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001-es BibID:BIBFORM048926
035-os BibID:PMID:24227782
Első szerző:Chimote, Ameet A.
Cím:Selective Inhibition of KCa3.1 Channels Mediates Adenosine Regulation of the Motility of Human T Cells / Ameet A. Chimote, Peter Hajdu, Vladimir Kucher, Nina Boiko, Zerrin Kuras, Orsolya Szilagyi, Yeo-Heung Yun, Laura Conforti
Dátum:2013
ISSN:0022-1767 1550-6606
Megjegyzések:Adenosine, a purine nucleoside, is present at high concentrations in tumors, where it contributes to the failure of immune cells to eliminate cancer cells. The mechanisms responsible for the immunosuppressive properties of adenosine are not fully understood. We tested the hypothesis that adenosine's immunosuppressive functions in human T lymphocytes are in part mediated via modulation of ion channels. The activity of T lymphocytes relies on ion channels. KCa3.1 and Kv1.3 channels control cytokine release and, together with TRPM7, regulate T cell motility. Adenosine selectively inhibited KCa3.1, but not Kv1.3 and TRPM7, in activated human T cells. This effect of adenosine was mainly mediated by A2A receptors, as KCa3.1 inhibition was reversed by SCH58261 (selective A2A receptor antagonist), but not by MRS1754 (A2B receptor antagonist), and it was mimicked by the A2A receptor agonist CGS21680. Furthermore, it was mediated by the cAMP/protein kinase A isoform (PKAI) signaling pathway, as adenylyl-cyclase and PKAI inhibition prevented adenosine effect on KCa3.1. The functional implication of the effect of adenosine on KCa3.1 was determined by measuring T cell motility on ICAM-1 surfaces. Adenosine and CGS21680 inhibited T cell migration. Comparable effects were obtained by KCa3.1 blockade with TRAM-34. Furthermore, the effect of adenosine on cell migration was abolished by pre-exposure to TRAM-34. Additionally, adenosine suppresses IL-2 secretion via KCa3.1 inhibition. Our data indicate that adenosine inhibits KCa3.1 in human T cells via A2A receptor and PKAI, thereby resulting in decreased T cell motility and cytokine release. This mechanism is likely to contribute to decreased immune surveillance in solid tumors.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Journal of Immunology. - 191 : 12 (2013), p. 6273-6280. -
További szerzők:Hajdu Péter (1975-) (biofizikus) Kucher, Vladimir Boiko, Nina Kuras, Zerrin Szilágyi Orsolya (1985-) (molekuláris biológus, biokémikus) Yun, YeoHeung Conforti, Laura
Pályázati támogatás:TÁMOP-4.2.4.A/2-11-1-2012-0001
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