Liver Immunology Laboratory, Institute of Immunology and School of Life Sciences, University of Science and Technology of China, Hefei, China; Intensive Care Unit, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, China.
Clin Exp Immunol. 2014 Apr;176(1):102-11. doi: 10.1111/cei.12259.
Transforming growth factor (TGF)-β, type I receptor (TβRI) and c-Jun N-terminal kinases (JNK) phosphorylate Smad3 differentially to create 2 isoforms phosphorylated (p) at the COOH-terminus (C) or at the linker region (L) and regulate hepatocytic fibrocarcinogenesis. This study aimed to compare the differences between how hepatitis B virus (HBV) infection affected hepatocytic Smad3 phosphorylated isoforms before and after anti-viral therapy. To clarify the relationship between Smad3 phosphorylation and liver disease progression, we studied 10 random patients in each stage of HBV-related fibrotic liver disease (F1-4) and also 10 patients with HBV-associated HCC. To examine changes in phosphorylated Smad3 signalling before and after anti-HBV therapies, we chose 27 patients with chronic hepatitis B who underwent baseline and follow-up biopsies at 52 weeks from the start of nucleoside analogue treatments (Lamivudine 100 mg daily or Telbivudine 600 mg daily). Fibrosis stage, inflammatory activity and phosphorylated Smad3 positivity in the paired biopsy samples were compared. Hepatocytic pSmad3C signalling shifted to fibrocarcinogenic pSmad3L signalling as the livers progressed from chronic hepatitis B infection to HCC. After nucleoside analogue treatment, serum alanine aminotransferase (ALT) and HBV-DNA levels in 27 patients with HBV-related chronic liver diseases were decreased dramatically. Decrease in HBV-DNA restored pSmad3C signalling in hepatocytes, while eliminating prior fibrocarcinogenic pSmad3L signalling. Oral nucleoside analogue therapies can suppress fibrosis and reduce HCC incidence by successfully reversing phosphorylated Smad3 signalling; even liver disease progressed to cirrhosis in chronic hepatitis B patients.
转化生长因子-β（TGF-β）、I 型受体（TβRI）和 c-Jun N 末端激酶（JNK）可使 Smad3 的羧基末端（C）或连接区（L）磷酸化，从而产生 2 种磷酸化异构体，并调节肝实质细胞纤维癌变。本研究旨在比较乙型肝炎病毒（HBV）感染前后抗病毒治疗对肝实质细胞 Smad3 磷酸化异构体的影响。为了阐明 Smad3 磷酸化与肝病进展的关系，我们研究了 HBV 相关纤维化肝病（F1-4）各期的 10 例随机患者，也研究了 10 例 HBV 相关性 HCC 患者。为了研究抗病毒治疗前后磷酸化 Smad3 信号的变化，我们选择了 27 例慢性乙型肝炎患者，这些患者在核苷类似物治疗开始后 52 周进行了基线和随访肝活检（拉米夫定 100mg 每日或替比夫定 600mg 每日）。比较了配对活检样本中的纤维化分期、炎症活动度和磷酸化 Smad3 阳性率。随着肝脏从慢性乙型肝炎感染进展为 HCC，肝实质细胞的 pSmad3C 信号向纤维癌变的 pSmad3L 信号转变。在 27 例 HBV 相关慢性肝病患者中，核苷类似物治疗后血清丙氨酸氨基转移酶（ALT）和 HBV-DNA 水平显著下降。HBV-DNA 的减少恢复了肝细胞中的 pSmad3C 信号，同时消除了先前的纤维癌变 pSmad3L 信号。口服核苷类似物疗法可通过成功逆转磷酸化 Smad3 信号来抑制纤维化并降低 HCC 发生率，即使慢性乙型肝炎患者的肝病进展为肝硬化。
