ABSTRACT
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.
Subject(s)
B-Lymphocytes/immunology , Homeodomain Proteins/immunology , Immunoglobulin Class Switching/immunology , Immunoglobulin E/immunology , Lymphocyte Activation/immunology , Animals , Disease Models, Animal , Flow Cytometry , Mice , Mice, Inbred BALB C , Mice, Transgenic , Rhinitis, Allergic , Rhinitis, Allergic, Perennial/immunologyABSTRACT
Phosphodiesterases (PDEs) are important modulators of inflammation and wound healing. In this capacity, specific targeting of PDEs for the treatment of many diseases, including chronic obstructive pulmonary disease (COPD), has been investigated. Currently, treatment of COPD is suboptimal. PDE4 modulates the inflammatory response of the lung, and inhibition of PDE4 may be a novel, COPD-specific approach toward more effective treatment strategies. This review describes the state of PDE4-inhibitor therapy for use in COPD treatment.
Subject(s)
Drug Delivery Systems/trends , Phosphodiesterase 4 Inhibitors/administration & dosage , Pulmonary Disease, Chronic Obstructive/drug therapy , Pulmonary Disease, Chronic Obstructive/enzymology , Animals , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Drug Delivery Systems/methods , Humans , Treatment OutcomeABSTRACT
BACKGROUND: There is synteny in the CC-type chemokine gene clusters between humans (CCL2/MCP-1, CCL7MCP-3, CCL11/eotaxin, CCL8/MCP-2, CCL13/MCP-4, and CCL1/I-309) and mice (CCL2, CCL7, CCL11, CCL12/MCP-5, CCL8, and CCL1). OBJECTIVE: As many putative Bcl6/STAT-binding sequences are observed in the clusters, we examined the roles of a transcriptional repressor Bcl6 and the regional histone modification in the expression of these chemokine genes in pulmonary epithelium. METHODS: We generated transgenic (Tg) mice carrying the Bcl6 or the dominant-negative (DN)-Bcl6 gene under the control of the surfactant protein C (SPC) promoter that induces the exogenous gene expression in the distal lung epithelium. For in vitro studies, A549, alveolar type II-like epithelial cell line transfected with the SPC-DN-Bcl6 gene were stimulated with IL-4+TNF-α, and Bcl6 or STAT6 binding to and histone modification of the cluster in the transfectants were analysed by chromatin immunoprecipitation assays. Tg mice sensitized with ovalbumin (OVA) were challenged with OVA inhalation. The amounts of mRNAs in each sample were analysed by quantitative RT-PCR. RESULTS: The amount of Bcl6 bound to the cluster decreased in A549 cells stimulated with IL-4 and TNF-α, whereas STAT6 binding increased in association with regional histone H3-K9/14 acetylation and H3-K4 methylation. The expression of all chemokine genes in the gene cluster was augmented in activated A549 cells transfected with the DN-Bcl6 gene. We also induced allergic airway inflammation in Tg mice. Expression of the chemokine genes and infiltrated cell numbers in the lungs of these Tg mice with allergic airway inflammation were inversely correlated with the amount of Bcl6 in the lungs. CONCLUSION AND CLINICAL RELEVANCE: Expression of the pulmonary epithelium-derived CC-type chemokine genes in the cluster is orchestrated by the conserved machinery related to Bcl6. Thus, Bcl6 in pulmonary epithelium may be a critical regulator for pathogenesis of various pulmonary inflammatory diseases.
Subject(s)
Chemokines, CC/genetics , DNA-Binding Proteins/metabolism , Epithelial Cells/metabolism , Lung/metabolism , Respiratory Hypersensitivity/genetics , Respiratory Hypersensitivity/immunology , Animals , Antigens/immunology , Binding Sites , Cell Line , Chemokines, CC/immunology , DNA-Binding Proteins/genetics , Epithelial Cells/immunology , Gene Expression , Gene Expression Regulation , Gene Order , Histones/metabolism , Humans , Inflammation/genetics , Inflammation/immunology , Lung/immunology , Lung/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Ovalbumin/immunology , Proto-Oncogene Proteins c-bcl-6Subject(s)
Kidney Diseases/etiology , Liver Diseases/etiology , Pleural Effusion/etiology , Pulmonary Embolism/etiology , Sclerosing Solutions/adverse effects , Esophageal and Gastric Varices/therapy , Female , Humans , Kidney Diseases/prevention & control , Liver Diseases/prevention & control , Middle Aged , Pleural Effusion/prevention & control , Pulmonary Embolism/prevention & control , RiskABSTRACT
Cefoxitin (CFX) was administered to 13 patients who were admitted to the surgical ward of the hospital. The results of the study as follows; Disc susceptibility tests of the 11 strains isolated from the patients to antibiotic were performed and 10 strains showed good susceptibility to CFX. The clinical response was good in all 4 patients with surgical infections. It is noted that 1 patient with mixed infection caused by E. coli, Clostridium sp. and Bacteroides sp. showed good response to CFX. Out of 9 patients treated with CFX for prophylaxis of postoperative infections, 8 patients responded effectively to CFX, and clinical efficacy rate was 88.9%. No side effects were noted due to CFX. It is considered from these results of the study that CFX is a highly effective and safe drug for treatment of infections and for the prevention of postoperative infections in surgery.
