title: 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.affiliation: Department of Immunology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Yonglian
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Immunology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Peng
authors.affiliation: Department of Pathology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Webster
authors.affiliation: Department of Immunology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Suto
authors.affiliation: Department of Immunology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Lesch
authors.affiliation: Department of Immunology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Xiumin
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Immunology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Kate
authors.initials: K
authors.lastname: Senger
authors.affiliation: Department of Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: George
authors.initials: G
authors.lastname: Francis
authors.affiliation: Department of Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Kathy
authors.initials: K
authors.lastname: Barrett
authors.affiliation: Department of Immunology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Jenna L
authors.initials: JL
authors.lastname: Collier
authors.affiliation: Department of Discovery Chemistry, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Burch
authors.affiliation: Department of Immunology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Meijuan
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Connie
authors.initials: C
authors.lastname: Chan
authors.affiliation: Department of Pathology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Eastham-Anderson
authors.affiliation: Department of Pathology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Hai
authors.initials: H
authors.lastname: Ngu
authors.affiliation: Department of Biomarker Development, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Li
authors.affiliation: Department of Biomarker Development, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Tracy
authors.initials: T
authors.lastname: Staton
authors.affiliation: Department of Pathology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Havnar
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Allan
authors.initials: A
authors.lastname: Jaochico
authors.affiliation: Department of Immunology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Jackman
authors.affiliation: Department of Immunology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Surinder
authors.initials: S
authors.lastname: Jeet
authors.affiliation: Department of Immunology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Lorena
authors.initials: L
authors.lastname: Riol-Blanco
authors.affiliation: Department of Immunology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Lawren C
authors.initials: LC
authors.lastname: Wu
authors.affiliation: Department of Immunology, Tissue Growth, and Repair Diagnostics Discovery, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: Choy
authors.affiliation: Department of Immunology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Arron
authors.affiliation: Department of Immunology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Brent S
authors.initials: BS
authors.lastname: McKenzie
authors.affiliation: Department of Immunology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Nico
authors.initials: N
authors.lastname: Ghilardi
authors.affiliation: Department of Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Moulay Hicham Alaoui
authors.initials: MH
authors.lastname: Ismaili
authors.affiliation: Department of Discovery Chemistry, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Pei
authors.affiliation: Department of Immunology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: DeVoss
authors.affiliation: Department of Pathology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Cary D
authors.initials: CD
authors.lastname: Austin
authors.affiliation: Department of Immunology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Wyne P
authors.initials: WP
authors.lastname: Lee
authors.affiliation: Department of Immunology, Genentech Inc., South San Francisco, CA 94080, USA. zarrin.ali@gene.com.
authors.forename: Ali A
authors.initials: AA
authors.lastname: Zarrin
mesh_terms: D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D051966:Phospholipase C gamma / Q000235:genetics / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology* / Q000473:pathology
chemical_list: D016207:Cytokines; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase; D051966:Phospholipase C gamma; C117399:Plcg1 protein, mouse