c-Ab1 in the allergic inflammatory lung disease

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): T helper type 2 (Th2) cells are crucial for causing the allergic inflammatory lung diseases such as asthma, by producing key cytokines, including interleukin (IL)-4, IL-5 and IL-13. The molecular mechanisms that mediate naive CD4+ T cells, after they are stimulated by specific antigens, to differentiate into Th1 or Th2 are still poorly understood. Here, our preliminary studies have demonstrated that loss of the functions of c-Abl, a Src family tyrosine kinase, skews CD4+ T cells to Th2 differentiation because the production of IL-4, IL-5 and IL-13 by c-Abl-/- CD4+ T cells is dramatically increased when compared to the production of these Th2 cytokines by c-Abl+/+ CD4+ T cells. While the production of Th1 cytokines from c-Abl-/- CD4+ T cells was impaired. Interestingly, we found that the tyrosine phosphorylation of Th1-linage transcription factor, T-bet, is dramatically reduced in c-Abl-/- T cells, suggesting that c-Abl regulates Th1/Th2 differentiation by, at least one of the mechanisms, phosphorylating T-bet. To support this, we found that over-expression of c-Abl but not its kinase-dead mutant, induced the tyrosine phosphorylation of T-bet. Expression of c-Abl in Jurkat T cells activates IFN? reporter activity and suppresses IL-4 reporters. These results indicate that c-Abl keeps the balance between Th1 and Th1 differentiation by activating T-bet, and loss of c-Abl functions enhances Th1 but impairs Th1 differentiation. Therefore, c-Abl-deficiency may cause allergic lung inflammations in mice. We will test this hypothesis by addressing the following two Specific Aims: Aim 1. How does c-Abl regulate Th1/Th2 differentiation? The fact that c-Abl phosphorylates, and thereby activates the Th1-lineage transcriptional factor T-bet, indicates that c-Abl regulates Th1/Th2 differentiation by targeting T-bet. We will further examine how T-bet transcription activity is regulated by c-Abl. Besides T-bet, several other transcription factors and signaling molecules are also involved in regulating CD4+ helper cell differentiation; thus, we will also determine whether c-Abl regulates T cell differentiation by targeting other molecules. Aim 2. Does c-Abl-deficiency cause asthma in mice? Th2 cytokines, particularly IL-4 and IL-13, plays a crucial role in asthma development in mice as well as in humans. The fact that the production of Th2 cytokines by c-Abl-/- CD4+ T cells is upregulated suggests that c-Abl-/- mice may potentially develop asthma. We will use an experimental asthma model to determine how c-Abl deficiency affects: 1. the airway resistance, 2. the IgE production, 3. the airway inflammation and the migration of inflammatory cells and 4. airway hyperresponsiveness. We anticipate that c-Abl-/- mice develop more severe allergic responses than wild-type mice. PUBLIC HEALTH RELEVANCE: About 10 million Americans have asthma, one of the most common and costly (over $18 billion annual health care costs) illnesses in the United States. Allergic asthma is the most common form of asthma, which is caused by elevated Th2 cytokine production. The results from our proposed research should uncover a previously unknown mechanism in regulating Th2 cytokine production. Further, c-Abl as a regulator might be a potential therapeutic target for controlling allergic inflammation in diseases such as asthma.