| 摘要: | B、C型肝炎病毒是兩種主要導致肝硬化和肝癌的病因，每年約有1.5億人死於B、C型肝炎感染的後遺症。雖然近幾十年中，已採取一系列預防及藥物措施，用以降低B、C型肝炎感染後的發病率和死亡率，仍無法提供令人滿意的結果，這可能和病毒感染後，與宿主細胞輔因子間的相互作用有著極大的關係。因此，了解病毒的生命週期和宿主的免疫反應間的相關性，應有助於肝臟疾病之預防和治療。
當病毒感染宿主細胞後，細胞激素與化學激素例如IL-6及IL-27會被激發，然而各激素所扮演的角色不盡相同，包括病毒清除和組織傷害。此外，血管生成是細胞生長所需，於動物實驗上知道對於門脈、側支循環、肝癌的形成扮演重要的角色例如TNF-α及VEGF。然而對這些分子的了解僅限於實驗細胞及動物，在臨床上所扮演的角色並不很清楚，尤其是對於各不同臨床階段的肝炎患者仍需作進一步釐清。
於本研究，相較於肝功能正常或異常之非B、C型肝炎族群，B、C型肝炎患者皆有較高IL-6、IL-27、TNF-α和VEGF的表現。此外，在B、C型肝炎之各臨床病理階段的患者，這些分子也有顯著表現。然而，我們發現，IL-27、TNF-α和VEGF的表現強度與肝臟惡化程度並無相關。相反的，IL-6不僅呈現顯著的差異且和肝癌的嚴重程度呈正相關。由用以評估肝臟受損的數據，例如白蛋白，膽紅素，INR，也支持IL-6對於肝臟惡化導致病人死亡的嚴重程度扮演重要的角色。相反的，IL-27、TNF-α和VEGF則與疾病的進展表現不相關或弱相關。
此外，在肝臟疾病的進展中，各有不同的訊息傳遞系統，Janus激?(JAK)和轉錄激活子（STAT）在肝臟疾病的病理機制扮演著關鍵作用。為了闡明IL-6和其下游分子，STAT1和STAT3，我們利用肝臟組織染色，發現相較於STAT1，STAT3在不同的臨床階段的B、C型肝炎患者有較強的免疫染色且與肝臟腫瘤的進展有顯著的相關性。
由上述的發現提供了，當受B、C型肝炎感染後，IL-6被激發以反應肝臟之受損程度，尤其在肝臟疾病的惡化過程、肝硬化與肝癌患者的存活扮演著關鍵的角色。其中，主要是透過IL-6/STAT3這個途徑，因而促使肝損傷和纖維化、腫瘤細胞的存活和增生，最後導致肝癌的進展。由於對IL-6/STAT3途徑的了解，則增加我們對臨床肝臟疾病的病生理的有著更深的了解。因此，我們相信利用患者血中IL-6 ELISA的檢測和組織STAT3的免疫染色，並且結合現行影像和生化檢查，將可提供臨床醫生對肝臟疾病預後的評估。進一步，於日後製造出有效的免疫治療藥物，以改善病人的死亡率。
Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are the two major contributive causes of liver cirrhosis (LC) and hepatocellular carcinoma (HCC) in the world. Globally, approximately 1.5 million people die each year from sequelae of chronic HBV and HCV infections. Although a series of preventive and therapeutic strategies have been well adopted and established in recent decades to reduce the morbidity and mortality associated with HBV and HCV infections, the result still does not provide an entirely satisfactory solution and is greatly influenced and determined by the interactions of virus factor and host immune response. An improved understanding of the correlation between viral life cycles and host immune response should contribute to the development of innovative therapeutic and preventive strategies for liver diseases caused by HBV and HCV infection.
During viral infection, various cytokines and chemokines such as interleukine-6 (IL-6) and IL-27 are triggered and perform duplicated roles of both viral clearance and tissue damage. Additionally, angiogenesis is a cascade of linked and sequential cellular signaling pathways that has been reported to be an important process in the formation of porto-systemic collateral vessels and hepatocarcinogenesis in animal studies such as tumor necrosis factor-alpha (TNF-α) and vascular endothelial growth factor (VEGF). However, these are limited in clinical scenarios, and need to be further clarified in patients with different clinical stages of HBV or HCV infection.
In our study, there were significantly strong IL-6 and IL-27 and TNF-α and VEGF expressions in the HBV-infected or HCV-infected group compared with the CG (control group) or NF (normal function) and DF (dysfunction) subgroups of CG. Furthermore, among the separated groups of HBV-infected or HCV-infected patients, they also presented significantly higher in patients with CHB, CHC, LC, or HCC groups than those with CG or NF subgroup of CG. However, our study found IL-27 and TNF-α and VEGF expressions could not show significant correlations with deteriorating liver condition. In turn, IL-6 presented significant differences with deteriorating liver condition according to Child-Pugh Classification and tumor progression in patients with advanced or terminal stage HCC than those with early stage HCC. Data associated with impaired liver function, including Albumin, Bilirubin, and INR, also supported IL-6 playing a significantly crucial role to determine the severity of liver condition resulting in patient mortality. In contrast, IL-27 and TNF-α and VEGF executed without or weak correlations with disease progression. Additionally, of the various downstream signaling pathways in liver disease progression, the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays a critical role in the pathogenesis of liver diseases. To elucidate the correlations between IL-6 and its downstream molecules, STAT1 and STAT3, we also stained liver tissues and found STAT3 rather than STAT1 expressed significant immunostaining in different clinical-stage patients with HBV or HCV infection and played positive correlation in the progression of liver tumor.
Together these findings provide clinical evidence IL-6 is triggered to respond to liver damage after HBV or HCV infection and plays an extremely crucial role in determining the progression of liver diseases and mortality in na??ve LC or HCC patients. The pathway of IL-6-STAT3 plays an important role to promote liver injury and fibrosis, tumor cell survival and proliferation and therefore HCC progression.
The identification of functions for the IL-6/STAT3 pathway has markedly increased our understanding of liver disease pathophysiology in the real world. Therefore, we believe that ELISA detection of circulating IL-6 and tissue immunostaining of STAT3 as biomarker when combined with the current practice of images and biochemical exams may provide clinicians with effective predictors of disease prognosis as well. Furthermore, this also creates an attractive candidate agent in immunotherapy of advanced liver diseases to prevent patient mortality in the future. |
