In:
Science Signaling, American Association for the Advancement of Science (AAAS), Vol. 8, No. 405 ( 2015-12)
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 (T H 2) cells. Compared to wild-type mice, ITK knockout mice are resistant to asthma and exhibit reduced lung inflammation and decreased amounts of T H 2-type cytokines in the bronchoalveolar lavage fluid. We found that a small-molecule selective inhibitor of ITK blocked TCR-mediated signaling in cultured T H 2 cells, including the tyrosine phosphorylation of phospholipase C–γ1 (PLC-γ1) and the secretion of IL-2 and T H 2-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 T H 2-type cytokines. Thus, our studies predict that inhibition of the kinase activity of ITK may not be therapeutic in patients with asthma.
Type of Medium:
Online Resource
ISSN:
1945-0877
,
1937-9145
DOI:
10.1126/scisignal.aab0949
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2015
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