Reduced airway hyperresponsiveness and tracheal responses during allergic asthma in mice lacking tyrosine kinase inducible T-cell kinase.

BACKGROUND: Patients with allergic asthma have symptoms of a predominant T(H)2 response, including airway eosinophilic inflammation and increased mucous production in the lungs. This accompanies increased airways responsiveness, which can be life threatening. Because T(H)2 cells and cytokines have been implicated in contributing to these symptoms, pathways that control the development of these cells or that regulate their cytokine production represent good targets for controlling this disease. OBJECTIVE: We have previously shown that mice lacking the tyrosine kinase inducible T-cell kinase (ITK) have drastically reduced airway inflammation in a model of allergic asthma. However, it was not clear whether this translated into reduced airways hyperresponsiveness. We have analyzed tracheal responsiveness and airways hyperresponsiveness of wild-type (WT) and ITK null mice during induction of experimental allergic asthma. METHODS: Experimental allergic asthma was induced in WT and ITK knockout mice. Tracheal responses to carbachol, acetylcholine, and potassium chloride were analyzed. Airways hyperresponsiveness to methacholine challenge was also analyzed in allergen-challenged mice, along with lung and bronchoalveolar lavage fluid T(H)2 cytokine message and protein. RESULTS: ITK null mice have reduced tracheal responses to cholinergic challenge in vitro before as well as after allergen challenge. These mice also have reduced airways hyperresponsiveness in response to allergen challenge, which could be rescued by transferring WT splenocytes or purified WT CD4+ T cells. This reduced airways response was preferentially accompanied by reduced expression of T(H)2 cytokines in the lungs. CONCLUSION: Our results indicate that the tyrosine kinase ITK and its function in T cells represent an attractive target for antiasthmatic drugs. CLINICAL IMPLICATIONS: Modulating the expression or activity of ITK may be a novel strategy to block allergic airway inflammation.

Modulation of tracheal smooth muscle responses in inducible T-cell kinase knockout mice.

It has been shown that the Tec family nonreceptor tyrosine kinase inducible T cell kinase (ITK) plays a role in the activation of naive T cells and in the differentiation of T helper (TH2)-type cells producing cytokines in a model of allergic inflammation, thereby possibly indirectly mediating hyperresponsivenes of airway smooth muscle tone. Using excised tracheae from wild type (WT) mice and those lacking ITK, we conducted a series of in vitro experiments in which isometric smooth muscle tones were assessed in response to several agonists to determine whether the absence of ITK would affect the responsiveness of tracheal smooth muscle cells. The resulting change in contractile responses was evaluated by measuring agonist cumulative concentration-response curves (CCRC). Our results indicate that the cholinergic agonist acetylcholine (ACh) and its analog carbachol (CCh) exhibited comparable CCRC profiles in contracting isolated tracheae from both WT and ITK-/- mice, with no alteration in their efficacies. However, the EC50 values for the two agonists were found to be significantly higher in ITK-/- tracheae than in those from WT mice, suggesting an alteration of the potencies of these cholinergic agonists in the trachea of ITK-/- mice. Moreover, we found that the depolarizing agent potassium chloride (KCl) had a significantly lower efficacy in contracting ITK-/- tracheae compared to those from WT mice. This difference in KCl efficacy was abolished in the presence of a calcium (Ca2+) voltage-dependent channel (VDC) agonist, Bay K8644, suggesting a modulation of the KCl induced permeability of VDC Ca2+ channels in the trachea of ITK-/- mice. Taken together, these results suggest that the presence of ITK may play a modulating role in the pharmacomechanical as well as in the electromechanical coupling of airway smooth muscle contraction.