title: Characterization of early IL-12, IFN-alphabeta, and TNF effects on antiviral state and NK cell responses during murine cytomegalovirus infection.
abstract: Murine cytomegalovirus (MCMV) infection of mice induces early cytokines. Although certain of these can directly inhibit viral replication, they also can promote defense by activating NK cells. MCMV induces IFN-alphabeta-dependent NK cell cytotoxicity and IL-12-dependent NK cell IFN-gamma production. Studies were initiated to define cytokine-mediated NK and T cell-independent antiviral defense and specific cytokine-elicited NK cell responses during MCMV infections. IFN-alphabeta, TNF, IL-12, and IFN-gamma were all shown to be induced 2 days after infection of immunocompetent mice. Infections of NK and T cell-deficient mice demonstrated that virus-induced IFN-alphabeta, TNF, and IL-12, but not IFN-gamma, were produced independently of these populations, and that IL-12 production occurred in the absence of detectable IFN-gamma. In vivo neutralization studies of IFN-alphabeta, TNF, and IL-12 showed that each of these factors had NK and T cell-independent antiviral functions, as well as specific effects on NK cell responses. Examination of NK cell cytotoxicity, blastogenesis, and IFN-gamma production demonstrated that: IL-12 was required for NK cell IFN-gamma production but not blastogenesis and cytotoxicity; IFN-alphabeta was necessary for NK cell blastogenesis and cytotoxicity but not IFN-gamma production; and TNF facilitated IFN-gamma production but inhibited NK cell cytotoxicity. This work defines the biologic consequences of early cytokine expression during viral infection.
authors.affiliation: Division of Biology and Medicine, Brown University, Providence, RI 02912, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Orange
authors.forename: C A
authors.initials: CA
authors.lastname: Biron
mesh_terms: D000818:Animals; D003586:Cytomegalovirus Infections / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D004334:Drug Administration Schedule; D006566:Herpesviridae Infections / Q000276:immunology; D007111:Immunity, Cellular; D007370:Interferon Type I / Q000008:administration & dosage*; D018664:Interleukin-12 / Q000008:administration & dosage*; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D016513:Mice, SCID; D018146:Muromegalovirus / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*
chemical_list: D007370:Interferon Type I; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12