Asthmatic changes in mice lacking T-bet are mediated by IL-13.
Mice with a targeted deletion of the T-bet gene exhibit spontaneous airway hyperresponsiveness (AHR), airway inflammation, enhanced recovery of T(h)2 cytokines from bronchoalveolar lavage fluid, sub-epithelial collagen deposition and myofibroblast transformation. Here we analyze the mechanisms responsible for the chronic airway remodeling observed in these mice. CD4+ T cells isolated from the lung of T-bet-deficient mice were spontaneously activated CD44(high)CD69(high) memory T cells, with a typical T(h)2 cytokine profile. Neutralization of IL-13 but not IL-4 resulted in amelioration of AHR in airways of mice lacking T-bet. IL-13 blockade also led to reduced eosinophilia and decreased vimentin, transforming growth factor beta (TGF-beta) and alpha smooth muscle actin (alphaSMA) levels. T-bet(-/-) lung fibroblasts proliferated very rapidly and released increased amounts of TGF-beta. Interestingly, neutralization of TGF-beta ameliorated aspects of the chronic airway remodeling phenotype but did not reduce AHR. These data highlight a T-bet-directed function for IL-13 in controlling lung remodeling that is both dependent on and independent of its interaction with TGF-beta in the asthmatic airway.
Finotto
Susetta
S
Laboratory of Cellular and Molecular Immunology of the Lung, University of Mainz, Mainz, Germany. finotto@mail.uni-mainz.de
Hausding
Michael
M
Doganci
Aysefa
A
Maxeiner
Joachim H
JH
Lehr
Hans A
HA
Luft
Cornelia
C
Galle
Peter R
PR
Glimcher
Laurie H
LH
D000199:Actins / Q000378:metabolism; D000818:Animals; D001249:Asthma / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism; D005347:Fibroblasts / Q000276:immunology / Q000473:pathology; D007156:Immunologic Memory; D018793:Interleukin-13 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015847:Interleukin-4 / Q000037:antagonists & inhibitors; D008168:Lung / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051900:Smad3 Protein; D051906:Smad7 Protein; D020825:T-Box Domain Proteins; D015534:Trans-Activators / Q000096:biosynthesis / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014746:Vimentin / Q000378:metabolism; D000098815:T-bet Transcription Factor
D000199:Actins; D016207:Cytokines; D004268:DNA-Binding Proteins; D018793:Interleukin-13; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D014746:Vimentin; D015847:Interleukin-4