Division of Therapeutic Proteins, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 29 Lincoln Dr., Bethesda, MD 20892, USA.
J Leukoc Biol. 2013 Mar;93(3):377-85. doi: 10.1189/jlb.0812395. Epub 2012 Dec 20.
This study compared the ability of IFN-α and IFN-λ to induce signal transduction and gene expression in primary human hepatocytes, PBLs, and monocytes. IFN-α drug products are widely used to treat chronic HCV infection; however, IFN-α therapy often induces hematologic toxicities as a result of the broad expression of IFNARs on many cell types, including most leukocytes. rIFN-λ1 is currently being tested as a potential alternative to IFN-α for treating chronic HCV. Although IFN-λ has been shown to be active on hepatoma cell lines, such as HepG2 and Huh-7, its ability to induce responses in primary human hepatocytes or leukocytes has not been examined. We found that IFN-λ induces activation of Jak/STAT signaling in mouse and human hepatocytes, and the ability of IFN-λ to induce STAT activation correlates with induction of numerous ISGs. Although the magnitude of ISG expression induced by IFN-λ in hepatocytes was generally lower than that induced by IFN-α, the repertoire of regulated genes was quite similar. Our findings demonstrate that although IFN-α and IFN-λ signal through distinct receptors, they induce expression of a common set of ISGs in hepatocytes. However, unlike IFN-α, IFN-λ did not induce STAT activation or ISG expression by purified lymphocytes or monocytes. This important functional difference may provide a clinical advantage for IFN-λ as a treatment for chronic HCV infection, as it is less likely to induce the leukopenias that are often associated with IFN-α therapy.
本研究比较了 IFN-α 和 IFN-λ 在原代人肝细胞、PBL 和单核细胞中诱导信号转导和基因表达的能力。IFN-α 药物产品广泛用于治疗慢性 HCV 感染；然而，IFN-α 治疗通常会引起血液学毒性，这是由于 IFNAR 在许多细胞类型上广泛表达，包括大多数白细胞。rIFN-λ1 目前正在作为 IFN-α 的替代药物用于治疗慢性 HCV 进行测试。尽管 IFN-λ 已被证明对肝癌细胞系（如 HepG2 和 Huh-7）具有活性，但尚未研究其在原代人肝细胞或白细胞中诱导反应的能力。我们发现 IFN-λ 诱导小鼠和人肝细胞中 Jak/STAT 信号的激活，IFN-λ 诱导 STAT 激活的能力与诱导大量 ISG 相关。尽管 IFN-λ 在肝细胞中诱导的 ISG 表达的幅度通常低于 IFN-α，但调节基因的谱非常相似。我们的研究结果表明，尽管 IFN-α 和 IFN-λ 通过不同的受体信号转导，但它们在肝细胞中诱导一组共同的 ISG 表达。然而，与 IFN-α 不同，IFN-λ 不会诱导纯化的淋巴细胞或单核细胞中的 STAT 激活或 ISG 表达。这种重要的功能差异可能为 IFN-λ 作为慢性 HCV 感染的治疗方法提供临床优势，因为它不太可能引起与 IFN-α 治疗相关的白细胞减少症。
