PMID- 26611796 OWN - NLM STAT- MEDLINE DCOM- 20161213 LR - 20181202 IS - 1435-1463 (Electronic) IS - 0300-9564 (Linking) VI - 123 IP - 3 DP - 2016 Mar TI - Normal human CD4(+) helper T cells express Kv1.1 voltage-gated K(+) channels, and selective Kv1.1 block in T cells induces by itself robust TNFalpha production and secretion and activation of the NFkappaB non-canonical pathway. PG - 137-57 LID - 10.1007/s00702-015-1446-9 [doi] AB - TNFalpha is a very potent and pleiotropic pro-inflammatory cytokine, essential to the immune system for eradicating cancer and microorganisms, and to the nervous system, for brain development and ongoing function. Yet, excess and/or chronic TNFalpha secretion causes massive tissue damage in autoimmune, inflammatory and neurological diseases and injuries. Therefore, many patients with autoimmune/inflammatory diseases receive anti-TNFalpha medications. TNFalpha is secreted primarily by CD4(+) T cells, macrophages, monocytes, neutrophils and NK cells, mainly after immune stimulation. Yet, the cause for the pathologically high and chronic TNFalpha secretion is unknown. Can blocking of a particular ion channel in T cells induce by itself TNFalpha secretion? Such phenomenon was never revealed or even hypothesized. In this interdisciplinary study we discovered that: (1) normal human T cells express Kv1.1 voltage-gated potassium channel mRNA, and the Kv1.1 membrane-anchored protein channel; (2) Kv1.1 is expressed in most CD4(+)CD3(+) helper T cells (mean CD4(+)CD3(+)Kv1.1(+) T cells of 7 healthy subjects: 53.09 +/- 22.17 %), but not in CD8(+)CD3(+) cytotoxic T cells (mean CD8(+)CD3(+)Kv1.1(+) T cells: 4.12 +/- 3.04 %); (3) electrophysiological whole-cell recordings in normal human T cells revealed Kv currents; (4) Dendrotoxin-K (DTX-K), a highly selective Kv1.1 blocker derived from snake toxin, increases the rate of rise and decay of Kv currents in both resting and activated T cells, without affecting the peak current; (5) DTX-K by itself induces robust TNFalpha production and secretion by normal human T cells, without elevating IFNgamma, IL-4 and IL-10; (6) intact Ca(2+) channels are required for DTX-induced TNFalpha secretion; (7) selective anti-Kv1.1 antibodies also induce by themselves TNFalpha secretion; (8) DTX-K activates NFkappaB in normal human T cells via the unique non-canonical-pathway; (9) injection of Kv1.1-blocked human T cells to SCID mice, causes recruitment of resident mouse cells into the liver, alike reported after TNFalpha injection into the brain. Based on our discoveries we speculate that abnormally blocked Kv1.1 in T cells (and other immune cells?), due to either anti-Kv1.1 autoimmune antibodies, or Kv1.1-blocking toxins alike DTX-K, or Kv1.1-blocking genetic mutations, may be responsible for the chronic/excessive TNFalpha in autoimmune/inflammatory diseases. Independently, we also hypothesize that selective block of Kv1.1 in CD4(+) T cells of patients with cancer or chronic infectious diseases could be therapeutic, since it may: a. augment beneficial secretion and delivery of TNFalpha to the disease-affected sites; b. induce recruitment and extravasation of curative immune cells and factors; c. improve accessibility of drugs to the brain and few peripheral organs thanks to TNFalpha-induced increased permeability of organ's barriers. FAU - Fellerhoff-Losch, Barbara AU - Fellerhoff-Losch B AD - Immunis e.V. and Immunotherapy Research Center, Munich, Bavaria, Germany. FAU - Korol, Sergiy V AU - Korol SV AD - Department of Neuroscience, Uppsala University, Uppsala, Sweden. FAU - Ganor, Yonatan AU - Ganor Y AD - Department of Infection, Immunity and Inflammation, Cochin Institute, CNRS UMR8104, INSERM U1016, Universite Paris Descartes, Sorbonne Paris Cite, Paris, France. FAU - Gu, Songhai AU - Gu S AD - Immunotherapy Research Center, Munich, Bavaria, Germany. FAU - Cooper, Itzik AU - Cooper I AD - The Joseph Sagol Neuroscience Center, Haim Sheba Medical Center, Tel Hashomer, Israel. FAU - Eilam, Raya AU - Eilam R AD - Veterinary Resources, The Weizmann Institute of Science, Rehovot, Israel. FAU - Besser, Michal AU - Besser M AD - Sheba Medical Center, The Ella Institute for Treatment and Research of Melanoma, Tel Hashomer, Israel. FAU - Goldfinger, Meidan AU - Goldfinger M AD - Pain Medicine Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. FAU - Chowers, Yehuda AU - Chowers Y AD - Department of Gastroenterology, Rambam Health Care Campus & Bruce Rappaport School of Medicine, Technion Institute of Technology, Haifa, Israel. FAU - Wank, Rudolf AU - Wank R AD - Immunotherapy Research Center, Munich, Bavaria, Germany. FAU - Birnir, Bryndis AU - Birnir B AD - Department of Neuroscience, Uppsala University, Uppsala, Sweden. FAU - Levite, Mia AU - Levite M AD - School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel. mial@ekmd.huji.ac.il. AD - Institute of Gene Therapy, Hadassah University Hospital, Jerusalem, Israel. mial@ekmd.huji.ac.il. AD - School of Behavioral Sciences, Academic College of Tel Aviv-Jaffa, Tel Aviv, Israel. mial@ekmd.huji.ac.il. LA - eng PT - Journal Article DEP - 20151126 PL - Austria TA - J Neural Transm (Vienna) JT - Journal of neural transmission (Vienna, Austria : 1996) JID - 9702341 RN - 0 (NF-kappa B) RN - 0 (Tumor Necrosis Factor-alpha) RN - 147173-20-4 (Kv1.1 Potassium Channel) SB - IM MH - Animals MH - *Autoimmune Diseases/immunology/metabolism MH - Blotting, Western MH - CD4-Positive T-Lymphocytes/immunology/*metabolism MH - Electrophoretic Mobility Shift Assay MH - Female MH - Humans MH - Immunohistochemistry MH - *Inflammation/immunology/metabolism MH - Kv1.1 Potassium Channel/*metabolism MH - Male MH - Mice MH - Mice, SCID MH - NF-kappa B/immunology/metabolism MH - Patch-Clamp Techniques MH - Polymerase Chain Reaction MH - Signal Transduction/immunology MH - Tumor Necrosis Factor-alpha/*metabolism OTO - NOTNLM OT - Autoimmune diseases OT - Immunotherapy OT - Inflammation OT - Kv1.1 OT - NFkappaB OT - Non-canonical pathway OT - Pro-inflammatory cytokines OT - T cells OT - TNFalpha OT - Voltage-gated potassium channels EDAT- 2015/11/28 06:00 MHDA- 2016/12/15 06:00 CRDT- 2015/11/28 06:00 PHST- 2015/02/20 00:00 [received] PHST- 2015/08/16 00:00 [accepted] PHST- 2015/11/28 06:00 [entrez] PHST- 2015/11/28 06:00 [pubmed] PHST- 2016/12/15 06:00 [medline] AID - 10.1007/s00702-015-1446-9 [pii] AID - 10.1007/s00702-015-1446-9 [doi] PST - ppublish SO - J Neural Transm (Vienna). 2016 Mar;123(3):137-57. doi: 10.1007/s00702-015-1446-9. Epub 2015 Nov 26.