Bao Suxia, Zheng Jianming, Li Ning, Huang Chong, Chen Mingquan, Cheng Qi, Li Qian, Lu Qing, Zhu Mengqi, Ling Qingxia, Yu Kangkang, Chen Shengshen, Shi Guangfeng
Department of infectious diseases, Fudan university, Huashan hospital, 200040 Shanghai, China.
Department of infectious diseases, Fudan university, Huashan hospital, 200040 Shanghai, China.
Clin Res Hepatol Gastroenterol. 2017 Mar;41(2):147-155. doi: 10.1016/j.clinre.2016.10.005. Epub 2016 Dec 29.
The role of interleukin-23 (IL-23) in monocyte-derived dendritic cells (MoDCs) from hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) patients remains unclear. The aim of this study was to observe the correlation between the activation of the IL-23 signaling pathway and the prognosis of HBV-ACLF patients.
The baseline levels of serum IL-6, IL-12, IL-17, IL-23, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) from immune tolerant (IT), chronic hepatitis B (CHB), HBV-ACLF patients and healthy individuals who served as healthy controls (HCs) were analyzed using the Luminex system, whereas serum IL-23 from HBV-ACLF patients was measured by ELISA before and after treatment. Purified monocytes were isolated from peripheral blood and were induced into MoDCs, IL-23, IL-23R, NF-κB and TRAF6 expression in MoDCs from 4 groups was analyzed using real-time PCR, and IL-23R and intracellular IL-23 were evaluated by flow cytometry.
Serum IL-6, IL-12, IL-17, IL-23 and TNF-α levels were upregulated in HBV-ACLF patients compared with IT patients, CHB patients and HCs (P<0.05 for all). Serum IL-23 was closely correlated with elevated serum IL-17 in HBV-ACLF patients (r=0.5935, P<0.0001). Moreover, IL-23 and IL-23R levels were significantly upregulated in MoDCs from patients with CHB or HBV-ACLF compared with HCs, and further upregulation of IL-23 and IL-23R was observed in HBV-ACLF patients compared to CHB patients (P<0.05 for all). IL-23 expression was markedly enhanced and was correlated with elevated NF-κB and TRAF6 in MoDCs from HBV-ACLF patients (P<0.05 for both). Linear correlation analysis demonstrated significant correlations between the expression of IL-23 and disease severity markers (MELD scoring system, international normalized ratio, prothrombin time and total bilirubin, r=0.6874, r=0.6475, r=0.6249, r=0.3771, respectively, P<0.05 for all) for individual HBV-ACLF patients, and IL-23 levels were significantly upregulated in non-survival HBV-ACLF patients compared with survival HBV-ACLF patients (P<0.05).
IL-23 in serum and MoDCs is significantly elevated in HBV-ACLF patients, TRAF6/NF-κB may play a role in IL-23 production by MoDCs in HBV-ACLF patients and high pre-treatment IL-23 levels in MoDCs are associated with mortality in HBV-ACLF patients.
白细胞介素-23（IL-23）在乙型肝炎病毒相关慢加急性肝衰竭（HBV-ACLF）患者单核细胞来源的树突状细胞（MoDCs）中的作用尚不清楚。本研究旨在观察IL-23信号通路激活与HBV-ACLF患者预后的相关性。
使用Luminex系统分析免疫耐受（IT）、慢性乙型肝炎（CHB）、HBV-ACLF患者及作为健康对照（HCs）的健康个体血清中IL-6、IL-12、IL-17、IL-23、肿瘤坏死因子-α（TNF-α）和干扰素-γ（IFN-γ）的基线水平，而用ELISA法检测HBV-ACLF患者治疗前后的血清IL-23。从外周血中分离纯化单核细胞并诱导其分化为MoDCs，采用实时PCR分析4组MoDCs中IL-23、IL-23R、NF-κB和TRAF6的表达，并用流式细胞术评估IL-23R和细胞内IL-23。
与IT患者、CHB患者和HCs相比，HBV-ACLF患者血清IL-6、IL-12、IL-17、IL-23和TNF-α水平上调（均P<0.05）。HBV-ACLF患者血清IL-23与血清IL-17升高密切相关（r=0.5935，P<0.0001）。此外，与HCs相比，CHB或HBV-ACLF患者MoDCs中IL-23和IL-23R水平显著上调，与CHB患者相比，HBV-ACLF患者中IL-23和IL-23R进一步上调（均P<0.05）。HBV-ACLF患者MoDCs中IL-23表达明显增强，且与NF-κB和TRAF6升高相关（均P<0.05）。线性相关分析表明，单个HBV-ACLF患者中IL-23表达与疾病严重程度标志物（终末期肝病模型评分系统、国际标准化比值、凝血酶原时间和总胆红素，r分别为0.6874、0.6475、0.6249、0.3771，均P<0.05）显著相关，与存活的HBV-ACLF患者相比，非存活HBV-ACLF患者的IL-23水平显著上调（P<0.05）。
HBV-ACLF患者血清和MoDCs中的IL-23显著升高，TRAF6/NF-κB可能在HBV-ACLF患者MoDCs产生IL-23中起作用，MoDCs中治疗前高IL-23水平与HBV-ACLF患者死亡率相关。
