AUTHOR=Ozmen Asli , Guzeloglu-Kayisli Ozlem , Tabak Selcuk , Guo Xiaofang , Semerci Nihan , Nwabuobi Chinedu , Larsen Kellie , Wells Ali , Uyar Asli , Arlier Sefa , Wickramage Ishani , Alhasan Hasan , Totary-Jain Hana , Schatz Frederick , Odibo Anthony O. , Lockwood Charles J. , Kayisli Umit A. 

TITLE=Preeclampsia is Associated With Reduced ISG15 Levels Impairing Extravillous Trophoblast Invasion

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=10

YEAR=2022

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2022.898088

DOI=10.3389/fcell.2022.898088

ISSN=2296-634X

ABSTRACT=<p>Among several interleukin (IL)-6 family members, only IL-6 and IL-11 require a gp130 protein homodimer for intracellular signaling due to lack of intracellular signaling domain in the IL-6 receptor (IL-6R) and IL-11R. We previously reported enhanced decidual IL-6 and IL-11 levels at the maternal-fetal interface with significantly higher peri-membranous IL-6 immunostaining in adjacent interstitial trophoblasts in preeclampsia (PE) vs. gestational age (GA)-matched controls. This led us to hypothesize that competitive binding of these cytokines to the gp130 impairs extravillous trophoblast (EVT) differentiation, proliferation and/or invasion. Using global microarray analysis, the current study identified inhibition of interferon-stimulated gene 15 (<italic>ISG15</italic>) as the only gene affected by both IL-6 plus IL-11 vs. control or IL-6 or IL-11 treatment of primary human cytotrophoblast cultures. <italic>ISG15</italic> immunostaining was specific to EVTs among other trophoblast types in the first and third trimester placental specimens, and significantly lower <italic>ISG15</italic> levels were observed in EVT from PE vs. GA-matched control placentae (<italic>p</italic> = 0.006). Induction of primary trophoblastic stem cell cultures toward EVT linage increased <italic>ISG15</italic> mRNA levels by 7.8-fold (<italic>p</italic> = 0.004). <italic>ISG15</italic> silencing in HTR8/SVneo cultures, a first trimester EVT cell line, inhibited invasion, proliferation, expression of <italic>ITGB1</italic> (a cell migration receptor) and filamentous actin while increasing expression of <italic>ITGB4</italic> (a receptor for hemi-desmosomal adhesion). Moreover, <italic>ISG15</italic> silencing further enhanced levels of IL-1β-induced pro-inflammatory cytokines (<italic>CXCL8</italic>, <italic>IL-6</italic> and <italic>CCL2</italic>) in HTR8/SVneo cells. Collectively, these results indicate that <italic>ISG15</italic> acts as a critical regulator of EVT morphology and function and that diminished <italic>ISG15</italic> expression is associated with PE, potentially mediating reduced interstitial trophoblast invasion and enhancing local inflammation at the maternal-fetal interface. Thus, agents inducing <italic>ISG15</italic> expression may provide a novel therapeutic approach in PE.</p>