Opposing Roles of Inter-α-Trypsin Inhibitor Heavy Chain 4 in Recurrent Pregnancy Loss

Abstract

Recurrent pregnancy loss (RPL) is usually defined as three or more consecutive spontaneous abortions prior to the 20-28 weeks of pregnancy. Although much progress has been made on immune-based etiology underlying unexplained RPL, the exact molecular mechanisms are still poorly understood. 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 with proteomics research tools. Yet, the precise molecular mechanism and pathways by which the cleaved form of ITI-H4 carries out its function remain obscure. In this study, we have identified significantly elevated expression of plasma kallikrein (KLKB1), and decreased expression of ITI-H4 in the peripheral blood monocytes cells (PBMCs) of RPL patients compared with those of the controls. We also showed that ITI-H4 as a biomarker of RPL could be regulated by KLKB1 through IL-6 signaling pathway, indicating a novel regulatory system for inflammation in RPL. Altogether, our study indicates that wild type and cleaved forms of ITI-H4 possess opposing functions on immune response, trophoblast invasion, and monocytes migration or proliferation. Therefore, it is expected that this study would give some insight into potential functional mechanisms involved in the pathogenesis of RPL. Funding Statement: This study was funded by the Korea Ministry of Environment (MOE) as “the Environmental Health Action Program (2016001360008).” Declaration of Interests: The authors state none declared. Ethics Approval Statement: This study was approved by the Ethics Committee of CHA General Hospital located in Seoul, Korea. Informed written consents were obtained from all participants and this study with human blood samples was approved by an Institutional Review Board (Reference Number: 08-16).