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1.
Cancer Lett ; 346(1): 122-8, 2014 Apr 28.
Article in English | MEDLINE | ID: mdl-24368188

ABSTRACT

Interferon Response Factor 3 (IRF3) induces several NK-cell activating factors, is activated by poly-I:C, an experimental cancer therapeutic, but is suppressed during many viral infections. IRF3 Knockout (KO) mice exhibited enhanced B16 melanoma growth, impaired intratumoral NK cell infiltration, but not an impaired poly-I:C therapeutic effect due to direct suppression of B16 growth. IRF3 was responsible for poly-I:C decrease in TIM-3 expression by intratumoral dendritic cells, induction of NK-cell Granzyme B and IFN-γ, and induction of macrophage IL-12, IL-15, IL-6, and IRF3-dependent NK-activating molecule (INAM). Thus, IRF3 is a key factor controlling melanoma growth through NK-cell activities, especially during poly-I:C therapy.


Subject(s)
Interferon Regulatory Factor-3/metabolism , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Melanoma, Experimental/immunology , Melanoma, Experimental/metabolism , Animals , Cell Proliferation , Flow Cytometry , Interferon Inducers/pharmacology , Lymphocyte Activation/immunology , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Melanoma, Experimental/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Poly I-C/pharmacology
2.
Virus Res ; 178(2): 226-33, 2013 Dec 26.
Article in English | MEDLINE | ID: mdl-24140628

ABSTRACT

IRF3 is an innate anti-viral factor whose role in limiting Theiler's murine encephalomyelitis virus (TMEV) infection and preventing TMEV-induced disease is unclear. Acute disease and innate immune responses of macrophages were examined in IRF3 knockout mice compared with C57Bl/6 mice following in vitro or intracranial infection with either TMEV GDVII or DA. IRF3 deficiency augmented viral infection, as well as morbidity and mortality following intracranial infection with neurovirulent TMEV GDVII. In contrast, IRF3 deficiency prevented hippocampal injury following intracranial infection with persistent TMEV DA. The extent of TMEV infection in macrophages from C57Bl/6 mice was significantly less than that in IRF3 deficient macrophages, which was associated with poor IFN-ß and IL-6 expression in response to TMEV. Reestablishing IRF3 expression in IRF3 deficient macrophages increased control of TMEV replication and increased expression of IFN-ß and IL-6. In addition, IRF3 deficient macrophages failed to exhibit IL-6 antiviral effects, which was associated with inability to sustain IL-6-induced STAT1 activation compared with C57BL/6 macrophages. Altogether, IRF3 contributes to early control of TMEV replication through induction of IL-6 and IFN-ß and support of IL-6 antiviral effects, but contributes to TMEV-induced hippocampal injury.


Subject(s)
Cardiovirus Infections/immunology , Cardiovirus Infections/pathology , Host-Pathogen Interactions , Interferon Regulatory Factor-3/metabolism , Interleukin-6/immunology , Theilovirus/immunology , Animals , Cardiovirus Infections/virology , Hippocampus/immunology , Hippocampus/pathology , Hippocampus/virology , Interferon Regulatory Factor-3/deficiency , Interferon-beta/biosynthesis , Interferon-beta/immunology , Interleukin-6/biosynthesis , Mice , Mice, Inbred C57BL , Mice, Knockout , Severity of Illness Index , Survival Analysis , Theilovirus/physiology
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