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1.
Oncotarget ; 5(10): 3220-33, 2014 May 30.
Article in English | MEDLINE | ID: mdl-24952599

ABSTRACT

Survival of colorectal cancer patients is strongly dependent on development of distant metastases. S100A4 is a prognostic biomarker and inducer for colorectal cancer metastasis. Besides exerting intracellular functions, S100A4 is secreted extracellularly. The receptor for advanced glycation end products (RAGE) is one of its interaction partners. The impact of the S100A4-RAGE interaction for cell motility and metastasis formation in colorectal cancer has not been elucidated so far. Here we demonstrate the RAGE-dependent increase in migratory and invasive capabilities of colorectal cancer cells via binding to extracellular S100A4. We show the direct interaction of S100A4 and RAGE, leading to hyperactivated MAPK/ERK and hypoxia signaling. The S100A4-RAGE axis increased cell migration (P<0.005) and invasion (P<0.005), which was counteracted with recombinant soluble RAGE and RAGE-specific antibodies. In colorectal cancer patients, not distantly metastasized at surgery, high RAGE expression in primary tumors correlated with metachronous metastasis, reduced overall (P=0.022) and metastasis-free survival (P=0.021). In summary, interaction of S100A4-RAGE mediates S100A4-induced colorectal cancer cell motility. RAGE by itself represents a biomarker for prognosis of colorectal cancer. Thus, therapeutic approaches targeting RAGE or intervening in S100A4-RAGE-dependent signaling early in tumor progression might represent alternative strategies restricting S100A4-induced colorectal cancer metastasis.


Subject(s)
Adenocarcinoma/pathology , Cell Hypoxia/physiology , Colorectal Neoplasms/pathology , MAP Kinase Signaling System/physiology , Receptor for Advanced Glycation End Products/metabolism , S100 Proteins/metabolism , Adenocarcinoma/metabolism , Biomarkers, Tumor/analysis , Blotting, Western , Cell Line, Tumor , Cell Movement , Colorectal Neoplasms/metabolism , Enzyme-Linked Immunosorbent Assay , Humans , Immunohistochemistry , Neoplasm Invasiveness/pathology , Prognosis , Real-Time Polymerase Chain Reaction , S100 Calcium-Binding Protein A4 , Signal Transduction/physiology , Transfection
2.
Proc Natl Acad Sci U S A ; 111(25): 9229-34, 2014 Jun 24.
Article in English | MEDLINE | ID: mdl-24927527

ABSTRACT

In the bone marrow, a population of memory T cells has been described that promotes efficient secondary immune responses and has been considered to be preactivated, owing to its expression of CD69 and CD25. Here we show that human bone marrow professional memory T cells are not activated but are resting in terms of proliferation, transcription, and mobility. They are in the G0 phase of the cell cycle, and their transcriptome is that of resting T cells. The repertoire of CD4(+) bone marrow memory T cells compared with CD4(+) memory T cells from the blood is significantly enriched for T cells specific for cytomegalovirus-pp65 (immunodominant protein), tetanus toxoid, measles, mumps, and rubella. It is not enriched for vaccinia virus and Candida albicans-MP65 (immunodominant protein), typical pathogens of skin and/or mucosa. CD4(+) memory T cells specific for measles are maintained nearly exclusively in the bone marrow. Thus, CD4(+) memory T cells from the bone marrow provide long-term memory for systemic pathogens.


Subject(s)
Antigens, CD/immunology , Antigens, Differentiation, T-Lymphocyte/immunology , Bone Marrow Cells/immunology , CD4-Positive T-Lymphocytes/immunology , Immunologic Memory/physiology , Interleukin-2 Receptor alpha Subunit/immunology , Lectins, C-Type/immunology , Resting Phase, Cell Cycle/immunology , Adult , Bone Marrow Cells/cytology , CD4-Positive T-Lymphocytes/cytology , Female , Humans , Male , Middle Aged
4.
Eur J Immunol ; 43(5): 1231-42, 2013 May.
Article in English | MEDLINE | ID: mdl-23423996

ABSTRACT

Immunoglobulin E (IgE) production is tightly regulated at the cellular and genetic levels and is believed to be central to allergy development. At least two cellular pathways exist that lead to systemic anaphylaxis reactions in vivo: IgE-sensitized mast cells and IgG1-sensitized basophils. Passive anaphylaxis, by application of allergen and allergen-specific antibodies in mice, indicates a differential contribution of immunoglobulin isotypes to anaphylaxis. However, analysis of a dynamic immunization-mediated antibody response in anaphylaxis is difficult. Here, we generated IgE knock-in mice (IgE(ki) ), which express the IgE heavy chain instead of IgG1, in order to analyze the contribution of IgG1 and IgE to active anaphylaxis in vivo. IgE(ki) mice display increased IgE production both in vitro and in vivo. The sensitization of IgE(ki) mice by immunization followed by antigen challenge leads to increased anaphylaxis. Homozygous IgE(ki) mice, which lack IgG1 due to the knock-in strategy, are most susceptible to active systemic anaphylaxis. The depletion of basophils demonstrates their importance in IgE-mediated anaphylaxis. Therefore, we propose that an enhanced, antigen-specific, polyclonal IgE response, as is the case in allergic patients, is probably the most efficient way to sensitize basophils to contribute to systemic anaphylaxis in vivo.


Subject(s)
Anaphylaxis/immunology , Anaphylaxis/pathology , Basophils/immunology , Basophils/pathology , Immunoglobulin E/immunology , Immunoglobulin G/immunology , Allergens/administration & dosage , Allergens/immunology , Anaphylaxis/genetics , Animals , Antibodies, Monoclonal/biosynthesis , Antibodies, Monoclonal/immunology , Gene Knock-In Techniques , Homozygote , Humans , Immunization , Immunoglobulin E/genetics , Immunoglobulin G/genetics , Mast Cells/immunology , Mast Cells/pathology , Mice , Ovalbumin/administration & dosage , Ovalbumin/immunology , Severity of Illness Index
5.
Eur J Immunol ; 43(3): 793-804, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23255246

ABSTRACT

Cytokine memory for IFN-γ production by effector/memory Th1 cells plays a key role in both protective and pathological immune responses. To understand the epigenetic mechanism determining the ontogeny of effector/memory Th1 cells characterized by stable effector functions, we identified a T-cell-specific methylation pattern at the IFNG promoter and CNS-1 in ex vivo effector/memory Th1 cells, and investigated methylation dynamics of these regions during the development of effector/memory Th1 cells. During Th1 differentiation, demethylation occurred at both the promoter and CNS-1 regions of IFNG as early as 16 h, and this process was independent of cell proliferation and DNA synthesis. Using an IFN-γ capture assay, we found early IFN-γ-producing cells from 2-day differentiating cultures acquired "permissive" levels of demethylation and developed into effector/memory Th1 cells undergoing progressive demethylation at the IFNG promoter and CNS-1 when induced by IL-12. Methylation levels of these regions in effector/memory Th1 cells of peripheral blood from rheumatoid arthritis patients correlated inversely with reduced frequencies of IFN-γ-producers, coincident with recruitment of effector/memory Th1 cells to the site of inflammation. Thus, after termination of TCR stimulation, IL-12 signaling potentiates the stable functional IFN-γ memory in effector/memory Th1 cells characterized by hypomethylation at the IFNG promoter and CNS-1.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , DNA Methylation , Immunologic Memory , Interferon-gamma/genetics , Regulatory Sequences, Nucleic Acid , Arthritis, Rheumatoid/genetics , Arthritis, Rheumatoid/immunology , Cell Differentiation , Cells, Cultured , Epigenesis, Genetic , Humans , Interferon-gamma/metabolism , Interleukin-12/metabolism , Promoter Regions, Genetic , Signal Transduction , Th1 Cells/cytology , Th1 Cells/immunology , Th1 Cells/metabolism
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