title: The anti-proliferative effect of cation channel blockers in T lymphocytes depends on the strength of mitogenic stimulation.
abstract: Ion channels are crucially important for the activation and proliferation of T lymphocytes, and thus, for the function of the immune system. Previous studies on the effects of channel blockers on T cell proliferation reported variable effectiveness due to differing experimental systems. Therefore our aim was to investigate how the strength of the mitogenic stimulation influences the efficiency of cation channel blockers in inhibiting activation, cytokine secretion and proliferation of T cells under standardized conditions. Human peripheral blood lymphocytes were activated via monoclonal antibodies targeting the TCR-CD3 complex and the co-stimulator CD28. We applied the blockers of Kv1.3 (Anuroctoxin), KCa3.1 (TRAM-34) and CRAC (2-Apb) channels of T cells either alone or in combination with rapamycin, the inhibitor of the mammalian target of rapamycin (mTOR). Five days after the stimulation ELISA and flow cytometric measurements were performed to determine IL-10 and IFN-γ secretion, cellular viability and proliferation. Our results showed that ion channel blockers and rapamycin inhibit IL-10 and IFN-γ secretion and cell division in a dose-dependent manner. Simultaneous application of the blockers for each channel along with rapamycin was the most effective, indicating synergy among the various activation pathways. Upon increasing the extent of mitogenic stimulation the anti-proliferative effect of the ion channel blockers diminished. This phenomenon may be important in understanding the fine-tuning of T cell activation.
authors: Department of Biophysics and Cell Biology, Faculty of General Medicine, University of Debrecen, Debrecen, Hungary.
authors: Zoltan
authors: Z
authors: Petho
authors: Department of Biophysics and Cell Biology, Faculty of General Medicine, University of Debrecen, Debrecen, Hungary.
authors: Andras
authors: A
authors: Balajthy
authors: Department of Biophysics and Cell Biology, Faculty of General Medicine, University of Debrecen, Debrecen, Hungary.
authors: Adam
authors: A
authors: Bartok
authors: Department of Immunology, Faculty of General Medicine, University of Debrecen, Debrecen, Hungary.
authors: Krisztian
authors: K
authors: Bene
authors: 1st Department of Internal Medicine, University of Debrecen, Debrecen, Hungary.
authors: Sandor
authors: S
authors: Somodi
authors: Department of Biophysics and Cell Biology, Faculty of General Medicine, University of Debrecen, Debrecen, Hungary.
authors: Orsolya
authors: O
authors: Szilagyi
authors: Department of Immunology, Faculty of General Medicine, University of Debrecen, Debrecen, Hungary.
authors: Eva
authors: E
authors: Rajnavolgyi
authors: Department of Biophysics and Cell Biology, Faculty of General Medicine, University of Debrecen, Debrecen, Hungary. Electronic address: panyi@med.unideb.hu.
authors: Gyorgy
authors: G
authors: Panyi
authors: Department of Biophysics and Cell Biology, Faculty of General Medicine, University of Debrecen, Debrecen, Hungary; MTA-DE-NAP B Ion Channel Structure-Function Research Group, RCMM, University of Debrecen, Debrecen, Egyetem tér 1, H-4032, Hungary.
authors: Zoltan
authors: Z
authors: Varga
mesh_terms: D001896:Boron Compounds / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D000071739:Calcium Release Activated Calcium Channels / Q000037:antagonists & inhibitors*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004357:Drug Synergism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors*; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008934:Mitogens / Q000276:immunology; D011720:Pyrazoles / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000502:physiology
chemical_list: D001896:Boron Compounds; D002121:Calcium Channel Blockers; D000071739:Calcium Release Activated Calcium Channels; D007166:Immunosuppressive Agents; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; D051664:Kv1.3 Potassium Channel; D008934:Mitogens; D011720:Pyrazoles; D011948:Receptors, Antigen, T-Cell; C411671:TRAM 34; D015847:Interleukin-4; D007371:Interferon-gamma; C109986:2-aminoethoxydiphenyl borate; D020123:Sirolimus
keywords: Cellular proliferation; Cytokine secretion; Immune regulation; Ion channel; Rapamycin; T cells