Involvement of IL-1beta and IL-10 in IFN-alpha-mediated antiviral gene induction in human hepatoma cells.
Crosstalk between interferons (IFNs) and several cytokines is likely to play an important role in viral clearance in chronic hepatitides B and C. We investigated the influence of this phenomenon on IFN-inducible antiviral gene expression in HuH-7 human hepatoma cells. HuH-7 cells were treated with IFN-alpha in the absence or presence of interleukin-1beta (IL-1beta) or IL-10 and the expression of antiviral genes such as 2(')5(')-oligoadenylate synthetase (2(')5(')-OAS) and double-stranded RNA-dependent protein kinase (PKR), as well as activation of signal transducer and activator of transcription 1 (STAT1), a key step for relaying the IFN-alpha signals, was analyzed by Northern blotting, Western blotting, and the reporter gene transfection assay. IL-1beta potentiated IFN-alpha-induced 2(')5(')-OAS and PKR gene expression, similar to expression of the transfected reporter genes containing the IFN-stimulated regulatory elements, while IL-10 suppressed IFN-alpha-stimulated gene expression. With regard to IFN-alpha signaling, IL-1beta enhanced both tyrosine and serine phosphorylation of STAT1 through p38 mitogen-activated protein kinase activation. In contrast, IL-10 inhibited IFN-alpha-mediated tyrosine phosphorylation of STAT1 by induction of a Janus kinase inhibitor, JAB. IL-1beta and IL-10 interact with IFN-alpha to up- and down-regulate antiviral gene expression, respectively, by modulating STAT1 activation induced by IFN-alpha.
Ichikawa
Tatsuki
T
The First Department of Internal Medicine, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.
Nakao
Kazuhiko
K
Nakata
Keisuke
K
Yamashita
Mayumi
M
Hamasaki
Keisuke
K
Shigeno
Masaya
M
Abiru
Seigou
S
Ishikawa
Hiroki
H
Ishii
Nobuko
N
Eguchi
Katsumi
K
D015088:2',5'-Oligoadenylate Synthetase / Q000096:biosynthesis; D015152:Blotting, Northern; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D017930:Genes, Reporter; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism* / Q000494:pharmacology; D007375:Interleukin-1 / Q000378:metabolism* / Q000494:pharmacology; D016753:Interleukin-10 / Q000378:metabolism* / Q000494:pharmacology; D014176:Protein Biosynthesis; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D019892:eIF-2 Kinase / Q000096:biosynthesis
D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D007375:Interleukin-1; D012097:Repressor Proteins; C106644:SOCS3 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D016753:Interleukin-10; D019892:eIF-2 Kinase; D015088:2',5'-Oligoadenylate Synthetase