Abstract Objective To study the expression of high-mobility group box 1 (HMGB1) in neonates with sepsis and its role in the pathogenesis of neonatal sepsis. Methods 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. Results 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). Conclusions 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.
Oza S, Lawn JE, Hogan DR, et al. Neonatal cause-of-death estimates for the early and late neonatal periods for 194 countries:2000-2013[J]. Bull World Health Organ, 2015, 93(1):19-28.
[2]
Richard SA, Jiang Y, Xiang LH, et al. Post-translational modifications of high mobility group box 1 and cancer[J]. Am J Transl Res, 2017, 9(12):5181-5196.
[3]
He SJ, Cheng J, Feng X, et al. The dual role and therapeutic potential of high-mobility group box 1 in cancer[J]. Oncotarget, 2017, 8(38):64534-64550.
[4]
Dipasquale V, Cutrupi MC, Colavita L, et al. Neuroinflammation in autism spectrum disorders:role of high mobility group box 1 protein[J]. Int J Mol Cell Med, 2017, 6(3):148-155.
[5]
Bianchi ME, Crippa MP, Manfredi AA, et al. High-mobility group box 1 protein orchestrates responses to tissue damage via inflammation, innate and adaptive immunity, and tissue repair[J]. Immunol Rev, 2017, 280(1):74-82.
[6]
Yu H, Qi Z, Zhao L, et al. Prognostic value of dynamic monitoring of cellular immunity and HMGB1 in severe sepsis:delayed chronic inflammation may be the leading cause of death in late severe sepsis[J]. Clin Lab, 2016, 62(12):2379-2385.
[7]
Lee W, Ku SK, Bae JS. Zingerone reduces HMGB1-mediated septic responses and improves survival in septic mice[J]. Toxicol Appl Pharmacol, 2017, 329:202-211.
[8]
Yang M, Cao L, Xie M, et al. Chloroquine inhibits HMGB1 inflammatory signaling and protects mice from lethal sepsis[J]. Biochem Pharmacol, 2013, 86(3):410-418.
[9]
Wang H, Liao H, Ochani M, et al. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis[J]. Nat Med, 2004, 10(11):1216-1221.
Huang Y, Zhou M, Li C, et al. Picroside Ⅱ protects against sepsis via suppressing inflammation in mice[J]. Am J Transl Res, 2016,8(12):5519-5531.
[13]
Xu M, Zhou GM, Wang LH, et al. Inhibiting high-mobility group box 1(HMGB1) attenuates inflammatory cytokine expression and neurological deficit in ischemic brain injury following cardiac arrest in rats[J]. Inflammation, 2016, 39(4):1594-1602.
[14]
Wang X, Guo Y, Wang C, et al. MicroRNA-142-3p inhibits chondrocyte apoptosis and inflammation in osteoarthritis by targeting HMGB1[J]. Inflammation, 2016, 39(5):1718-1728.
[15]
Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation[J]. Nature, 2002, 418(6894):191-195.
[16]
Zhang H, Yang N, Wang T, et al. Vitamin D reduces inflammatory response in asthmatic mice through HMGB1/TLR4/NFkappaB signaling pathway[J]. Mol Med Rep, 2018, 17(2):2915-2920.
[17]
Dong LY, Chen F, Xu M, et al. Quercetin attenuates myocardial ischemia-reperfusion injury via downregulation of the HMGB1-TLR4-NF-kappaB signaling pathway[J]. Am J Transl Res, 2018, 10(5):1273-1283.
[18]
Li MJ, Li F, Xu J, et al. rhHMGB1 drives osteoblast migration in a TLR2/TLR4-and NF-kappaB-dependent manner[J]. Biosci Rep, 2016, 36(1):e00300.
[19]
Li G, Wu X, Yang L, et al. TLR4-mediated NF-kappaB signaling pathway mediates HMGB1-induced pancreatic injury in mice with severe acute pancreatitis[J]. Int J Mol Med, 2016, 37(1):99-107.
[20]
Xiong X, Gu L, Wang Y, et al. Glycyrrhizin protects against focal cerebral ischemia via inhibition of T cell activity and HMGB1-mediated mechanisms[J]. J Neuroinflammation, 2016, 13(1):241.
[21]
Ekanayaka SA, McClellan SA, Barrett RP, et al. Glycyrrhizin reduces HMGB1 and bacterial load in pseudomonas aeruginosa keratitis[J]. Invest Ophthalmol Vis Sci, 2016, 57(13):5799-5809.
