title: Interferon-lambda (IFN-λ) induces signal transduction and gene expression in human hepatocytes, but not in lymphocytes or monocytes.
abstract: 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.
authors.affiliation: Division of Therapeutic Proteins, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 29 Lincoln Dr., Bethesda, MD 20892, USA.
authors.forename: Harold
authors.initials: H
authors.lastname: Dickensheets
authors.forename: Faruk
authors.initials: F
authors.lastname: Sheikh
authors.forename: Ogyi
authors.initials: O
authors.lastname: Park
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Donnelly
mesh_terms: D000818:Animals; D005260:Female; D056945:Hep G2 Cells; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000276:immunology; D022781:Hepatocytes / Q000276:immunology*; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology / Q000627:therapeutic use; D007372:Interferons; D007378:Interleukins / Q000276:immunology* / Q000627:therapeutic use; D053612:Janus Kinases / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology*; D008297:Male; D051379:Mice; D009000:Monocytes / Q000276:immunology*; D009928:Organ Specificity / Q000276:immunology; D050791:STAT Transcription Factors / Q000276:immunology; D015398:Signal Transduction / Q000502:physiology*; D000095022:Interferon Lambda
chemical_list: D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D053612:Janus Kinases; D050791:STAT Transcription Factors; C000624353:interferon-lambda, human; D000095022:Interferon Lambda