Activation of invariant natural killer T cells in regional lymph nodes as new antigen-specific immunotherapy via induction of interleukin-21 and interferon-γ.

Invariant natural killer T (iNKT) cells play important immunoregulatory functions in allergen-induced airway hyperresponsiveness and inflammation. To clarify the role of iNKT cells in allergic rhinitis (AR), we generated bone marrow-derived dendritic cells (BMDCs), which were pulsed by ovalbumin (OVA) and α-galactosylceramide (OVA/α-GalCer-BMDCs) and administered into the oral submucosa of OVA-sensitized mice before nasal challenge. Nasal symptoms, level of OVA-specific immunoglobulin (IgE), and T helper type 2 (Th2) cytokine production in cervical lymph nodes (CLNs) were significantly ameliorated in wild-type (WT) mice treated with OVA/α-GalCer-BMDCs, but not in WT mice treated with OVA-BMDCs. These anti-allergic effects were not observed in Jα18(-/-) recipients that lack iNKT cells, even after similar treatment with OVA/α-GalCer-BMDCs in an adoptive transfer study with CD4(+) T cells and B cells from OVA-sensitized WT mice. In WT recipients of OVA/α-GalCer-BMDCs, the number of interleukin (IL)-21-producing iNKT cells increased significantly and the Th1/Th2 balance shifted towards the Th1 dominant state. Treatment with anti-IL-21 and anti-interferon (IFN)-γ antibodies abrogated these anti-allergic effects in mice treated with α-GalCer/OVA-BMDCs. These results suggest that activation of iNKT cells in regional lymph nodes induces anti-allergic effects through production of IL-21 or IFN-γ, and that these effects are enhanced by simultaneous stimulation with antigen. Thus, iNKT cells might be a useful target in development of new treatment strategies for AR.

Plant homeodomain finger protein 11 promotes class switch recombination to IgE in murine activated B cells.

BACKGROUND: Polymorphisms of the Plant homeodomain finger protein 11 (PHF11) are strongly associated with high serum IgE levels and clinical severity of atopic patients. However, the precise mechanism has not been fully elucidated. We investigated the role of Phf11 in class switch recombination (CSR) to IgE by activated B cells. METHODS: We generated Phf11 transgenic (Lckd-Phf11-Tg) mice that express the exogenous murine Phf11 in lymphocytes under the control of distal Lck promoter. We examined IL-4-induced CSR to IgE in activated Lckd-Phf11-Tg B cells in vitro. We analyzed production of ovalbumin (OVA)-specific IgE and nose-scratching symptoms in Lckd-Phf11-Tg mice using an OVA-induced allergic rhinitis model. RESULTS: The exogenous Phf11 promoted CSR to IgG1 and IgE in activated B cells with an increase in germ line transcript (GLT) γ1 and GLT ε expression. The exogenous Phf11 augmented transcriptional activity of the GLT γ1 and GLT ε promoters through permissive histone modifications and binding of NF-κB and STAT6. Furthermore, the exogenous Phf11 bound to the GLT ε promoter with increased binding of NF-κB. Silencing of the endogenous Phf11 reduced the frequency of CSR to IgE and GLT ε expression, but not to IgG1 or GLT γ1 expression, in activated B cells. In an allergic rhinitis model, Lckd-Phf11-Tg mice showed a significant increase in the production of OVA-specific IgE and the frequency of nose scratching. CONCLUSION: Phf11 accelerates CSR to IgE in activated B cells by increasing the transcriptional activity of GLT ε promoter and contributes to the exacerbation of allergic responses. These findings provide a novel therapeutic target for allergic diseases.

Tumour-suppressive microRNA-874 contributes to cell proliferation through targeting of histone deacetylase 1 in head and neck squamous cell carcinoma.

BACKGROUND: Our recent studies of microRNA (miRNA) expression signature demonstrated that microRNA-874 (miR-874) was significantly downregulated in maxillary sinus squamous cell carcinoma (MSSCC), and a putative tumour-suppressive miRNA in human cancers. Our aim of this study was to investigate the functional significance of miR-874 in cancer cells and to identify novel miR-874-mediated cancer pathways and responsible genes in head and neck squamous cell carcinoma (HNSCC). METHODS: Gain-of-function studies using mature miR-874 were performed to investigate cell proliferation and cell cycle distribution in HNSCC cell lines (SAS and FaDu). To identify miR-874-mediated molecular pathways and targets, we utilised gene expression analysis and in silico database analysis. Loss-of-function assays were performed to investigate the functional significance of miR-874 target genes. RESULTS: Expression levels of miR-874 were significantly downregulated in HNSCC tissues (including oral, pharyngeal and laryngeal SCCs) compared with normal counterpart epithelia. Restoration of miR-874 in SAS and FaDu cell lines revealed significant inhibition of cell proliferation and induction of G2/M arrest and cell apoptosis. Our expression data and in silico analysis demonstrated that miR-874 modulated the cell cycle pathway. Moreover, histone deacetylase 1 (HDAC1) was a candidate target of miR-874 regulation. Luciferase reporter assays showed that miR-874 directly regulated HDAC1. Silencing of the HDAC1 gene significantly inhibited cell proliferation and induced G2/M arrest and cell apoptosis in SAS cells. CONCLUSIONS: Downregulation of miR-874 was a frequent event in HNSCC. miR-874 acted as a tumour suppressor and directly targeted HDAC1. Recognition of tumour-suppressive miRNA-mediated cancer pathways provides new insights into the potential mechanisms of HNSCC oncogenesis and suggests novel therapeutic strategies for the disease.