Journal
SCIENCE SIGNALING
Volume 8, Issue 405, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.aab0949
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- Genentech
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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-gamma 1 (PLC-gamma 1) 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 mousemodel of asthma failed to reduce airway hyperresponsiveness and inflammation. Rather, inmice, 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.
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