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. 1997 Nov 15;100(10):2501–2511. doi: 10.1172/JCI119792

Regulated overexpression of interleukin 11 in the lung. Use to dissociate development-dependent and -independent phenotypes.

P Ray 1, W Tang 1, P Wang 1, R Homer 1, C Kuhn 3rd 1, R A Flavell 1, J A Elias 1
PMCID: PMC508450  PMID: 9366564

Abstract

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.

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Selected References

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  1. Amy R. W., Bowes D., Burri P. H., Haines J., Thurlbeck W. M. Postnatal growth of the mouse lung. J Anat. 1977 Sep;124(Pt 1):131–151. [PMC free article] [PubMed] [Google Scholar]
  2. Boström H., Willetts K., Pekny M., Levéen P., Lindahl P., Hedstrand H., Pekna M., Hellström M., Gebre-Medhin S., Schalling M. PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis. Cell. 1996 Jun 14;85(6):863–873. doi: 10.1016/s0092-8674(00)81270-2. [DOI] [PubMed] [Google Scholar]
  3. Busse W., Banks-Schlegel S. P., Larsen G. L. Childhood- versus adult-onset asthma. Am J Respir Crit Care Med. 1995 May;151(5):1635–1639. doi: 10.1164/ajrccm.151.5.7735626. [DOI] [PubMed] [Google Scholar]
  4. Castleman W. L., Sorkness R. L., Lemanske R. F., Grasee G., Suyemoto M. M. Neonatal viral bronchiolitis and pneumonia induces bronchiolar hypoplasia and alveolar dysplasia in rats. Lab Invest. 1988 Sep;59(3):387–396. [PubMed] [Google Scholar]
  5. DiCosmo B. F., Geba G. P., Picarella D., Elias J. A., Rankin J. A., Stripp B. R., Whitsett J. A., Flavell R. A. Airway epithelial cell expression of interleukin-6 in transgenic mice. Uncoupling of airway inflammation and bronchial hyperreactivity. J Clin Invest. 1994 Nov;94(5):2028–2035. doi: 10.1172/JCI117556. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Efrat S., Fusco-DeMane D., Lemberg H., al Emran O., Wang X. Conditional transformation of a pancreatic beta-cell line derived from transgenic mice expressing a tetracycline-regulated oncogene. Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3576–3580. doi: 10.1073/pnas.92.8.3576. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Einarsson O., Geba G. P., Zhu Z., Landry M., Elias J. A. Interleukin-11: stimulation in vivo and in vitro by respiratory viruses and induction of airways hyperresponsiveness. J Clin Invest. 1996 Feb 15;97(4):915–924. doi: 10.1172/JCI118514. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Elias J. A., Zheng T., Einarsson O., Landry M., Trow T., Rebert N., Panuska J. Epithelial interleukin-11. Regulation by cytokines, respiratory syncytial virus, and retinoic acid. J Biol Chem. 1994 Sep 2;269(35):22261–22268. [PubMed] [Google Scholar]
  9. Elias J. A., Zheng T., Whiting N. L., Trow T. K., Merrill W. W., Zitnik R., Ray P., Alderman E. M. IL-1 and transforming growth factor-beta regulation of fibroblast-derived IL-11. J Immunol. 1994 Mar 1;152(5):2421–2429. [PubMed] [Google Scholar]
  10. Escolar J. D., Gallego B., Tejero C., Escolar M. A. Changes occurring with increasing age in the rat lung: morphometrical study. Anat Rec. 1994 Jul;239(3):287–296. doi: 10.1002/ar.1092390307. [DOI] [PubMed] [Google Scholar]
  11. Fishman G. I., Kaplan M. L., Buttrick P. M. Tetracycline-regulated cardiac gene expression in vivo. J Clin Invest. 1994 Apr;93(4):1864–1868. doi: 10.1172/JCI117174. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Furth P. A., St Onge L., Böger H., Gruss P., Gossen M., Kistner A., Bujard H., Hennighausen L. Temporal control of gene expression in transgenic mice by a tetracycline-responsive promoter. Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9302–9306. doi: 10.1073/pnas.91.20.9302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Geppert E. F., Lester L. A., Ober C. Prioritizing asthma research: the need to investigate childhood asthma. Am J Respir Crit Care Med. 1995 May;151(5):1294–1295. doi: 10.1164/ajrccm.151.5.7735577. [DOI] [PubMed] [Google Scholar]
  14. Gossen M., Bonin A. L., Bujard H. Control of gene activity in higher eukaryotic cells by prokaryotic regulatory elements. Trends Biochem Sci. 1993 Dec;18(12):471–475. doi: 10.1016/0968-0004(93)90009-c. [DOI] [PubMed] [Google Scholar]
  15. Gossen M., Bujard H. Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5547–5551. doi: 10.1073/pnas.89.12.5547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gossen M., Freundlieb S., Bender G., Müller G., Hillen W., Bujard H. Transcriptional activation by tetracyclines in mammalian cells. Science. 1995 Jun 23;268(5218):1766–1769. doi: 10.1126/science.7792603. [DOI] [PubMed] [Google Scholar]
  17. Gross I., Wilson C. M. Fetal rat lung maturation: initiation and modulation. J Appl Physiol Respir Environ Exerc Physiol. 1983 Dec;55(6):1725–1732. doi: 10.1152/jappl.1983.55.6.1725. [DOI] [PubMed] [Google Scholar]
  18. Gu Z. J., Wijdenes J., Zhang X. G., Hallet M. M., Clement C., Klein B. Anti-gp130 transducer monoclonal antibodies specifically inhibiting ciliary neurotrophic factor, interleukin-6, interleukin-11, leukemia inhibitory factor or oncostatin M. J Immunol Methods. 1996 Mar 28;190(1):21–27. doi: 10.1016/0022-1759(95)00232-4. [DOI] [PubMed] [Google Scholar]
  19. Gundersen H. J., Osterby R. Optimizing sampling efficiency of stereological studies in biology: or 'do more less well!'. J Microsc. 1981 Jan;121(Pt 1):65–73. doi: 10.1111/j.1365-2818.1981.tb01199.x. [DOI] [PubMed] [Google Scholar]
  20. Ho Y. S. Transgenic models for the study of lung biology and disease. Am J Physiol. 1994 Apr;266(4 Pt 1):L319–L353. doi: 10.1152/ajplung.1994.266.4.L319. [DOI] [PubMed] [Google Scholar]
  21. Kistner A., Gossen M., Zimmermann F., Jerecic J., Ullmer C., Lübbert H., Bujard H. Doxycycline-mediated quantitative and tissue-specific control of gene expression in transgenic mice. Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10933–10938. doi: 10.1073/pnas.93.20.10933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kitamura M. Creation of a reversible on/off system for site-specific in vivo control of exogenous gene activity in the renal glomerulus. Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):7387–7391. doi: 10.1073/pnas.93.14.7387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Korfhagen T. R., Swantz R. J., Wert S. E., McCarty J. M., Kerlakian C. B., Glasser S. W., Whitsett J. A. Respiratory epithelial cell expression of human transforming growth factor-alpha induces lung fibrosis in transgenic mice. J Clin Invest. 1994 Apr;93(4):1691–1699. doi: 10.1172/JCI117152. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Leng S. X., Elias J. A. Interleukin-11 inhibits macrophage interleukin-12 production. J Immunol. 1997 Sep 1;159(5):2161–2168. [PubMed] [Google Scholar]
  25. Mader S., White J. H. A steroid-inducible promoter for the controlled overexpression of cloned genes in eukaryotic cells. Proc Natl Acad Sci U S A. 1993 Jun 15;90(12):5603–5607. doi: 10.1073/pnas.90.12.5603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Margraf L. R., Tomashefski J. F., Jr, Bruce M. C., Dahms B. B. Morphometric analysis of the lung in bronchopulmonary dysplasia. Am Rev Respir Dis. 1991 Feb;143(2):391–400. doi: 10.1164/ajrccm/143.2.391. [DOI] [PubMed] [Google Scholar]
  27. Massaro D., Teich N., Maxwell S., Massaro G. D., Whitney P. Postnatal development of alveoli. Regulation and evidence for a critical period in rats. J Clin Invest. 1985 Oct;76(4):1297–1305. doi: 10.1172/JCI112103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Mayford M., Bach M. E., Huang Y. Y., Wang L., Hawkins R. D., Kandel E. R. Control of memory formation through regulated expression of a CaMKII transgene. Science. 1996 Dec 6;274(5293):1678–1683. doi: 10.1126/science.274.5293.1678. [DOI] [PubMed] [Google Scholar]
  29. Miyazaki Y., Araki K., Vesin C., Garcia I., Kapanci Y., Whitsett J. A., Piguet P. F., Vassalli P. Expression of a tumor necrosis factor-alpha transgene in murine lung causes lymphocytic and fibrosing alveolitis. A mouse model of progressive pulmonary fibrosis. J Clin Invest. 1995 Jul;96(1):250–259. doi: 10.1172/JCI118029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Pack R. J., Al-Ugaily L. H., Morris G. The cells of the tracheobronchial epithelium of the mouse: a quantitative light and electron microscope study. J Anat. 1981 Jan;132(Pt 1):71–84. [PMC free article] [PubMed] [Google Scholar]
  31. Palmiter R. D., Chen H. Y., Brinster R. L. Differential regulation of metallothionein-thymidine kinase fusion genes in transgenic mice and their offspring. Cell. 1982 Jun;29(2):701–710. doi: 10.1016/0092-8674(82)90186-6. [DOI] [PubMed] [Google Scholar]
  32. Peterson R. L., Bozza M. M., Dorner A. J. Interleukin-11 induces intestinal epithelial cell growth arrest through effects on retinoblastoma protein phosphorylation. Am J Pathol. 1996 Sep;149(3):895–902. [PMC free article] [PubMed] [Google Scholar]
  33. Rankin J. A., Picarella D. E., Geba G. P., Temann U. A., Prasad B., DiCosmo B., Tarallo A., Stripp B., Whitsett J., Flavell R. A. Phenotypic and physiologic characterization of transgenic mice expressing interleukin 4 in the lung: lymphocytic and eosinophilic inflammation without airway hyperreactivity. Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7821–7825. doi: 10.1073/pnas.93.15.7821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Redlich C. A., Gao X., Rockwell S., Kelley M., Elias J. A. IL-11 enhances survival and decreases TNF production after radiation-induced thoracic injury. J Immunol. 1996 Aug 15;157(4):1705–1710. [PubMed] [Google Scholar]
  35. Rochester C. L., Ackerman S. J., Zheng T., Elias J. A. Eosinophil-fibroblast interactions. Granule major basic protein interacts with IL-1 and transforming growth factor-beta in the stimulation of lung fibroblast IL-6-type cytokine production. J Immunol. 1996 Jun 1;156(11):4449–4456. [PubMed] [Google Scholar]
  36. Sigurs N., Bjarnason R., Sigurbergsson F., Kjellman B., Björkstén B. Asthma and immunoglobulin E antibodies after respiratory syncytial virus bronchiolitis: a prospective cohort study with matched controls. Pediatrics. 1995 Apr;95(4):500–505. [PubMed] [Google Scholar]
  37. Stripp B. R., Sawaya P. L., Luse D. S., Wikenheiser K. A., Wert S. E., Huffman J. A., Lattier D. L., Singh G., Katyal S. L., Whitsett J. A. cis-acting elements that confer lung epithelial cell expression of the CC10 gene. J Biol Chem. 1992 Jul 25;267(21):14703–14712. [PubMed] [Google Scholar]
  38. Tang W., Geba G. P., Zheng T., Ray P., Homer R. J., Kuhn C., 3rd, Flavell R. A., Elias J. A. Targeted expression of IL-11 in the murine airway causes lymphocytic inflammation, bronchial remodeling, and airways obstruction. J Clin Invest. 1996 Dec 15;98(12):2845–2853. doi: 10.1172/JCI119113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Trepicchio W. L., Bozza M., Pedneault G., Dorner A. J. Recombinant human IL-11 attenuates the inflammatory response through down-regulation of proinflammatory cytokine release and nitric oxide production. J Immunol. 1996 Oct 15;157(8):3627–3634. [PubMed] [Google Scholar]
  40. Zheng T., Nathanson M. H., Elias J. A. Histamine augments cytokine-stimulated IL-11 production by human lung fibroblasts. J Immunol. 1994 Nov 15;153(10):4742–4752. [PubMed] [Google Scholar]
  41. Zhou L., Dey C. R., Wert S. E., Whitsett J. A. Arrested lung morphogenesis in transgenic mice bearing an SP-C-TGF-beta 1 chimeric gene. Dev Biol. 1996 May 1;175(2):227–238. doi: 10.1006/dbio.1996.0110. [DOI] [PubMed] [Google Scholar]

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