Interleukin-29 uses a type 1 interferon-like program to promote antiviral responses in human hepatocytes.
Interleukin-28A (IL-28A), IL-28B and IL-29 are a family of class II cytokines that stimulate antiviral responses through a heterodimeric receptor that is distinct from the type I interferon (IFN) receptor. To better understand how this newly described family of cytokines regulates the antiviral state, we compared various cellular responses elicited by IL-29 and IFN-alpha. Here we show that these cytokines stimulate similar patterns of signal transducer and activator of transcription 1 (STAT-1), -2, -3, and -5 phosphorylation and nearly identical patterns of gene expression when analyzed in two distinct cell types by microarray analysis. Interestingly, the IL-29 receptor is preferentially expressed on primary hepatocytes within normal liver and pegylated forms of IL-29 and IFN-alpha induced equivalent 2'5' oligoadenylate synthetase (OAS) and MX1 gene expression in this cell type. Pegylated IL-29 also produced a significant reduction in human hepatitis B and hepatitis C viral load in vitro and reduced the cytopathic effect caused by the fully replicating flavivirus, West Nile virus. In conclusion, IL-29 and IFN-alpha stimulate identical antiviral responses despite their utilization of different receptors. This fact, combined with significant receptor expression in hepatitis virus-infected livers, suggests that IL-29 may have therapeutic value against chronic viral hepatitis in human patients.
Doyle
Sean E
SE
ZymoGenetics, Inc., Seattle, WA 98102, USA.
Schreckhise
Heidi
H
Khuu-Duong
Kien
K
Henderson
Katherine
K
Rosler
Robert
R
Storey
Harold
H
Yao
Lena
L
Liu
Hong
H
Barahmand-pour
Fariba
F
Sivakumar
Pallavur
P
Chan
Chung
C
Birks
Carl
C
Foster
Don
D
Clegg
Christopher H
CH
Wietzke-Braun
Perdita
P
Mihm
Sabine
S
Klucher
Kevin M
KM
D000818:Animals; D000998:Antiviral Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D016466:CHO Cells / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D016207:Cytokines / Q000494:pharmacology* / Q000627:therapeutic use; D005416:Flavivirus / Q000235:genetics; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D016174:Hepacivirus / Q000235:genetics; D006515:Hepatitis B virus / Q000235:genetics; D006525:Hepatitis, Viral, Human / Q000188:drug therapy* / Q000821:virology; D022781:Hepatocytes / Q000378:metabolism / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D007372:Interferons; D007378:Interleukins / Q000494:pharmacology* / Q000627:therapeutic use; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D012313:RNA / Q000032:analysis / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects; D000095022:Interferon Lambda
D000998:Antiviral Agents; D016207:Cytokines; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D012313:RNA; D018123:Receptors, Interleukin; D050794:STAT1 Transcription Factor; C000624353:interferon-lambda, human; D000095022:Interferon Lambda