Opposing roles of inter-α-trypsin inhibitor heavy chain 4 in recurrent pregnancy loss.

Abstract

BackgroundThe mechanism behind an increased risk of recurrent pregnancy loss (RPL) remains largely unknown. In our previous study, we identified that inter-α-trypsin inhibitor heavy chain 4 (ITI-H4) is highly expressed at a modified molecular weight of 36 kDa in serum derived from RPL patients. Yet, the precise molecular mechanism and pathways by which the short form of ITI-H4 carries out its function remain obscure.MethodsHuman sera and peripheral blood mononucleated cells (PBMCs) were collected from patients and normal controls to compare the expression levels of ITI-H4 and plasma kallikrein (KLKB1). Flow cytometric assay was performed to measure inflammatory markers in sera and culture supernatants. Furthermore, to investigate the functions of the two isoforms of ITI-H4, we performed migration, invasion, and proliferation assays.FindingsIn the current study, we showed that ITI-H4 as a biomarker of RPL could be regulated by KLKB1 through the IL-6 signaling cascade, indicating a novel regulatory system for inflammation in RPL. In addition, our study indicates that the two isoforms of ITI-H4 possess opposing functions on immune response, trophoblast invasion, and monocytes migration or proliferation.InterpretationThe ITI-H4 (∆N688) might be a crucial inflammatory factor which contributes to the pathogenesis of RPL. Moreover, it is expected that this study would give some insights into potential functional mechanisms underlying RPL.FundThis study was supported by the Ministry of Health & Welfare of the Republic of Korea (HI18C0378) through the Korea Health Industry Development Institute.