Browse views: by Year, by Function, by GLF, by Subfunction, by Conference, by Journal

Inhibition of the inositol kinase Itpkb augments calcium signaling in lymphocytes and reveals a novel strategy to treat autoimmune disease

Miller, Andrew and Dahlberg-Bohl, Carol and Sandberg, Mark and Wen, Ben and Beisner, Daniel and Hoerter, John and Parker, Albert and Schmedt, Christian and Stinson, Monique and Avis, Jacqueline and Cienfuegos, Cynthia and Mcpate, Mark and Tranter, Pamela and Gosling, Martin and Groot Kormelink, Paul and Dawson King, Janet and Pan, Shifeng and Tian, Shin-Shay and Seidel, Martin and Cooke, Michael (2015) Inhibition of the inositol kinase Itpkb augments calcium signaling in lymphocytes and reveals a novel strategy to treat autoimmune disease. PLOS One.

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.

Item Type: Article
Date Deposited: 13 Oct 2015 13:11
Last Modified: 13 Oct 2015 13:11
URI: https://oak.novartis.com/id/eprint/25604

Search

Email Alerts

Register with OAK to receive email alerts for saved searches.