title: Inhibition of the Inositol Kinase Itpkb Augments Calcium Signaling in Lymphocytes and Reveals a Novel Strategy to Treat Autoimmune Disease.
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.
authors.affiliation: The Genomics Institute of the Novartis Research Foundation (GNF), San Diego, California, United States of America.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Miller
authors.affiliation: The Genomics Institute of the Novartis Research Foundation (GNF), San Diego, California, United States of America.
authors.forename: Carol
authors.initials: C
authors.lastname: Dahlberg
authors.affiliation: The Genomics Institute of the Novartis Research Foundation (GNF), San Diego, California, United States of America.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Sandberg
authors.affiliation: The Genomics Institute of the Novartis Research Foundation (GNF), San Diego, California, United States of America.
authors.forename: Ben G
authors.initials: BG
authors.lastname: Wen
authors.affiliation: The Genomics Institute of the Novartis Research Foundation (GNF), San Diego, California, United States of America.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Beisner
authors.affiliation: The Genomics Institute of the Novartis Research Foundation (GNF), San Diego, California, United States of America.
authors.forename: John A H
authors.initials: JA
authors.lastname: Hoerter
authors.affiliation: The Genomics Institute of the Novartis Research Foundation (GNF), San Diego, California, United States of America.
authors.forename: Albert
authors.initials: A
authors.lastname: Parker
authors.affiliation: The Genomics Institute of the Novartis Research Foundation (GNF), San Diego, California, United States of America.
authors.forename: Christian
authors.initials: C
authors.lastname: Schmedt
authors.affiliation: The Genomics Institute of the Novartis Research Foundation (GNF), San Diego, California, United States of America.
authors.forename: Monique
authors.initials: M
authors.lastname: Stinson
authors.affiliation: The Genomics Institute of the Novartis Research Foundation (GNF), San Diego, California, United States of America.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Avis
authors.affiliation: The Genomics Institute of the Novartis Research Foundation (GNF), San Diego, California, United States of America.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Cienfuegos
authors.affiliation: Novartis Pharmaceuticals UK Limited, Respiratory Disease Area, Horsham, West Sussex, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: McPate
authors.affiliation: Novartis Pharmaceuticals UK Limited, Respiratory Disease Area, Horsham, West Sussex, United Kingdom.
authors.forename: Pamela
authors.initials: P
authors.lastname: Tranter
authors.affiliation: Novartis Pharmaceuticals UK Limited, Respiratory Disease Area, Horsham, West Sussex, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Gosling
authors.affiliation: Novartis Institutes for Biomedical Research, Musculoskeletal Disease Area, Basel, Switzerland.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Groot-Kormelink
authors.affiliation: Novartis Pharma AG, Novartis Institutes for Biomed. Research, Basel, Switzerland.
authors.forename: Janet
authors.initials: J
authors.lastname: Dawson
authors.affiliation: The Genomics Institute of the Novartis Research Foundation (GNF), San Diego, California, United States of America.
authors.forename: Shifeng
authors.initials: S
authors.lastname: Pan
authors.affiliation: The Genomics Institute of the Novartis Research Foundation (GNF), San Diego, California, United States of America.
authors.forename: Shin-Shay
authors.initials: SS
authors.lastname: Tian
authors.affiliation: The Genomics Institute of the Novartis Research Foundation (GNF), San Diego, California, United States of America.
authors.forename: H Martin
authors.initials: HM
authors.lastname: Seidel
authors.affiliation: The Genomics Institute of the Novartis Research Foundation (GNF), San Diego, California, United States of America.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Cooke
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001327:Autoimmune Diseases / Q000201:enzymology* / Q000473:pathology / Q000628:therapy*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D019169:Jurkat Cells; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071740:ORAI1 Protein; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011917:Rats, Inbred Lew
chemical_list: D015220:Calcium Channels; D007295:Inositol Phosphates; D000071740:ORAI1 Protein; C520430:Orai1 protein, mouse; D047428:Protein Kinase Inhibitors; C081655:inositol-1,3,4,5-tetrakisphosphate; D017853:Phosphotransferases (Alcohol Group Acceptor); C051038:Inositol 1,4,5-trisphosphate 3-kinase