Inhibition of the Inositol Kinase Itpkb Augments Calcium Signaling in Lymphocytes and Reveals a Novel Strategy to Treat Autoimmune Disease

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

doi:10.1371/journal.pone.0131071

Inhibition of the Inositol Kinase Itpkb Augments Calcium Signaling in Lymphocytes and Reveals a Novel Strategy to Treat Autoimmune Disease

PLoS One. 2015 Jun 29;10(6):e0131071. doi: 10.1371/journal.pone.0131071. eCollection 2015.

Authors

Andrew T Miller¹, Carol Dahlberg¹, Mark L Sandberg¹, Ben G Wen¹, Daniel R Beisner¹, John A H Hoerter¹, Albert Parker¹, Christian Schmedt¹, Monique Stinson¹, Jacqueline Avis¹, Cynthia Cienfuegos¹, Mark McPate², Pamela Tranter², Martin Gosling², Paul J Groot-Kormelink³, Janet Dawson⁴, Shifeng Pan¹, Shin-Shay Tian¹, H Martin Seidel¹, Michael P Cooke¹

Affiliations

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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects
Apoptosis / genetics
Autoimmune Diseases / enzymology*
Autoimmune Diseases / pathology
Autoimmune Diseases / therapy*
CD4-Positive T-Lymphocytes / drug effects
CD4-Positive T-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / metabolism*
Calcium Channels / metabolism
Calcium Signaling* / drug effects
Calcium Signaling* / genetics
Gene Expression Regulation / drug effects
HEK293 Cells
Humans
Inositol Phosphates / metabolism
Jurkat Cells
Mice, Inbred C57BL
Mice, Knockout
ORAI1 Protein
Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*
Phosphotransferases (Alcohol Group Acceptor) / metabolism
Protein Kinase Inhibitors / pharmacology
Rats, Inbred Lew

Substances

Calcium Channels
Inositol Phosphates
ORAI1 Protein
Orai1 protein, mouse
Protein Kinase Inhibitors
inositol-1,3,4,5-tetrakisphosphate
Phosphotransferases (Alcohol Group Acceptor)
Inositol 1,4,5-trisphosphate 3-kinase

Grants and funding

All work was funded by the Novartis Institutes for Biomedical Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The Novartis Institutes for Biomedical Research, Novartis Pharmaceuticals UK Limited, or Novartis Pharma AG has provided support in the form of salaries for all authors, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.