Inhibition of the kinase ITK in a mouse model of asthma reduces cell death and fails to inhibit the inflammatory response.

Abstract

Interleukin-2 (IL-2)-inducible T cell kinase (ITK) mediates T cell receptor (TCR) signaling primarily to stimulate the production of cytokines, such as IL-4, IL-5, and IL-13, from T helper 2 (TH2) cells. Compared to wild-type mice, ITK knockout mice are resistant to asthma and exhibit reduced lung inflammation and decreased amounts of TH2-type cytokines in the bronchoalveolar lavage fluid. We found that a small-molecule selective inhibitor of ITK blocked TCR-mediated signaling in cultured TH2 cells, including the tyrosine phosphorylation of phospholipase C-γ1 (PLC-γ1) and the secretion of IL-2 and TH2-type cytokines. Unexpectedly, inhibition of the kinase activity of ITK during or after antigen rechallenge in an ovalbumin-induced mouse model of asthma failed to reduce airway hyperresponsiveness and inflammation. Rather, in mice, pharmacological inhibition of ITK resulted in T cell hyperplasia and the increased production of TH2-type cytokines. Thus, our studies predict that inhibition of the kinase activity of ITK may not be therapeutic in patients with asthma.

• Authors: Yonglian Sun, Ivan Peng, Joshua D Webster, Eric Suto, Justin Lesch, Xiumin Wu, Kate Senger, George Francis, Kathy Barrett, Jenna L Collier, Jason D Burch, Meijuan Zhou, Yuan Chen, Connie Chan, Jeff Eastham-Anderson, Hai Ngu, Olga Li, Tracy Staton, Charles Havnar, Allan Jaochico, Janet Jackman, Surinder Jeet, Lorena Riol-Blanco, Lawren C Wu, David F Choy, Joseph R Arron, Brent S McKenzie, Nico Ghilardi, Moulay Hicham Alaoui Ismaili, Zhonghua Pei, Jason DeVoss, Cary D Austin, Wyne P Lee, Ali A Zarrin
• Journal: Science signaling (Sci Signal) Vol. 8 Issue 405 Pg. ra122 (Dec 01 2015) ISSN: 1937-9145 [Electronic] United States
• PMID: 26628680 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Association for the Advancement of Science.

Chemical References

• Cytokines
• Protein Kinase Inhibitors
• Protein-Tyrosine Kinases
• emt protein-tyrosine kinase
• Phospholipase C gamma
• Plcg1 protein, mouse

Topics

• Animals
• Asthma (genetics, immunology, pathology)
• Cell Death (drug effects)
• Cytokines (genetics, immunology)
• Disease Models, Animal
• Female
• Humans
• Inflammation (genetics, immunology, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Knockout
• Phospholipase C gamma (genetics, immunology)
• Protein Kinase Inhibitors (pharmacology)
• Protein-Tyrosine Kinases (antagonists & inhibitors, genetics, immunology)
• Th2 Cells (immunology, pathology)