Antiviral activity of limitin against encephalomyocarditis virus, herpes simplex virus, and mouse hepatitis virus: diverse requirements by limitin and alpha interferon for interferon regulatory factor 1.
Limitin has sequence homology with alpha interferon (IFN-alpha) and IFN-beta and utilizes the IFN-alpha/beta receptor. However, it has no influence on the proliferation of normal myeloid and erythroid progenitors. In this study, we show that limitin has antiviral activity in vitro as well as in vivo. Limitin inhibited not only cytopathic effects in encephalomyocarditis virus- or herpes simplex virus (HSV) type 1-infected L929 cells, but also plaque formation in mouse hepatitis virus (MHV) type 2-infected DBT cells. In addition, administration of limitin to mice suppressed MHV-induced hepatitis and HSV-induced death. The antiviral activity may be mediated in part by 2',5'-oligoadenylate synthetase, RNA-dependent protein kinase, and Mx protein, which inhibit viral replication or degrade viral components, because limitin induced their mRNA expression and enzyme activity. While limitin has antiviral activity as strong as that of IFN-alpha in vitro (the concentration that provided 50% inhibition of cytopathic effect is approximately 30 pg/ml), IFN regulatory factor 1 (IRF-1) dependencies for induction of an antiviral state were different for limitin and IFN-alpha. In IRF-1-deficient fibroblasts, a higher concentration of limitin than of IFN-alpha was required for the induction of antiviral activity and the transcription of proteins from IFN-stimulated response element. The unique signals and the fewer properties of myelosuppression suggest that a human homolog of limitin may be used as a new antiviral drug.
Kawamoto
Shin-Ichiro
S
Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
Oritani
Kenji
K
Asada
Hideo
H
Takahashi
Isao
I
Ishikawa
Jun
J
Yoshida
Hitoshi
H
Yamada
Masahide
M
Ishida
Naoko
N
Ujiie
Hidetoshi
H
Masaie
Hiroaki
H
Tomiyama
Yoshiaki
Y
Matsuzawa
Yuji
Y
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D016207:Cytokines / Q000494:pharmacology*; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000502:physiology*; D004686:Encephalomyocarditis virus / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology; D050856:Interferon Regulatory Factor-1; D007370:Interferon Type I / Q000494:pharmacology*; D051379:Mice; D006517:Murine hepatitis virus / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology; D010750:Phosphoproteins / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D016207:Cytokines; D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; D007370:Interferon Type I; C494258:Irf1 protein, mouse; D010750:Phosphoproteins; D011994:Recombinant Proteins; C410906:limitin