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T-bet is induced by interferon-? to mediate chemokine secretion and migration in human airway smooth muscle cells.


ABSTRACT: An inappropriate balance between T-helper (Th)1 and Th2 cytokine production underlies inflammatory changes that result in airway disease. Expression of the T-box transcription factor T-bet regulates differentiation of Th cells and production of Th1 cytokines, particularly IFN?. T-bet-deficient mice develop airway hyperreactivity, undergo airway remodeling, and exhibit defects in IFN? production while overproducing Th2 cytokines. T-bet is also reduced in the airways of asthmatic patients, suggesting loss of T-bet expression or activity promotes development of inflammatory airway disease. We present novel data demonstrating T-bet expression is induced in human airway smooth muscle cells (ASMC) by IFN?. This IFN?-stimulated expression of T-bet is dependent on signaling through JAK2 and signal transducers and activators of transcription 1 (STAT1) and activates T-bet-dependent DNA binding activity. Expression of T-bet stimulates IFN?-stimulated IFN? expression, secretion, and promoter activity, while inhibiting IFN?-stimulated release of chemokines including monocyte chemoattractant protein (MCP)-1/CCL2, regulated on activation normal T-expressed and secreted (RANTES)/CCL5, and eotaxin/CCL11. This is accompanied by changes in expression of the chemokine receptors CCR3 and IL12R?2 and TNF?. T-bet expression also reduces chemotactic migration of ASMC in response to serum and PDGF, which contributes to airway hyperplasia. These results are the first to identify T-bet expression and activity in a structural cell of the lung and may provide new insights into therapeutic targets for inflammatory airway disease.

SUBMITTER: Singer CA 

PROVIDER: S-EPMC3075099 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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T-bet is induced by interferon-γ to mediate chemokine secretion and migration in human airway smooth muscle cells.

Singer Cherie A CA  

American journal of physiology. Lung cellular and molecular physiology 20110114 4


An inappropriate balance between T-helper (Th)1 and Th2 cytokine production underlies inflammatory changes that result in airway disease. Expression of the T-box transcription factor T-bet regulates differentiation of Th cells and production of Th1 cytokines, particularly IFNγ. T-bet-deficient mice develop airway hyperreactivity, undergo airway remodeling, and exhibit defects in IFNγ production while overproducing Th2 cytokines. T-bet is also reduced in the airways of asthmatic patients, suggest  ...[more]

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