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J Leukoc Biol 2013 Mar;93(3):377-85

Interferon-lambda (IFN-lambda) induces signal transduction and gene expression in human hepatocytes but not in lymphocytes or monocytes.

Dickensheets H, Sheikh F, Park O, Gao B, Donnelly RP

Abstract

This study compared the ability of IFN-alpha and IFN-lambda to induce signal transduction and gene expression in primary human hepatocytes, PBLs, and monocytes. IFN-alpha drug products are widely used to treat chronic HCV infection; however, IFN-alpha therapy often induces hematologic toxicities as a result of the broad expression of IFNARs on many cell types, including most leukocytes. rIFN-lambda1 is currently being tested as a potential alternative to IFN-alpha for treating chronic HCV. Although IFN-lambda 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-lambda induces activation of Jak/STAT signaling in mouse and human hepatocytes, and the ability of IFN-lambda to induce STAT activation correlates with induction of numerous ISGs. Although the magnitude of ISG expression induced by IFN-lambda in hepatocytes was generally lower than that induced by IFN-alpha, the repertoire of regulated genes was quite similar. Our findings demonstrate that although IFN-alpha and IFN-lambda signal through distinct receptors, they induce expression of a common set of ISGs in hepatocytes. However, unlike IFN-alpha, IFN-lambda did not induce STAT activation or ISG expression by purified lymphocytes or monocytes. This important functional difference may provide a clinical advantage for IFN-lambda as a treatment for chronic HCV infection, as it is less likely to induce the leukopenias that are often associated with IFN-alpha therapy.


Category: Journal Article
PubMed ID: #23258595 DOI: 10.1189/jlb.0812395
PubMed Central ID: #PMC3579021
Includes FDA Authors from Scientific Area(s): Drugs
Entry Created: 2012-12-22 Entry Last Modified: 2014-11-07
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