adhesion (ICAM1 expression and myometrial adhesion), contraction‐associated proteins (PTGS2, FP, PGE2, and PGF2α), as well as suppressing contractions in myometrial cells and in myometrial tissues obtained from laboring women. In addition, LMP7 silencing reduced NF‐κB RelA activity. ONX‐0914 alleviated inflammation (CCL3, CXCL1, PTGS2, and IL‐6) in myometrium, placenta, fetal brain, amniotic fluid, and maternal serum induced by LPS in pregnant mice. Collectively, our data suggest a novel role for ONX‐014 to suppress uterine activation and contractility associated with preterm labor. Abstract : Treatment with ONX‐0914 or LMP7 siRNA knockdown in myometrium in vitro reduces inflammation, cell adhesion, and contractions. ONX‐0914 treatment in pregnant mice reduces LPS‐induced myometrial and fetal brain inflammation in utero.