Differential expression and biochemical activity of the immune receptor Tim-3 in healthy and malignant human myeloid cells
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Isabel Gonçalves Silva1, Bernhard F. Gibbs1, Marco Bardelli2, Luca Varani2, Vadim V. Sumbayev1
1School of Pharmacy, University of Kent, Anson Building, Kent, ME4 4TB, United Kingdom
2Institute for Research in Biomedicine, Universita' della Svizzera italiana (USI) 6500 Bellinzona, Switzerland
Vadim V. Sumbayev, e-mail: [email protected]
Bernhard F. Gibbs, e-mail: [email protected]
Luca Varani, e-mail: [email protected]
Keywords: Tim-3, acute myeloid leukaemia, myeloid cells
Received: July 01, 2015 Accepted: September 04, 2015 Published: September 16, 2015
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.
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