Transgenic Research

, Volume 25, Issue 6, pp 829–837 | Cite as

Generation of IL10 and TGFB1 coexpressed mice displaying resistance to ovalbumin-induced asthma

  • Fei Xu
  • Xiuhua Kang
  • Liang Chen
  • Chuanhui Chen
  • Gen Hu
  • Wei Bai
  • Wei Zhang
Original Paper

Abstract

Asthma is a common chronic inflammatory disease in the airways with wide prevalence, and it is thought to be caused by the combinational factors in environment and genetics. A large body of studies has suggested that cell immunity played a vital role in regulating the airway hyperreactivity (AHR) and inflammation. Therefore, we here developed a mouse model of asthma by microinjecting the pronucleus with a vector spontaneously coding human IL10 and TGFB1 gene to explore the possible interaction between these two potent molecules during asthma progression. From the total 35 newborn mice, we successfully obtained 3 founders expressing exogenous genes. In the transgenic mice, we observed profoundly enhanced expression of IL10 and TGFB1. In the condition of ovalbumin challenge, transgenic mice displayed a 1.9-fold higher MCh50 score than wild-type counterparts, indicating reminiscent AHR. Meanwhile, a three-fold decrease of cell counts in bronchoalveolar lavage fluid (BALF) was recorded as well. These results suggested that IL10 and TGFB1 cooperatively protected the respiratory system in response to antigenic stimulus. To interrogate the respective behaviors of the two genes, we quantified the expression of downstream genes in IL10 signaling or TGFB1 signaling. We observed that the examined genes in IL10 signaling were significantly repressed, especially IL5, which showed 5.4-fold decreased expression. Most genes were not altered in TGFB1 signaling, and the production of endogenous TGFB1 was significantly inhibited. These evidences collectively proved that the activation of IL0 and TGFB1 protected the host from antigen-induced asthma, possibly through IL10 signaling. This study shed some light on the modulations of IL10 and TGFB1, and related networks to asthma progression.

Keywords

Asthma IL10 TGFB1 Mouse model 

References

  1. Al-Alawi M et al (2014) Transforming growth factor beta and severe asthma: a perfect storm. Respir Med 108:1409–1423CrossRefPubMedGoogle Scholar
  2. Al-Khateeb AJ, Al Khateeb JM (2015) Research on psychosocial aspects of asthma in the Arab world: a literature review. Multidiscip Respir Med 10:15CrossRefPubMedPubMedCentralGoogle Scholar
  3. Bentley AM et al (1996) Prednisolone treatment in asthma. Reduction in the numbers of eosinophils, T cells, tryptase-only positive mast cells, and modulation of IL-4, IL-5, and interferon-gamma cytokine gene expression within the bronchial mucosa. Am J Respir Crit Care Med 153:551–556CrossRefPubMedGoogle Scholar
  4. Berkman N et al (1995) Inhibition of macrophage inflammatory protein-1 alpha expression by IL-10. Differential sensitivities in human blood monocytes and alveolar macrophages. J Immunol 155:4412–4418PubMedGoogle Scholar
  5. Bogdan C et al (1991) Macrophage deactivation by interleukin 10. J Exp Med 174:1549–1555CrossRefPubMedGoogle Scholar
  6. Daniels RW et al (2014) Expression of multiple transgenes from a single construct using viral 2A peptides in Drosophila. PLoS One 9:e100637CrossRefPubMedPubMedCentralGoogle Scholar
  7. Daubeuf F, Frossard N (2014) Eosinophils and the ovalbumin mouse model of asthma. Methods Mol Biol 1178:283–293CrossRefPubMedGoogle Scholar
  8. Dekkers BG et al (2010) The integrin-blocking peptide RGDS inhibits airway smooth muscle remodeling in a guinea pig model of allergic asthma. Am J Respir Crit Care Med 181:556–565CrossRefPubMedGoogle Scholar
  9. Dunn RM, Wechsler ME (2015) Anti-interleukin therapy in asthma. Clin Pharmacol Ther 97:55–65CrossRefPubMedGoogle Scholar
  10. Duvernelle C et al (2003) Transforming growth factor-beta and its role in asthma. Pulm Pharmacol Ther 16:181–196CrossRefPubMedGoogle Scholar
  11. Gleich GJ (2000) Mechanisms of eosinophil-associated inflammation. J Allergy Clin Immunol 105:651–663CrossRefPubMedGoogle Scholar
  12. Grissell TV et al (2005) Interleukin-10 gene expression in acute virus-induced asthma. Am J Respir Crit Care Med 172:433–439CrossRefPubMedGoogle Scholar
  13. Hinck AP (2012) Structural studies of the TGF-betas and their receptors—insights into evolution of the TGF-beta superfamily. FEBS Lett 586:1860–1870CrossRefPubMedGoogle Scholar
  14. Hsu CY et al (2010) Synergistic therapeutic effects of combined adenovirus-mediated interleukin-10 and interleukin-12 gene therapy on airway inflammation in asthmatic mice. J Gene Med 12:11–21CrossRefPubMedGoogle Scholar
  15. Kim JH et al (2011) High cleavage efficiency of a 2A peptide derived from porcine teschovirus-1 in human cell lines, zebrafish and mice. PLoS One 6:e18556CrossRefPubMedPubMedCentralGoogle Scholar
  16. Kokturk N et al (2003) Expression of transforming growth factor beta1 in bronchial biopsies in asthma and COPD. J Asthma Off J Assoc Care Asthma 40:887–893CrossRefGoogle Scholar
  17. Makinde T et al (2007) The regulatory role of TGF-beta in airway remodeling in asthma. Immunol Cell Biol 85:348–356CrossRefPubMedGoogle Scholar
  18. Michaeloudes C et al (2011) TGF-beta regulates Nox4, MnSOD and catalase expression, and IL-6 release in airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 300:L295–L304CrossRefPubMedGoogle Scholar
  19. Moore KW et al (2001) Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 19:683–765CrossRefPubMedGoogle Scholar
  20. Nair P (2013) What is an “eosinophilic phenotype” of asthma? J Allergy Clin Immunol 132:81–83CrossRefPubMedGoogle Scholar
  21. Olin JT, Wechsler ME (2014) Asthma: pathogenesis and novel drugs for treatment. BMJ 349:g5517CrossRefPubMedGoogle Scholar
  22. Overbeek PA et al (1986) Tissue-specific expression in transgenic mice of a fused gene containing RSV terminal sequences. Science 231:1574–1577CrossRefPubMedGoogle Scholar
  23. Palmiter RD et al (1982) Differential regulation of metallothionein-thymidine kinase fusion genes in transgenic mice and their offspring. Cell 29:701–710CrossRefPubMedGoogle Scholar
  24. Patella V et al (2015) Asthma is associated with increased susceptibility to infection. Minerva Med 106:1–7Google Scholar
  25. Ryan MD et al (1991) Cleavage of foot-and-mouth disease virus polyprotein is mediated by residues located within a 19 amino acid sequence. J Gen Virol 72(Pt 11):2727–2732CrossRefPubMedGoogle Scholar
  26. Schramm C et al (2003) TGF-beta regulates airway responses via T cells. J Immunol 170:1313–1319CrossRefPubMedGoogle Scholar
  27. Sims JE et al (1988) cDNA expression cloning of the IL-1 receptor, a member of the immunoglobulin superfamily. Science 241:585–589CrossRefPubMedGoogle Scholar
  28. Szymczak AL, Vignali DA (2005) Development of 2A peptide-based strategies in the design of multicistronic vectors. Expert Opin Biol Ther 5:627–638CrossRefPubMedGoogle Scholar
  29. Zhang Q et al (2015) Link between environmental air pollution and allergic asthma: East meets West. J Thorac Dis 7:14–22PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Fei Xu
    • 1
  • Xiuhua Kang
    • 1
  • Liang Chen
    • 1
  • Chuanhui Chen
    • 1
  • Gen Hu
    • 1
  • Wei Bai
    • 1
  • Wei Zhang
    • 1
  1. 1.The First Affiliated Hospital of Nanchang UniversityNanchang CityChina

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