Regulated overexpression of interleukin 11 in the lung. Use to dissociate development-dependent and -independent phenotypes.
Standard overexpression transgenic approaches are limited in their ability to model waxing and waning diseases and frequently superimpose development-dependent and -independent phenotypic manifestations. We used the clara cell 10-kD protein (CC10) promoter and the reverse tetracycline transactivator (rtTA) to create a lung-specific, externally regulatable, overexpression transgenic system and used this system to express human interleukin 11 (IL-11) in respiratory structures. Gene induction could be achieved in utero, in neonates and in adult animals. Moreover, gene expression could be turned off by removal of the inducing stimulus. When gene activation was initiated in utero and continued into adulthood, subepithelial airway fibrosis, peribronchiolar mononuclear nodules, and alveolar enlargement (emphysema) were noted. Induction in the mature lung caused airway remodeling and peribronchiolar nodules, but alveolar enlargement was not appreciated. In contrast, induction in utero and during the first 14 d of life caused alveolar enlargement without airway remodeling or peribronchiolar nodules. Thus, IL-11 overexpression causes abnormalities that are dependent (large alveoli) and independent (airway remodeling, peribronchiolar nodules) of lung growth and development, and the CC10-rtTA system can be used to differentiate among these effector functions. The CC10-rtTA transgenic system can be used to model waxing and waning, childhood and growth and development-related biologic processes with enhanced fidelity.
Ray
P
P
Yale University School of Medicine, Department of Internal Medicine, New Haven, Connecticut 06520-8057, USA.
Tang
W
W
Wang
P
P
Homer
R
R
Kuhn
C
C
Flavell
R A
RA
Elias
J A
JA
D000375:Aging / Q000276:immunology; D000818:Animals; D000831:Animals, Newborn; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D018507:Gene Expression Regulation, Developmental / Q000276:immunology*; D006801:Humans; D017370:Interleukin-11 / Q000096:biosynthesis* / Q000235:genetics; D008168:Lung / Q000196:embryology / Q000201:enzymology* / Q000254:growth & development; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011650:Pulmonary Alveoli / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D017370:Interleukin-11; D012333:RNA, Messenger