PMID- 26861999
OWN - NLM
STAT- MEDLINE
DCOM- 20161213
LR  - 20161230
IS  - 1879-0542 (Electronic)
IS  - 0165-2478 (Linking)
VI  - 171
DP  - 2016 Mar
TI  - The anti-proliferative effect of cation channel blockers in T lymphocytes depends 
      on the strength of mitogenic stimulation.
PG  - 60-9
LID - S0165-2478(16)30012-8 [pii]
LID - 10.1016/j.imlet.2016.02.003 [doi]
AB  - 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-gamma secretion, cellular 
      viability and proliferation. Our results showed that ion channel blockers and 
      rapamycin inhibit IL-10 and IFN-gamma 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.
CI  - Copyright (c) 2016 European Federation of Immunological Societies. Published by 
      Elsevier B.V. All rights reserved.
FAU - Petho, Zoltan
AU  - Petho Z
AD  - Department of Biophysics and Cell Biology, Faculty of General Medicine, 
      University of Debrecen, Debrecen, Hungary.
FAU - Balajthy, Andras
AU  - Balajthy A
AD  - Department of Biophysics and Cell Biology, Faculty of General Medicine, 
      University of Debrecen, Debrecen, Hungary.
FAU - Bartok, Adam
AU  - Bartok A
AD  - Department of Biophysics and Cell Biology, Faculty of General Medicine, 
      University of Debrecen, Debrecen, Hungary.
FAU - Bene, Krisztian
AU  - Bene K
AD  - Department of Immunology, Faculty of General Medicine, University of Debrecen, 
      Debrecen, Hungary.
FAU - Somodi, Sandor
AU  - Somodi S
AD  - 1st Department of Internal Medicine, University of Debrecen, Debrecen, Hungary.
FAU - Szilagyi, Orsolya
AU  - Szilagyi O
AD  - Department of Biophysics and Cell Biology, Faculty of General Medicine, 
      University of Debrecen, Debrecen, Hungary.
FAU - Rajnavolgyi, Eva
AU  - Rajnavolgyi E
AD  - Department of Immunology, Faculty of General Medicine, University of Debrecen, 
      Debrecen, Hungary.
FAU - Panyi, Gyorgy
AU  - Panyi G
AD  - Department of Biophysics and Cell Biology, Faculty of General Medicine, 
      University of Debrecen, Debrecen, Hungary. Electronic address: 
      panyi@med.unideb.hu.
FAU - Varga, Zoltan
AU  - Varga Z
AD  - 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 ter 1, H-4032, Hungary.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160206
PL  - Netherlands
TA  - Immunol Lett
JT  - Immunology letters
JID - 7910006
RN  - 0 (Boron Compounds)
RN  - 0 (Calcium Channel Blockers)
RN  - 0 (Calcium Release Activated Calcium Channels)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Intermediate-Conductance Calcium-Activated Potassium Channels)
RN  - 0 (KCNN4 protein, human)
RN  - 0 (Kv1.3 Potassium Channel)
RN  - 0 (Mitogens)
RN  - 0 (Pyrazoles)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - 0 (TRAM 34)
RN  - 207137-56-2 (Interleukin-4)
RN  - 82115-62-6 (Interferon-gamma)
RN  - E4ES684O93 (2-aminoethoxydiphenyl borate)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Boron Compounds/pharmacology
MH  - Calcium Channel Blockers/*pharmacology
MH  - Calcium Release Activated Calcium Channels/*antagonists & inhibitors
MH  - Cell Proliferation/*drug effects
MH  - Cells, Cultured
MH  - Drug Synergism
MH  - Humans
MH  - Immunosuppressive Agents/pharmacology
MH  - Interferon-gamma/metabolism
MH  - Interleukin-4/metabolism
MH  - Intermediate-Conductance Calcium-Activated Potassium Channels/*antagonists & 
      inhibitors
MH  - Kv1.3 Potassium Channel/*antagonists & inhibitors
MH  - Lymphocyte Activation/*drug effects
MH  - Mitogens/immunology
MH  - Pyrazoles/pharmacology
MH  - Receptors, Antigen, T-Cell/metabolism
MH  - Sirolimus/pharmacology
MH  - T-Lymphocytes/*drug effects/physiology
OTO - NOTNLM
OT  - Cellular proliferation
OT  - Cytokine secretion
OT  - Immune regulation
OT  - Ion channel
OT  - Rapamycin
OT  - T cells
EDAT- 2016/02/11 06:00
MHDA- 2016/12/15 06:00
CRDT- 2016/02/11 06:00
PHST- 2015/12/08 00:00 [received]
PHST- 2016/01/29 00:00 [revised]
PHST- 2016/02/04 00:00 [accepted]
PHST- 2016/02/11 06:00 [entrez]
PHST- 2016/02/11 06:00 [pubmed]
PHST- 2016/12/15 06:00 [medline]
AID - S0165-2478(16)30012-8 [pii]
AID - 10.1016/j.imlet.2016.02.003 [doi]
PST - ppublish
SO  - Immunol Lett. 2016 Mar;171:60-9. doi: 10.1016/j.imlet.2016.02.003. Epub 2016 Feb 
      6.