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1.
J Allergy Clin Immunol ; 144(2): 561-573.e6, 2019 08.
Article in English | MEDLINE | ID: mdl-30928652

ABSTRACT

BACKGROUND: IL-33, levels of which are known to be increased in patients with eosinophilic asthma and which is suggested as a therapeutic target for it, activates endothelial cells in which Sry-related high-mobility-group box (Sox) 17, an endothelium-specific transcription factor, was upregulated. OBJECTIVE: We investigated the relationship between Sox17 and IL-33 and the possible role of Sox17 in the pathogenesis of asthma using a mouse model of airway inflammation. METHODS: We used ovalbumin (OVA) to induce airway inflammation in endothelium-specific Sox17 null mutant mice and used IL-33 neutralizing antibody to evaluate the interplay between IL-33 and Sox17. We evaluated airway inflammation and measured levels of various cytokines, chemokines, and adhesion molecules. We also carried out loss- or gain-of-function experiments for Sox17 in human endothelial cells. RESULTS: Levels of IL-33 and Sox17 were significantly increased in the lungs of OVA-challenged mice. Anti-IL-33 neutralizing antibody treatment attenuated not only OVA-induced airway inflammation but also Sox17 expression in pulmonary endothelial cells. Importantly, endothelium-specific deletion of Sox17 resulted in significant alleviation of various clinical features of asthma, including airway inflammation, immune cell infiltration, cytokine/chemokine production, and airway hyperresponsiveness. Sox17 deletion also resulted in decreased densities of Ly6chigh monocytes and inflammatory dendritic cells in the lungs. In IL-33-stimulated human endothelial cells, Sox17 showed positive correlation with CCL2 and intercellular adhesion molecule 1 levels. Lastly, Sox17 promoted monocyte adhesion to endothelial cells and upregulated the extracellular signal-regulated kinase-signal transducer and activator of transcription 3 pathway. CONCLUSION: Sox17 was regulated by IL-33, and its genetic ablation in endothelial cells resulted in alleviation of asthma-related pathophysiologic features. Sox17 might be a potential target for asthma management.


Subject(s)
Asthma/immunology , Endothelium, Vascular/immunology , HMGB Proteins/immunology , Lung/immunology , SOXF Transcription Factors/immunology , Animals , Asthma/genetics , Asthma/pathology , Chemokines/genetics , Chemokines/immunology , Endothelium, Vascular/pathology , HMGB Proteins/genetics , Humans , Inflammation/genetics , Inflammation/immunology , Inflammation/pathology , Interleukin-33/genetics , Interleukin-33/immunology , Lung/pathology , Mice , Mice, Mutant Strains , SOXF Transcription Factors/genetics
2.
J Immunol ; 194(5): 2424-38, 2015 Mar 01.
Article in English | MEDLINE | ID: mdl-25653427

ABSTRACT

Human and murine studies showed that GM-CSF exerts beneficial effects in intestinal inflammation. To explore whether GM-CSF mediates its effects via monocytes, we analyzed effects of GM-CSF on monocytes in vitro and assessed the immunomodulatory potential of GM-CSF-activated monocytes (GMaMs) in vivo. We used microarray technology and functional assays to characterize GMaMs in vitro and used a mouse model of colitis to study GMaM functions in vivo. GM-CSF activates monocytes to increase adherence, migration, chemotaxis, and oxidative burst in vitro, and primes monocyte response to secondary microbial stimuli. In addition, GMaMs accelerate epithelial healing in vitro. Most important, in a mouse model of experimental T cell-induced colitis, GMaMs show therapeutic activity and protect mice from colitis. This is accompanied by increased production of IL-4, IL-10, and IL-13, and decreased production of IFN-γ in lamina propria mononuclear cells in vivo. Confirming this finding, GMaMs attract T cells and shape their differentiation toward Th2 by upregulating IL-4, IL-10, and IL-13 in T cells in vitro. Beneficial effects of GM-CSF in Crohn's disease may possibly be mediated through reprogramming of monocytes to simultaneously improved bacterial clearance and induction of wound healing, as well as regulation of adaptive immunity to limit excessive inflammation.


Subject(s)
Adaptive Immunity/drug effects , Colitis/drug therapy , Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology , Intestine, Large/drug effects , Monocytes/drug effects , Adoptive Transfer , Animals , Cell Adhesion/drug effects , Chemotaxis/drug effects , Colitis/immunology , Colitis/pathology , Gene Expression Regulation , Humans , Interferon-gamma/pharmacology , Interleukin-10/genetics , Interleukin-10/immunology , Interleukin-13/genetics , Interleukin-13/immunology , Interleukin-4/genetics , Interleukin-4/immunology , Interleukin-4/pharmacology , Intestine, Large/immunology , Intestine, Large/pathology , Mice , Mice, Knockout , Monocytes/cytology , Monocytes/immunology , Primary Cell Culture , Respiratory Burst/drug effects , SOXF Transcription Factors/deficiency , SOXF Transcription Factors/genetics , SOXF Transcription Factors/immunology , Signal Transduction , T-Lymphocytes/immunology , T-Lymphocytes/pathology , T-Lymphocytes/transplantation
3.
Methods Mol Biol ; 1222: 175-80, 2015.
Article in English | MEDLINE | ID: mdl-25287346

ABSTRACT

During the last decade it has been shown that most mammalian blastocysts consisted of three cell lineages. Immunofluorescence with multiple antibodies enables to identify each cell type allowing an easy detection of eventual defects. It is complementary to RT-PCR experiments as this technique allows to look at cell position and to analyze and count the proportions between the different cell types. Thus after any kind of embryo manipulation such as nuclear transfer (NT), the analysis of the three cell lineages by immunofluorescence will provide criteria for good or poor development.


Subject(s)
Blastocyst/cytology , Immunohistochemistry , Animals , Biomarkers/metabolism , CDX2 Transcription Factor , Cell Death , Cell Lineage , GATA6 Transcription Factor/immunology , Homeodomain Proteins/immunology , Mice , Molecular Imaging/instrumentation , Molecular Imaging/methods , Nanog Homeobox Protein , SOXF Transcription Factors/immunology , Transcription Factors/immunology
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