Advertisement

Inflammation

, Volume 40, Issue 6, pp 2012–2019 | Cite as

Transgenic Mice Overexpressing Vitamin D Receptor (VDR) Show Anti-Inflammatory Effects in Lung Tissues

  • Masaki IshiiEmail author
  • Yasuhiro Yamaguchi
  • Kyoko Isumi
  • Sumito Ogawa
  • Masahiro Akishita
ORIGINAL ARTICLE

Abstract

Vitamin D insufficiency is increasingly recognized as a prevalent problem worldwide, especially in patients with a chronic lung disease. Chronic obstructive pulmonary disease (COPD) is a type of chronic inflammatory lung disease. Previous clinical studies have shown that COPD leads to low vitamin D levels, which further increase the severity of COPD. Vitamin D homeostasis represents one of the most important factors that potentially determine the severity of COPD. Nonetheless, the mechanisms underlying the anti-inflammatory effects of vitamin D receptor (VDR) in lung tissues are still unclear. To investigate the anti-inflammatory effects of VDR, we generated transgenic mice that show lung-specific VDR overexpression under the control of the surfactant protein C promoter (TG mice). The TG mice were used to study the expression patterns of proinflammatory cytokines using real-time polymerase chain reaction and immunohistochemistry. The TG mice had lower levels of T helper 1 (Th1)-related cytokines than wild-type (WT) mice did. No significant differences in the expression of Th2 cytokines were observed between TG and WT mice. This study is the first to achieve lung-specific overexpression of VDR in TG mice: an interesting animal model useful for studying the relation between airway cell inflammation and vitamin D signaling. VDR expression is an important factor that influences anti-inflammatory responses in lung tissues. Our results show the crucial role of VDR in anti-inflammatory effects in lungs; these data are potentially useful for the treatment or prevention of COPD.

KEY WORDS

vitamin D receptor inflammation transgenic mouse COPD 

ABBREVIATIONS

COPD

Chronic obstructive pulmonary disease

VDR

vitamin D receptor

SP-C

surfactant protein C

TG

transgenic

WT

wild type

Th1

T helper 1

Th2

T helper 2

MMP

matrix metalloproteinase

PCR

polymerase chain reaction

MCP-1α

macrophage inflammatory protein 1α

IP-10

interferon gamma-induced protein 10

MCP-2

monocyte chemotactic protein 2

IL-4

interleukin 4

IL-10

interleukin 10

IL-13

interleukin 13

TIMP-1

tissue inhibitor of metalloproteinase 1

FW

forward

RV

reverse

SE

standard error

ANOVA

analysis of variance

qRT

Quantitative reverse transcription

FEV1

forced expiratory volume in 1 s

Notes

Acknowledgements

The authors are grateful to Dr. Jeffrey A. Whitsett (Division of Neonatology Perinatal and Pulmonary Biology at Cincinnati Children’s Hospital Medical Center, USA) for providing the plasmids containing the SP-C promoter, the SV40 small T intron, and polyadenylation sequence.

Compliance with Ethical Standards

Experiments were conducted in accordance with the Guidelines for the Care and Use of Laboratory Animals of the National Institutes of Health. All the protocols were approved by the University of Tokyo Institutional Review Board for Laboratory Animal Use.

Funding

This work was supported by the Grant-in-Aid for Scientific Research (C) from Japan Society for the Promotion of Science (JSPS KAKENHI Grant Number 20724438).

Conflict of Interest

The authors declare that they have no conflicts of interest.

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

References

  1. 1.
    Buist, A.S., M.A. McBurnie, W.M. Vollmer, S. Gillespie, P. Burney, D.M. Mannino, A.M. Menzes, S.D. Sullivan, T.A. Lee, K.B. Weiss, R.L. Jensen, G.B. Marks, A. Gulsvik, E. Nizankowska-Mogilnicka, and BOLD Collaborative Research Group. 2007. International variation in the prevalence of COPD (the BOLD study): A population-based prevalence study. Lancet 370: 741–750.CrossRefPubMedGoogle Scholar
  2. 2.
    Fukuchi, Y., M. Nishimura, M. Ichinose, M. Adachi, A. Nagai, T. Kuriyama, K. Takahashi, K. Nishimura, S. Ishioka, H. Aizawa, and C. Zaher. 2004. COPD in Japan: The Nippon COPD epidemiology study. Respirology 9: 458–465.CrossRefPubMedGoogle Scholar
  3. 3.
    Hogg, J.C., F. Chu, S. Utokaparch, R. Woods, W.M. Elliott, L. Buzatu, R.M. Cherniack, R.M. Rogers, F.C. Sciurba, H.O. Coxson, and P.D. Paré. 2004. The nature of small-airway obstruction in chronic obstructive pulmonary disease. New England Journal of Medicine 350: 2645–2653.CrossRefPubMedGoogle Scholar
  4. 4.
    Vernooy, J.H.J., M.A. Dentener, R.J. Van Suylen, W.A. Buurman, and E.F. Wouters. 2002. Long-term intratracheal lipopolysaccharide exposure in mice results in chronic lung inflammation and persistent pathology. American Journal of Respiratory Cell and Molecular Biology 26: 152–159.CrossRefPubMedGoogle Scholar
  5. 5.
    Hurst, J.R., J. Vestbo, A. Anzueto, N. Locantore, H. Müllerova, R. Tal-Singer, B. Miller, D.A. Lomas, A. Agusti, W. Macnee, P. Calverley, S. Rennard, E.F. Wouters, J.A. Wedzicha, and Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. 2010. Susceptibility to exacerbation in chronic obstructive pulmonary disease. New England Journal of Medicine 363: 1128–1138.CrossRefPubMedGoogle Scholar
  6. 6.
    Smolonska, J., C. Wijmenga, D.S. Postma, and H.M. Boezen. 2009. Meta-analysis on suspected chronic obstructive pulmonary disease genes. American Journal of Respiratory and Critical Care Medicine 180: 618–631.CrossRefPubMedGoogle Scholar
  7. 7.
    Janssens, W., R. Bouillon, B. Claes, C. Carremans, A. Lehouck, I. Buysschaert, J. Coolen, C. Mathieu, M. Decramer, and D. Lambrechts. 2010. Vitamin D deficiency is highly prevalent in COPD and correlates with variants in the vitamin D-binding gene. Thorax 65: 215–220.CrossRefPubMedGoogle Scholar
  8. 8.
    Herr, C., T. Greulich, R.A. Koczulla, S. Meyer, T. Zakharkina, M. Branscheidt, R. Eschmann, and R. Bals. 2011. The role of vitamin D in pulmonary disease: COPD, asthma, infection, and cancer. Respiratory Research 12: 31.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Malinovschi, A., M. Masoero, M. Bellocchia, A. Ciuffreda, P. Solidoro, A. Mattei, L. Mercante, E. Heffler, G. Rolla, and C. Bucca. 2014. Severe vitamin D deficiency is associated with frequent exacerbations and hospitalization in COPD patients. Respiratory Research 15: 131.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Mahon, B.D., A. Wittke, V. Weaver, and M.T. Cantorna. 2003. The targets of vitamin D depend on the differentiation and activation status of CD4-positive T cells. Journal of Cellular Biochemistry 89: 922–932.CrossRefPubMedGoogle Scholar
  11. 11.
    Betsuyaku, T., M. Nishimura, K. Takeyabu, M. Tanino, P. Venge, S. Xu, and Y. Kawakami. 1999. Neutrophil granule proteins in bronchoalveolar lavage fluid from subjects with subclinical emphysema. American Journal of Respiratory and Critical Care Medicine 159: 1985–1991.CrossRefPubMedGoogle Scholar
  12. 12.
    Zhou, H., Y. Wu, Y. Jin, J. Zhou, C. Zhang, L. Che, J. Jing, Z. Chen, W. Li, and H. Shen. 2013. Genetic polymorphism of matrix metalloproteinase family and chronic obstructive pulmonary disease susceptibility: A meta-analysis. Scientific Reports 3: 2818.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Devereux, G., A.A. Litonjua, S.W. Turner, L.C. Craig, G. McNeill, S. Martindale, P.J. Helms, A. Seaton, and S.T. Weiss. 2007. Maternal vitamin D intake during pregnancy and early childhood wheezing. American Journal of Clinical Nutrition 85: 853–859.PubMedGoogle Scholar
  14. 14.
    Han, J.C., J. Du, Y.J. Zhang, G.B. Qi, H.B. Li, Y.J. Zhang, and X.L. Yu. 2016. Vitamin D receptor polymorphisms may contribute to asthma risk. Journal of Asthma 53: 790–800.CrossRefPubMedGoogle Scholar
  15. 15.
    Haussler, M.R., G.K. Whitfield, C.A. Haussler, J.C. Hsieh, P.D. Thompson, S.H. Selznick, C.E. Dominguez, and P.W. Jurutka. 1998. The nuclear vitamin D receptor: Biological and molecular regulatory properties revealed. Journal of Bone and Mineral Research 13: 325–349.CrossRefPubMedGoogle Scholar
  16. 16.
    Sundar, I.K., J.W. Hwang, S. Wu, and I. Rahman. 2011. Deletion of vitamin D receptor leads to premature emphysema/COPD by increased matrix metalloproteinases and lymphoid aggregates formation. Biochemical and Biophysical Research Communications 406: 127–133.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Kuro-o, M., Y. Matsumura, H. Aizawa, H. Kawaguchi, T. Suga, T. Utsugi, Y. Ohyama, M. Kurabayashi, T. Kaname, E. Kume, H. Iwasaki, A. Iida, T. Shiraki-Iida, S. Nishikawa, R. Nagai, and Y.I. Nabeshima. 1997. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390: 45–51.CrossRefPubMedGoogle Scholar
  18. 18.
    Ishii, M., Y. Yamaguchi, H. Yamamoto, Y. Hanaoka, and Y. Ouchi. 2008. Airspace enlargement with airway cell apoptosis in klotho mice: A model of aging lung. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 63: 1289–1298.CrossRefPubMedGoogle Scholar
  19. 19.
    Forster, R.E., P.W. Jurutka, J.C. Hsieh, C.A. Haussler, C.L. Lowmiller, I. Kaneko, M.R. Haussler, and G. Kerr Whitfield. 2011. Vitamin D receptor controls expression of the anti-aging klotho gene in mouse and human renal cells. Biochemical and Biophysical Research Communications 414: 557–562.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Korfhagen, T.R., S.W. Glasser, S.E. Wert, M.D. Bruno, C.C. Daugherty, J.D. McNeish, J.L. Stock, S.S. Potter, and J.A. Whitsett. 1990. Cis-acting sequences from a human surfactant protein gene confer pulmonary-specific gene expression in transgenic mice. Proceedings of the National Academy of Sciences of the United States of America 87: 6122–6126.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Aoshiba, K., J. Tamaoki, and A. Nagai. 2001. Acute cigarette smoke exposure induces apoptosis of alveolar macrophages. American Journal of Physiology. Lung Cellular and Molecular Physiology 281: L1392–L1401.PubMedGoogle Scholar
  22. 22.
    Bikle, D.D. 2010. Vitamin D: Newly discovered actions require reconsideration of physiologic requirements. Trends in Endocrinology and Metabolism 21: 375–384.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Shirai, T., T. Suda, N. Inui, and K. Chida. 2010. Correlation between peripheral blood T-cell profiles and clinical and inflammatory parameters in stable COPD. Allergology International 59: 75–82.CrossRefPubMedGoogle Scholar
  24. 24.
    Majori, M., M. Corradi, A. Caminati, G. Cacciani, S. Bertacco, and A. Pesci. 1999. Predominant TH1 cytokine pattern in peripheral blood from subjects with chronic obstructive pulmonary disease. Journal of Allergy and Clinical Immunology 103: 458–462.CrossRefPubMedGoogle Scholar
  25. 25.
    D'Armiento, J., S.S. Dalal, Y. Okada, R.A. Berg, and K. Chada. 1992. Collagenase expression in the lungs of transgenic mice causes pulmonary emphysema. Cell 71: 955–961.CrossRefPubMedGoogle Scholar
  26. 26.
    Churg, A., R. Wang, X. Wang, P.O. Onnervik, K. Thim, and J.L. Wright. 2007. Effect of an MMP-9/MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigs. Thorax 62: 706–713.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Shaheen, S.O., K.A. Jameson, S.M. Robinson, B.J. Boucher, H.E. Syddall, Sayer A. Aihie, C. Cooper, J.W. Holloway, and E.M. Dennison. 2011. Relationship of vitamin D status to adult lung function and COPD. Thorax 66: 692–698.CrossRefPubMedGoogle Scholar
  28. 28.
    Wasse, H., F. Cardarelli, C. De Staercke, C. Hooper, E. Veledar, and I. Guessous. 2011. 25-hydroxyvitamin D concentration is inversely associated with serum MMP-9 in a cross-sectional study of African American ESRD patients. BMC Nephrology 12: 24.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Masaki Ishii
    • 1
    Email author
  • Yasuhiro Yamaguchi
    • 1
  • Kyoko Isumi
    • 1
  • Sumito Ogawa
    • 1
  • Masahiro Akishita
    • 1
  1. 1.Department of Geriatric Medicine, Graduate School of MedicineThe University of TokyoTokyoJapan

Personalised recommendations