Zhuo Su-Yan, Liao Li
Department of Pediatrics, People's Hospital of Chongqing Shapingba District, Chongqing 400030, China.
Zhongguo Dang Dai Er Ke Za Zhi. 2019 Feb;21(2):131-138. doi: 10.7499/j.issn.1008-8830.2019.02.005.
To study the expression of high-mobility group box 1 (HMGB1) in neonates with sepsis and its role in the pathogenesis of neonatal sepsis.
A total of 62 neonates with sepsis were enrolled as the sepsis group, 66 neonates with local infection were enrolled as the local infection group, and 70 healthy neonates were enrolled as the healthy control group. Serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-17 (IL-17), interleukin-23 (IL-23), C-reactive protein (CRP) and procalcitonin (PCT) were measured. The mRNA expression of HMGB1, Toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB) and the protein expression of TLR4 and NF-κB in peripheral blood mononuclear cells (PBMCs) were also measured. PBMCs from healthy neonates were divided into 4 groups: control, HMGB1 treatment, HMGB1+TAK-242 (a TLR4 inhibitor) treatment and HMGB1+PDTC (an NF-κB inhibitor) treatment, and the mRNA expression of TLR4, NF-κB and IL-8 and the protein expression of TLR4 and NF-κB were measured. PBMCs from healthy neonates were divided into another 3 groups: control, LPS treatment and LPS+glycyrrhizin (an HMGB1 inhibitor) treatment, and the mRNA expression of HMGB1, TLR4, NF-κB and IL-8 and the protein expression of TLR4 and NF-κB were measured.
Compared with the local infection and healthy control groups, the sepsis group had significantly higher serum levels of IL-6, IL-8, IL-17, IL-23, CRP and PCT (P<0.05), as well as significantly higher mRNA expression of HMGB1, TLR4 and NF-κB and protein expression of TLR4 and NF-κB in PBMCs (P<0.05). HMGB1 significantly induced the mRNA and protein expression of TLR4 and NF-κB in PBMCs (P<0.05). TAK-242 inhibited the mRNA and protein expression of TLR4 and NF-κB and mRNA expression of IL-8 (P<0.05). PDTC inhibited the mRNA and protein expression of NF-κB and the mRNA expression of IL-8 (P<0.05). LPS significantly induced the mRNA expression of HMGB1 and the mRNA and protein expression of TLR4 and NF-κB and then stimulated the mRNA expression of IL-8 (P<0.05). Glycyrrhizin inhibited the mRNA expression of HMGB1 and the mRNA and protein expression of TLR4 and NF-κB and then reduced the mRNA expression of IL-8 (P<0.05).
HMGB1 plays an important role in the pathogenesis of neonatal sepsis by activating the TLR4/NF-κB signaling pathway and inducing the secretion of inflammatory factors including IL-8. The HMGB1 blocker glycyrrhizin can inhibit activation of the TLR4/NF-κB signaling pathway and the secretion of inflammatory factors.
研究高迁移率族蛋白B1（HMGB1）在新生儿脓毒症中的表达及其在新生儿脓毒症发病机制中的作用。
选取62例新生儿脓毒症患儿作为脓毒症组，66例局部感染新生儿作为局部感染组，70例健康新生儿作为健康对照组。检测血清白细胞介素-6（IL-6）、白细胞介素-8（IL-8）、白细胞介素-17（IL-17）、白细胞介素-23（IL-23）、C反应蛋白（CRP）和降钙素原（PCT）水平。同时检测外周血单个核细胞（PBMCs）中HMGB1、Toll样受体4（TLR4）和核因子-κB（NF-κB）的mRNA表达以及TLR4和NF-κB的蛋白表达。将健康新生儿的PBMCs分为4组：对照组、HMGB1处理组、HMGB1+TAK-242（一种TLR4抑制剂）处理组和HMGB1+PDTC（一种NF-κB抑制剂）处理组，检测TLR4、NF-κB和IL-8的mRNA表达以及TLR4和NF-κB的蛋白表达。将健康新生儿的PBMCs分为另外3组：对照组、脂多糖（LPS）处理组和LPS+甘草酸（一种HMGB1抑制剂）处理组，检测HMGB1、TLR4、NF-κB和IL-8的mRNA表达以及TLR4和NF-κB的蛋白表达。
与局部感染组和健康对照组相比，脓毒症组血清IL-6、IL-8、IL-17、IL-23、CRP和PCT水平显著升高（P<0.05），PBMCs中HMGB1、TLR4和NF-κB的mRNA表达以及TLR4和NF-κB的蛋白表达也显著升高（P<0.05）。HMGB1显著诱导PBMCs中TLR4和NF-κB的mRNA和蛋白表达（P<0.05）。TAK-242抑制TLR4和NF-κB的mRNA和蛋白表达以及IL-8的mRNA表达（P<0.05）。PDTC抑制NF-κB的mRNA和蛋白表达以及IL-8的mRNA表达（P<0.05）。LPS显著诱导HMGB1的mRNA表达以及TLR4和NF-κB的mRNA和蛋白表达，进而刺激IL-8的mRNA表达（P<0.05）。甘草酸抑制HMGB1的mRNA表达以及TLR4和NF-κB的mRNA和蛋白表达，进而降低IL-8的mRNA表达（P<0.05）。
HMGB1通过激活TLR4/NF-κB信号通路并诱导包括IL-8在内的炎症因子分泌，在新生儿脓毒症发病机制中起重要作用。HMGB1阻滞剂甘草酸可抑制TLR4/NF-κB信号通路的激活和炎症因子的分泌。
