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Inhibition of the Inositol Kinase Itpkb Augments Calcium Signaling in Lymphocytes and Reveals a Novel Strategy to Treat Autoimmune Disease |
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| Authors: | Andrew T Miller Carol Dahlberg Mark L Sandberg Ben G Wen Daniel R Beisner John A H Hoerter Albert Parker Christian Schmedt Monique Stinson Jacqueline Avis Cynthia Cienfuegos Mark McPate Pamela Tranter Martin Gosling Paul J Groot-Kormelink Janet Dawson Shifeng Pan Shin-Shay Tian H Martin Seidel Michael P Cooke |
| Institution: | 1. The Genomics Institute of the Novartis Research Foundation (GNF), San Diego, California, United States of America.; 2. Novartis Pharmaceuticals UK Limited, Respiratory Disease Area, Horsham, West Sussex, United Kingdom.; 3. Novartis Institutes for Biomedical Research, Musculoskeletal Disease Area, Basel, Switzerland.; 4. Novartis Pharma AG, Novartis Institutes for Biomed. Research, Basel, Switzerland.; Jackson Laboratory, UNITED STATES, |
| Abstract: | 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. |
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