title: Differential expression and biochemical activity of the immune receptor Tim-3 in healthy and malignant human myeloid cells.
abstract: The T cell immunoglobulin and mucin domain 3 (Tim-3) is a plasma membrane-associated receptor which is involved in a variety of biological responses in human immune cells. It is highly expressed in most acute myeloid leukaemia (AML) cells and therefore may serve as a possible target for AML therapy. However, its biochemical activities in primary human AML cells remain unclear. We therefore analysed the total expression and surface presence of the Tim-3 receptor in primary human AML blasts and healthy primary human leukocytes isolated from human blood. We found that Tim-3 expression was significantly higher in primary AML cells compared to primary healthy leukocytes. Tim-3 receptor molecules were distributed largely on the surface of primary AML cells, whereas in healthy leukocytes Tim-3 protein was mainly expressed intracellularly. In primary human AML blasts, both Tim-3 agonistic antibody and galectin-9 (a Tim-3 natural ligand) significantly upregulated mTOR pathway activity. This was in line with increased accumulation of hypoxia-inducible factor 1 alpha (HIF-1α) and secretion of VEGF and TNF-α. Similar results were obtained in primary human healthy leukocytes. Importantly, in both types of primary cells, Tim-3-mediated effects were compared with those induced by lipopolysaccharide (LPS) and stem cell factor (SCF). Tim-3 induced comparatively moderate responses in both AML cells and healthy leukocytes. However, Tim-3, like LPS, mediated the release of both TNF-α and VEGF, while SCF induced mostly VEGF secretion and did not upregulate TNF-α release.
authors.affiliation: School of Pharmacy, University of Kent, Kent, ME4 4TB, United Kingdom.
authors.forename: Isabel
authors.initials: I
authors.lastname: Gonçalves Silva
authors.affiliation: School of Pharmacy, University of Kent, Kent, ME4 4TB, United Kingdom.
authors.forename: Bernhard F
authors.initials: BF
authors.lastname: Gibbs
authors.affiliation: Institute for Research in Biomedicine, Universita' della Svizzera Italiana (USI) 6500 Bellinzona, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Bardelli
authors.affiliation: Institute for Research in Biomedicine, Universita' della Svizzera Italiana (USI) 6500 Bellinzona, Switzerland.
authors.forename: Luca
authors.initials: L
authors.lastname: Varani
authors.affiliation: School of Pharmacy, University of Kent, Kent, ME4 4TB, United Kingdom.
authors.forename: Vadim V
authors.initials: VV
authors.lastname: Sumbayev
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D037161:Galectins / Q000737:chemistry; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D022423:Myeloid Cells / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D017434:Protein Structure, Tertiary; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D019089:Stem Cell Factor / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D037161:Galectins; D000072597:Hepatitis A Virus Cellular Receptor 2; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D019089:Stem Cell Factor; D058570:TOR Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C087000:EIF4EBP1 protein, human; C448908:HAVCR2 protein, human; C497442:HIF1A protein, human; C508600:IL6 protein, human; C105032:LGALS9 protein, human; C467484:VEGFA protein, human
keywords: Tim-3; acute myeloid leukaemia; myeloid cells