RESUMEN
Therapeutic use of type I IFN (IFN-alpha/beta) has become common. Many of the diverse diseases targeted are marked by pathogenetic abnormalities in cell-mediated immunity (CMI), these cellular immune responses either causing injury to the host, lacking sufficient vigor for virus or tumor clearance, or both. In general, therapeutic efficacy is limited. It is thus notable that the pleiotropic effects of type I IFN on CMI remain poorly understood. We characterized the effects of type I IFN on the production of IL-12, the central immunoregulatory cytokine of the CD4(+) T cell arm of CMI. We show that type I IFN are potent inhibitors of IL-12 production by human monocytes/macrophages. The underlying mechanism involves transcriptional inhibition of the IL-12p40 gene, marked by down-regulation of PU.1 binding activity at the upstream Ets site of the IL-12p40 promoter. Type I IFN have previously been shown to be able to substitute for IL-12 in driving IFN-gamma production from T and NK cells. The ability of IFN-alpha/beta to suppress IL-12 production while up-regulating IFN-gamma production suggests a possible mechanistic basis for the difficulties of employing these cytokines in diseases involving abnormalities of CMI.
Asunto(s)
Interferón-alfa/farmacología , Interferón beta/farmacología , Interleucina-12/genética , Monocitos/inmunología , Células Cultivadas , Proteínas de Unión al ADN/metabolismo , Regulación hacia Abajo , Humanos , Inmunidad Celular , Interleucina-10/fisiología , Interleucina-12/biosíntesis , Macrófagos/inmunología , Monocinas/biosíntesis , Monocinas/genética , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas/metabolismo , ARN Mensajero/biosíntesis , Elementos de Respuesta , Transactivadores/metabolismo , Transcripción GenéticaRESUMEN
Among vaccine-preventable diseases, measles is the preeminent killer of children worldwide. Infection with measles virus (MV) is associated with prolonged suppression of cell-mediated immune responses, a phenomenon that is thought to underlie the susceptibility to secondary infections that accounts for most measles-related mortality. Interleukin (IL)-12 is critical for the orchestration of cellular immunity. MV specifically ablates IL-12 production by monocyte/macrophages in vitro through binding to CD46, a complement regulatory protein that is an MV receptor. To address the effect of MV on IL-12 responses in vivo, cytokine production was examined in Gambian patients with measles. IL-12 production by peripheral blood monocytes from such patients is markedly suppressed, which provides a unifying mechanism for many of the immunologic abnormalities associated with measles. This suppression is prolonged, with significant, stimulus-specific inhibition of IL-12 production demonstrable months after recovery from acute infection. However, despite this suppression, IL-12 responsiveness remains intact.
Asunto(s)
Interleucina-12/biosíntesis , Sarampión/inmunología , Adolescente , Adulto , Antígenos CD/metabolismo , Niño , Preescolar , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Gambia , Humanos , Lactante , Interferón gamma/biosíntesis , Macrófagos/inmunología , Masculino , Vacuna Antisarampión , Proteína Cofactora de Membrana , Glicoproteínas de Membrana/metabolismo , Monocitos/inmunología , Linfocitos T Citotóxicos/inmunologíaRESUMEN
Interferon-beta is a remarkably pleiotropic molecule. Antiviral, pro- and antiproliferative, pro- and antiapoptotic, and complex immunoregulatory activities have all been described. The precise mechanism(s) that underlie the beneficial effects of interferon-beta in multiple sclerosis remain poorly understood; this has hindered progress in the search for more effective therapies. An increasing body of literature supports the hypothesis that interferon-beta-mediated changes in the production and activities of the immunoregulatory cytokines interleukin-12 and interleukin-10 are important to the therapeutic benefits of interferon-beta in multiple sclerosis. These data are reviewed here.