Inhibition of the Inositol Kinase Itpkb Augments Calcium Signaling in Lymphocytes and Reveals a Novel Strategy to Treat Autoimmune Disease
| Autor: | Jacqueline Avis, Janet Dawson, Paul J. Groot-Kormelink, Albert E. Parker, Shifeng Pan, Mark L. Sandberg, Ben G. Wen, Andrew T. Miller, Cynthia Cienfuegos, H. Martin Seidel, Monique Stinson, Daniel R. Beisner, John A. H. Hoerter, Michael P. Cooke, Shin-Shay Tian, Pamela Tranter, Martin Gosling, Christian Schmedt, Mark McPate, Carol Dahlberg |
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| Rok vydání: | 2015 |
| Předmět: |
CD4-Positive T-Lymphocytes
ORAI1 Protein Inositol Phosphates T cell lcsh:Medicine Apoptosis Biology Jurkat cells Autoimmune Diseases Jurkat Cells Conditional gene knockout medicine Animals Humans Calcium Signaling lcsh:Science Protein Kinase Inhibitors Calcium signaling Mice Knockout Multidisciplinary Kinase ORAI1 lcsh:R T-cell receptor Molecular biology Cell biology Mice Inbred C57BL Phosphotransferases (Alcohol Group Acceptor) HEK293 Cells medicine.anatomical_structure Gene Expression Regulation Rats Inbred Lew lcsh:Q Calcium Channels Intracellular Research Article |
| Zdroj: | PLoS ONE PLoS ONE, Vol 10, Iss 6, p e0131071 (2015) |
| ISSN: | 1932-6203 |
| Popis: | Emerging approaches to treat immune disorders target positive regulatory kinases downstream of antigen receptors with small molecule inhibitors. Here we provide evidence for an alternative approach in which inhibition of the negative regulatory inositol kinase Itpkb in mature T lymphocytes results in enhanced intracellular calcium levels following antigen receptor activation leading to T cell death. Using Itpkb conditional knockout mice and LMW Itpkb inhibitors these studies reveal that Itpkb through its product IP4 inhibits the Orai1/Stim1 calcium channel on lymphocytes. Pharmacological inhibition or genetic deletion of Itpkb results in elevated intracellular Ca2+ and induction of FasL and Bim resulting in T cell apoptosis. Deletion of Itpkb or treatment with Itpkb inhibitors blocks T-cell dependent antibody responses in vivo and prevents T cell driven arthritis in rats. These data identify Itpkb as an essential mediator of T cell activation and suggest Itpkb inhibition as a novel approach to treat autoimmune disease. |
| Databáze: | OpenAIRE |
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