RESUMO
Prion-induced chronic neurodegeneration has a substantial inflammatory component, and the activation of glia cells may play an important role in disease development and progression. However, the functional contribution of cytokines to the development of the gliosis in vivo was never systematically studied. We report here that the expression of interleukin-1beta (IL-1beta), IL-1beta-converting enzyme, and IL-1 receptor type 1 (IL-1RI) is up-regulated in a murine scrapie model. The scrapie-induced gliosis in IL-1RI(-/-) mice was characterized by an attenuated activation of astrocytes in the asymptomatic stage of the disease and a reduced expression of CXCR3 ligands. Furthermore, the accumulation of the misfolded isoform of the prion protein PrP(Sc) was significantly delayed in the IL-1RI(-/-) mice. These observations indicate that IL-1 is a driver of the scrapie-associated astrocytosis and possibly the accompanying amyloid deposition. In addition, scrapie-infected IL-1RI-deficient (IL-1RI(-/-)) mice showed a delayed disease onset and significantly prolonged survival times suggesting that an anti-inflammatory therapeutical approach to suppress astrocyte activation and/or glial IL-1 expression may help to delay disease onset in established prion infections of the central nervous system.
Assuntos
Astrócitos/metabolismo , Caspase 1/metabolismo , Gliose/etiologia , Interleucina-1/metabolismo , Doenças Priônicas/metabolismo , Receptores de Interleucina-1/fisiologia , Animais , Astrócitos/patologia , Modelos Animais de Doenças , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/patologia , Proteínas PrPSc/metabolismo , Doenças Priônicas/patologia , Receptores CXCR3 , Receptores de Quimiocinas/metabolismo , Receptores de Interleucina-1/genética , Receptores Tipo I de Interleucina-1 , Taxa de Sobrevida , Regulação para CimaRESUMO
We identified cDNAs coding for homologues to tetrapod prion proteins (PrPs) in Atlantic salmon (Salmo salar) and Japanese pufferfish (Fugu rubripes), which were termed 'similar to PrPs' (stPrPs). Besides significant sequence homologies the fish stPrPs display characteristic structural features in common with tetrapod PrPs. In addition, two stPrPs were shown to be highly expressed in brain tissue. None of the so far identified PrP-homologues of fish resembles doppel. Hence, the duplication of the PrP gene, which generated doppel, may have occurred not in fish but later in the tetrapod lineage. The identification of fish PrPs provides a basis to address concerns about a possible susceptibility of fish to prion infections.
