分类: 生物学 >> 生物物理学 >> 免疫学 提交时间: 2016-05-12
摘要: Scavenger receptor class B, member 2 (SCARB2) is essential for endosome biogenesis and reorganization and serves as a receptor for both beta-glucocerebrosidase and enterovirus 71. However, little is known about its function in innate immune cells. In this study, we show that, among human peripheral blood cells, SCARB2 is most highly expressed in plasmacytoid dendritic cells (pDCs), and its expression is further upregulated by CpG oligodeoxynucleotide stimulation. Knockdown of SCARB2 in pDC cell line GEN2.2 dramatically reduces CpG-induced type I IFN production. Detailed studies reveal that SCARB2 localizes in late endosome/lysosome of pDCs, and knockdown of SCARB2 does not affect CpG oligodeoxynucleotide uptake but results in the retention of TLR9 in the endoplasmic reticulum and an impaired nuclear translocation of IFN regulatory factor 7. The IFN-I production by TLR7 ligand stimulation is also impaired by SCARB2 knockdown. However, SCARB2 is not essential for influenza virus or HSV-induced IFN-I production. These findings suggest that SCARB2 regulates TLR9-dependent IFN-I production of pDCs by mediating endosomal translocation of TLR9 and nuclear translocation of IFN regulatory factor 7.
分类: 生物学 >> 生物物理学 提交时间: 2016-05-11
摘要: CD24 is overexpressed in nearly 70% human cancers, whereas TP53 is the most frequently mutated tumour-suppressor gene that functions in a context-dependent manner. Here we show that both targeted mutation and short hairpin RNA (shRNA) silencing of CD24 retard the growth, progression and metastasis of prostate cancer. CD24 competitively inhibits ARF binding to NPM, resulting in decreased ARF, increase MDM2 and decrease levels of p53 and the p53 target p21/CDKN1A. CD24 silencing prevents functional inactivation of p53 by both somatic mutation and viral oncogenes, including the SV40 large T antigen and human papilloma virus 16 E6-antigen. In support of the functional interaction between CD24 and p53, in silico analyses reveal that TP53 mutates at a higher rate among glioma and prostate cancer samples with higher CD24 mRNA levels. These data provide a general mechanism for functional inactivation of ARF and reveal an important cellular context for genetic and viral inactivation of TP53.
分类: 生物学 >> 生物物理学 >> 免疫学 提交时间: 2016-05-05
摘要: Development of therapeutic vaccines/strategies to control chronic hepatitis B virus (HBV) infection has been challenging because of HBV-induced tolerance. In this study, we explored strategies for breaking tolerance and restoring the immune response to the HBV surface Ag in tolerant mice. We demonstrated that immune tolerance status is attributed to the level and duration of circulating HBsAg in HBV carrier models. Removal of circulating HBsAg by a monoclonal anti-HBsAg Ab in tolerant mice could gradually reduce tolerance and reestablish B cell and CD4(+) T cell responses to subsequent Engerix-B vaccination, producing protective IgG. Furthermore, HBsAg-specific CD8(+) T cells induced by the addition of a TLR agonist resulted in clearance of HBV in both serum and liver. Thus, generation of protective immunity can be achieved by clearing extracellular viral Ag with neutralizing Abs followed by vaccination.