Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
Front Immunol. 2022 Apr 25;13:810671. doi: 10.3389/fimmu.2022.810671. eCollection 2022.
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease with unknown etiology. CCN1, an extracellular matrix-associated protein, is associated with carcinoma, inflammation, liver fibrosis, and even autoimmune diseases. However, the role that CCN1 plays in AIH has remained undetermined. In this study, expression of CCN1 in liver was detected by real-time PCR, western blot and immunohistochemistry (IHC). CCN1 level in serum was detected by ELISA. Diagnostic value of CCN1 was determined by receiver operating characteristic (ROC) curve analysis. CCN1 conditional knockout (CCN1 Cre) mice were generated by mating CCN1 C57BL/6J and CAG-Cre-ERT C57BL/6J mice. Autoimmune hepatitis mice model was induced by concanavalin A (ConA). IKKα/β, IκBα, NF-κB p65 and Akt phosphorylation were determined by western blot. NF-κB p65 nuclear translocation was examined by immunofluorescence. Here, we found that CCN1 was over-expressed in hepatocytes of AIH patients. CCN1 level also increased in serum of AIH patients compared to healthy controls (HC). ROC curve analysis results showed that serum CCN1 was able to distinguish AIH patients from HD. In ConA induced hepatitis mice model, CCN1 conditional knockout (CCN1 Cre) attenuated inflammation by reducing ALT/AST level and IL-6 expression. , CCN1 treatment dramatically induced IL-6 production in LO2 cells. Moreover, the production of IL-6 was attenuated by CCN1 knockdown. Furthermore, we showed that CCN1 could activate IL-6 production the PI3K/Akt/NF-κB signaling pathway by binding to α6β1 receptor. In summary, our results reveal a novel role of CCN1 in promoting inflammation by upregulation of IL-6 production in AIH. Our study also suggests that targeting of CCN1 may represent a novel strategy in AIH treatment.
自身免疫性肝炎（AIH）是一种病因不明的慢性炎症性肝病。细胞外基质相关蛋白 CCN1 与癌、炎症、肝纤维化，甚至自身免疫性疾病有关。然而，CCN1 在 AIH 中的作用仍未确定。在这项研究中，通过实时 PCR、western blot 和免疫组织化学（IHC）检测肝组织中 CCN1 的表达。通过 ELISA 检测血清中 CCN1 的水平。通过接收者操作特征（ROC）曲线分析确定 CCN1 的诊断价值。通过交配 CCN1 C57BL/6J 和 CAG-Cre-ERT C57BL/6J 小鼠生成 CCN1 条件性敲除（CCN1 Cre）小鼠。通过使用伴刀豆球蛋白 A（ConA）诱导 AIH 小鼠模型。通过 western blot 检测 IKKα/β、IκBα、NF-κB p65 和 Akt 磷酸化。通过免疫荧光检测 NF-κB p65 核转位。在这里，我们发现 CCN1 在 AIH 患者的肝细胞中过度表达。与健康对照组（HC）相比，AIH 患者血清中的 CCN1 水平也升高。ROC 曲线分析结果表明，血清 CCN1 能够区分 AIH 患者和 HD。在 ConA 诱导的肝炎小鼠模型中，CCN1 条件性敲除（CCN1 Cre）通过降低 ALT/AST 水平和 IL-6 表达来减轻炎症。此外，CCN1 处理可显著诱导 LO2 细胞中 IL-6 的产生。此外，CCN1 敲低可减弱 IL-6 的产生。此外，我们还表明，CCN1 可以通过与α6β1 受体结合激活 IL-6 的产生 该通路的 PI3K/Akt/NF-κB 信号通路。总之，我们的结果揭示了 CCN1 在 AIH 中通过上调 IL-6 产生促进炎症的新作用。我们的研究还表明，针对 CCN1 可能代表 AIH 治疗的一种新策略。
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