T-bet is induced by interferon-γ to mediate chemokine secretion and migration in human airway smooth muscle cells.
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, 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 IFNγ. This IFNγ-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 IFNγ-stimulated IFNγ expression, secretion, and promoter activity, while inhibiting IFNγ-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 IL12Rβ2 and TNFα. 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.
Univ. of Nevada School of Medicine, Dept. of Pharmacology CMM MS-0573, Reno, NV 89557-0046, USA. csinger@medicine.nevada.edu
Cherie A
CA
Singer
D000818:Animals; D002465:Cell Movement / Q000187:drug effects*; D018925:Chemokines / Q000378:metabolism*; D002633:Chemotaxis / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000494:pharmacology*; D053612:Janus Kinases / Q000378:metabolism; D008168:Lung / Q000166:cytology*; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D000098815:T-bet Transcription Factor
D018925:Chemokines; D034741:RNA, Small Interfering; D050791:STAT Transcription Factors; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma; D004247:DNA; D053612:Janus Kinases
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