Ren Jun, Meng Shanshan, Yan Bingdi, Yu Jinyan, Liu Jing
Department of Digestive System, Yantaishan Hospital, Yantai, Shandong 264000, P.R. China.
Department of Respiratory Medicine, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China.
Mol Med Rep. 2016 Apr;13(4):3627-38. doi: 10.3892/mmr.2016.4980. Epub 2016 Mar 4.
Protectin D1 (PD1) is a bioactive product generated from docosahexaenoic acid, which may exert anti-inflammatory effects in various inflammatory diseases. However, the underlying molecular mechanism of its anti‑inflammatory activity on concanavalin A (Con A)-induced hepatitis remains unknown. The aim of the present study was to investigate the protective effects of PD1 against Con A‑induced liver injury and the underlying mechanisms via intravenous injection of PD1 prior to Con A administration. C57BL/6 mice were randomly divided into four experimental groups as follows: Control group, Con A group (30 mg/kg), 20 µg/kg PD1 + Con A (30 mg/kg) group and 10 µg/kg PD1 + Con A (30 mg/kg) group. PD1 pretreatment was demonstrated to significantly inhibit elevated plasma aminotransferase levels, high mobility group box 1 and liver necrosis, which were observed in Con A‑induced hepatitis. Furthermore, compared with the Con A group, PD1 pretreatment prevented the production of pro‑inflammatory cytokines, including tumor necrosis factor‑α, interferon‑γ and interleukin‑2, ‑1β and ‑6. In addition, pretreatment with PD1 markedly downregulated cluster of differentiation (CD)4+, CD8+ and natural killer T (NKT) cell infiltration in the liver. PD1 pretreatment was observed to suppress the messenger RNA and protein expression levels of NLR family, pyrin domain containing 3 and Toll‑like receptor (TLR) 4 in liver tissue samples. Further data indicated that PD1 pretreatment inhibited the activation of the nuclear factor κ‑light‑chain‑enhancer of activated B cells (NF‑κB) signaling pathway and chemokine (C‑X3‑C motif) ligand 1 (CX3CL1)/chemokine (C-X3-C motif) receptor 1 (CX3CR1) axis by preventing phosphorylation of nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor, α and NF‑κB in Con A‑induced liver injury. Therefore, these results suggest that PD1 administration protects mice against Con A‑induced liver injury via inhibition of various inflammatory cytokines and, in part, by suppressing CD4+, CD8+ and NKT cell infiltration in the liver and the NF‑κB‑activated CX3CL1/CX3CR1 signaling pathway. The beneficial effect of PD1 may be associated with the inhibition of TLR4 expression and the downregulation of NF‑κB activation. In conclusion, PD1 appears to be a potential natural bioproduct, and provide a promising strategy, for the prevention of hepatic injury in patients with chronic or acute liver disease.
保护素D1（PD1）是一种由二十二碳六烯酸生成的生物活性产物，其可能在多种炎症性疾病中发挥抗炎作用。然而，其对刀豆蛋白A（Con A）诱导的肝炎的抗炎活性的潜在分子机制仍不清楚。本研究的目的是通过在给予Con A之前静脉注射PD1，研究PD1对Con A诱导的肝损伤的保护作用及其潜在机制。将C57BL/6小鼠随机分为以下四个实验组：对照组、Con A组（30 mg/kg）、20 μg/kg PD1 + Con A（30 mg/kg）组和10 μg/kg PD1 + Con A（30 mg/kg）组。结果表明，PD1预处理可显著抑制Con A诱导的肝炎中观察到的血浆转氨酶水平升高、高迁移率族蛋白B1和肝坏死。此外，与Con A组相比，PD1预处理可抑制促炎细胞因子的产生，包括肿瘤坏死因子-α、干扰素-γ和白细胞介素-2、-1β和-6。此外，PD1预处理可显著下调肝脏中分化簇（CD）4+、CD8+和自然杀伤T（NKT）细胞浸润。观察到PD1预处理可抑制肝组织样本中NLR家族含pyrin结构域3和Toll样受体（TLR）4的信使核糖核酸和蛋白表达水平。进一步的数据表明，PD1预处理通过防止B细胞κ轻链增强子核因子α和Con A诱导的肝损伤中的核因子κB磷酸化，抑制活化B细胞核因子κ轻链增强子（NF-κB）信号通路和趋化因子（C-X3-C基序）配体1（CX3CL1）/趋化因子（C-X3-C基序）受体1（CX3CR1）轴。因此，这些结果表明，给予PD1可通过抑制多种炎性细胞因子，并部分通过抑制肝脏中CD4+、CD8+和NKT细胞浸润以及NF-κB激活的CX3CL1/CX3CR1信号通路，保护小鼠免受Con A诱导的肝损伤。PD1的有益作用可能与抑制TLR4表达和下调NF-κB激活有关。总之，PD1似乎是一种潜在的天然生物产物，并为预防慢性或急性肝病患者的肝损伤提供了一种有前景的策略。
