High-mobility group box 1 protein (HMGB1) in maternal plasma affects Th17/Treg balance via receptor for advanced glycation end products (RAGE)-IL-6 pathway in preeclamptic pregnancies
Objective 
To analyze the relationships of high mobility group box 1 protein (HMGB1) with regulatory T cells (Treg), T helper 17 cells (Th17) and cytokine secrtion in peripheral blood of gravidas with preeclampsia (PE), and to investigate the mechanism of HMGB1 in regulating Th17/Treg ratio via receptor for advanced glycation end products (RAGE)-IL-6 pathway. 
 
 
Methods 
Forty gravidas with mild (20 cases) and severe (20 cases) PE were recruited as experimental groups, 20 heathy gravidas in the third trimester of pregnancy were enrolled as control group. Concentrations of HMGB1, IL-6, IL-17 and TGF-β in peripheral blood of all subjects were determined by enzyme-linked immunosorbent assay (ELISA). Real-time quantitative PCR (RT-PCR) was used to detect the expression of RAGE at mRNA level in peripheral blood mononuclear cells (PBMCs). The percentages of Treg and Th17 cells were determined by flow cytometry. RT-PCR was performed to analyze changes in the expression of RAGE, IL-6, Foxp3 and RORγt at mRNA level after the PBMCs isolated from 20 garvidas with PE were cultured in vitro and stimulated with recombinant human HMGB1 (rhHMGB1). 
 
 
Results 
The levels of HMGB1, IL-6, Th17 and IL-17 in peripheral blood of gravidas with PE were significantly higher than those in the normal pregnancy group. Moreover, HMGB1 level was positively correlated with IL-6 level and ratios of Th17/Treg and IL-17/TGF-β in preeclamptic pregancies. In vitro stimulation of PBMCs with rhHMGB1 significantly enhanced the expression of RAGE, IL-6 and RORγt at mRNA level, but suppressed the expression of Foxp3 at mRNA level. 
 
 
Conclusion 
Enriched HMGB1 in plasma shifts the Th17/Treg balance towards Th17 dominance via the RAGE-IL-6 pathway, which exacerbates inflammation and participates in the onset of preeclampsia during pregnancy. 
 
 
Key words: 
Preeclampsia; High mobility group box 1 protein; Receptor for advanced glycation end products; Th17/Treg balance