IL-1 beta attenuates IFN-alpha beta-induced antiviral activity and STAT1 activation in the liver: involvement of proteasome-dependent pathway.
IFN-alphabeta is the only established treatment for viral hepatitis; however, more than 60% of patients are poorly responsive. Because viral hepatitis is associated with inflammation, we hypothesized that inflammation may attenuate the efficacy of IFN therapy. To test this hypothesis, the effect of IL-1beta, one of the major proinflammatory cytokines, on IFN signaling pathway in the liver was examined. Administration of IL-1beta in vivo attenuated IFN-alphabeta-induced STAT1 tyrosine phosphorylation in the liver but not in the spleen. The inhibitory action of IL-1beta in vivo was not affected by depleting hepatic Kupffer cells, suggesting that IL-1beta may directly target IFN-alphabeta signaling in hepatocytes. Indeed, pretreatment of human hepatocellular carcinoma HepG2 cells with IL-1beta suppressed IFN-alphabeta-induced antiviral activity and antiviral protein MxA mRNA expression. Furthermore, IL-1beta attenuated IFN-alphabeta-induced STAT1 binding and tyrosine phosphorylation without affecting the level of STAT1 protein. This inhibitory effect can be reversed by pretreatment with either proteasome inhibitors or transfection of dominant negative NF-kappaB inducing kinase mutants. Taken together, these findings suggest that IL-1beta attenuates IFN-alphabeta-induced STAT1 activation by a proteasome-dependent mechanism. In view of high levels of IL-1beta in the serum or within the liver of patients with chronic liver diseases, attenuation of IFN-alphabeta signaling in the liver by IL-1beta could be one of the mechanisms underlying the resistance to IFN therapy in chronic hepatitis C, and IL-1beta could be a potential therapeutic target for improving the efficacy of IFN therapy.
Tian
Z
Z
Department of Pharmacology and Toxicology, Medical College of Virginia Commonwealth University, Richmond 23298, USA.
Shen
X
X
Feng
H
H
Gao
B
B
D000276:Adjuvants, Immunologic / Q000502:physiology*; D000818:Animals; D000998:Antiviral Agents / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D001667:Binding, Competitive / Q000276:immunology; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000821:virology; D003546:Cysteine Endopeptidases / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D004789:Enzyme Activation / Q000276:immunology; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007275:Injections, Intravenous; D007370:Interferon Type I / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016898:Interferon-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007375:Interleukin-1 / Q000502:physiology*; D053613:Janus Kinase 1; D007728:Kupffer Cells / Q000276:immunology / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D051379:Mice; D008813:Mice, Inbred ICR; D009097:Multienzyme Complexes / Q000502:physiology*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D014176:Protein Biosynthesis; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism / Q000502:physiology; D051381:Rats; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D053634:TYK2 Kinase; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D000276:Adjuvants, Immunologic; D000998:Antiviral Agents; D004268:DNA-Binding Proteins; D007166:Immunosuppressive Agents; D007370:Interferon Type I; D016898:Interferon-alpha; D007375:Interleukin-1; D009097:Multienzyme Complexes; D011506:Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; C494081:Stat1 protein, rat; D015534:Trans-Activators; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507905:Jak1 protein, mouse; C507906:Jak1 protein, rat; D053613:Janus Kinase 1; D053634:TYK2 Kinase; C070139:TYK2 protein, human; C499356:Tyk2 protein, mouse; C499357:Tyk2 protein, rat; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex