Pigment epithelium‑derived factor facilitates NLRP3 inflammasome activation through downregulating cytidine monophosphate kinase 2: A potential treatment strategy for missed abortion

Zhang,Xi; Zhang,Kun; Zhang,Yi

doi:10.3892/ijmm.2020.4517

Pigment epithelium‑derived factor facilitates NLRP3 inflammasome activation through downregulating cytidine monophosphate kinase 2: A potential treatment strategy for missed abortion

Authors:
- Xi Zhang
- Kun Zhang
- Yi Zhang
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Affiliations: Department of Gynecology and Obstetrics, Changning Maternity and Infant Health Hospital, Shanghai 200050, P.R. China, Department of Pediatrics, Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200233, P.R. China
Published online on: February 26, 2020 https://doi.org/10.3892/ijmm.2020.4517
Pages: 1436-1446
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

A number of conditions may underlie the occurrence of missed abortion (MA), including inflammation. Pigment epithelium‑derived factor (PEDF) is a novel mediator of the inflammation‑related nucleotide‑binding oligomerization domain‑like receptor protein 3 (NLRP3) inflammasome, which is associated with several human diseases. However, the association between MA and NLRP3 inflammasome, and whether PEDF is reduced in MA, remain unknown. In the present study, the decidua and chorion tissues of patients who had suffered a MA were examined, and a lipopolysaccharide (LPS)‑induced human chorionic trophoblast HTR8/SVneo cell model was established to mimic MA in vitro. The results revealed that cytidine monophosphate kinase 2 (CMPK2) expression and NLRP3 inflammasome activation, downstream pro‑IL‑18 and pro‑IL‑1β expression, and IL‑18 and IL‑1β release, were all significantly increased in MA tissues or LPS‑induced HTR8/SVneo cells. PEDF reversed the increase in CMPK2 expression and activation of the NLRP3 inflammasome axis and, thus, downregulated the production of mitochondrial reactive oxygen species and mitochondrial DNA release, resulting in reduced lactate dehydrogenase release, and a resultant decrease in cell viability. Recovery of CMPK2 expression abolished all the effects of PEDF, indicating that CMPK2 may be an effector downstream of PEDF. PEDF reduced CMPK2 protein levels but did not affect the mRNA levels, and treatment with the proteasomal inhibitor MG132 significantly reversed this reduction in CMPK2 protein levels. Furthermore, a ubiquitination assay of immunoprecipitation demonstrated that CMPK2 was polyubiquitinated in the presence of LPS, PEDF and MG132. These results indicated that the NLRP3 inflammasome is implicated in the pathogenesis of MA, and PEDF may reduce MA through ubiquitin‑dependent proteasomal degradation of CMPK2 to inhibit NLRP3 activation, which may serve as a novel strategy for preventing or reducing the risk of MA.

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