, Volume 42, Issue 2, pp 702–713 | Cite as

1,25-Dihydroxy Vitamin D3 Attenuates the Oxidative Stress-Mediated Inflammation Induced by PM2.5via the p38/NF-κB/NLRP3 Pathway

  • Lili Xin
  • Bizhong Che
  • Bingzhong Zhai
  • Qiulin Luo
  • Chen Zhang
  • Jianshu Wang
  • Shengli Wang
  • Guoqiang Fan
  • Zhiyong Liu
  • Jialiang Feng
  • Zengli ZhangEmail author


Vitamin D3 is reported to be involved in the regulation of inflammatory processes. In this study, biomarkers related to oxidative stress and inflammation were investigated to clarify the protective effects and possible mechanism of 1,25-dihydroxy vitamin D3 (1,25-(OH)2D3) on PM2.5-induced inflammatory response. In the in vitro study using human bronchial epithelial (HBE) cells, aqueous extracts of PM2.5 could induce oxidative damage which is characterized by significant increases in production of reactive oxygen species, malonaldehyde concentration, and protein expression of HSPA1A and HO-1. Meanwhile, PM2.5 caused secretion of inflammatory factors (IL-6, IL-8) in the culture medium as well as phosphorylation of p38, nuclear factor-kappa B (NF-κB) inhibitor alpha (IκBα), and NF-κB p65 proteins. Increases in NLRP3 expression was also observed in HBE cells after PM2.5 exposure. However, all these biomarkers were remarkably attenuated by a 24-h pretreatment of 1 nM 1,25-(OH)2D3. Furthermore, 1,25-(OH)2D3 also reduced transcriptional activation of NF-κB induced by PM2.5 as indicated by a significant decrease in luciferase activity in HBE cells stably transfected with the NF-κB response element (RE)-driven luciferase reporter. Taken together, our findings provided novel experimental evidences supporting that vitamin D3 could reduce the predominantly oxidative stress-mediated inflammation induced by PM2.5via the p38/NF-κB/NLRP3 signaling pathway.


vitamin D3 PM2.5 oxidative stress inflammation NF-κB bronchial epithelial cells 



This work was supported by the National Natural Scientific Foundation of China grant (81402705, 81773414); Natural Science Foundation of Jiangsu Province (BK20140367); Youth Program of Reinvigorating the Health through Science and Education in Suzhou, China (KJXW2017053); and Open project of Key Laboratory of Environment and Health, Ministry of Education (2018GWKFJJ02). The authors wish to thank Andy Kiorpes for his aid in editing this paper.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Forouzanfar, M.H., L. Alexander, H.R. Anderson, et al. 2015. Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990-2013: A systematic analysis for the Global Burden of Disease Study 2013. Lancet 386: 2287–2323.CrossRefGoogle Scholar
  2. 2.
    Thurston, G.D., H. Kipen, and I. Annesi-Maesano, et al. 2017. A joint ERS/ATS policy statement: what constitutes an adverse health effect of air pollution? An analytical framework. European Respiratory Journal 49.Google Scholar
  3. 3.
    Leung, P.Y., H.T. Wan, M.B. Billah, J.J. Cao, K.F. Ho, and C.K.C. Wong. 2014. Chemical and biological characterization of air particulate matter 2.5, collected from five cities in China. Environmental Pollution 194: 188–195.CrossRefGoogle Scholar
  4. 4.
    Brauer, M., G. Freedman, J. Frostad, A. van Donkelaar, R.V. Martin, F. Dentener, R. Dingenen, K. Estep, H. Amini, J.S. Apte, K. Balakrishnan, L. Barregard, D. Broday, V. Feigin, S. Ghosh, P.K. Hopke, L.D. Knibbs, Y. Kokubo, Y. Liu, S. Ma, L. Morawska, J.L.T. Sangrador, G. Shaddick, H.R. Anderson, T. Vos, M.H. Forouzanfar, R.T. Burnett, and A. Cohen. 2016. Ambient air pollution exposure estimation for the Global Burden of Disease 2013. Environmental Science & Technology 50: 79–88.CrossRefGoogle Scholar
  5. 5.
    Chen, Z.H., Y.F. Wu, P.L. Wang, Y.P. Wu, Z.Y. Li, Y. Zhao, J.S. Zhou, C. Zhu, C. Cao, Y.Y. Mao, F. Xu, B.B. Wang, S.A. Cormier, S.M. Ying, W. Li, and H.H. Shen. 2016. Autophagy is essential for ultrafine particle-induced inflammation and mucus hyperproduction in airway epithelium. Autophagy 12: 297–311.CrossRefGoogle Scholar
  6. 6.
    Gehring, U., O. Gruzieva, R.M. Agius, R. Beelen, A. Custovic, J. Cyrys, M. Eeftens, C. Flexeder, E. Fuertes, J. Heinrich, B. Hoffmann, J.C. de Jongste, M. Kerkhof, C. Klümper, M. Korek, A. Mölter, E.S. Schultz, A. Simpson, D. Sugiri, M. Svartengren, A. von Berg, A.H. Wijga, G. Pershagen, and B. Brunekreef. 2013. Air pollution exposure and lung function in children: The ESCAPE project. Environmental Health Perspectives 121: 1357–1364.CrossRefGoogle Scholar
  7. 7.
    Karakatsani, A., A. Analitis, D. Perifanou, J.G. Ayres, R.M. Harrison, A. Kotronarou, I.G. Kavouras, J. Pekkanen, K. Hämeri, G.P.A. Kos, J.J. de Hartog, G. Hoek, and K. Katsouyanni. 2012. Particulate matter air pollution and respiratory symptoms in individuals having either asthma or chronic obstructive pulmonary disease: A European multicentre panel study. Environmental Health 11: 75.CrossRefGoogle Scholar
  8. 8.
    Raaschou-Nielsen, O., Z.J. Andersen, R. Beelen, E. Samoli, M. Stafoggia, G. Weinmayr, B. Hoffmann, P. Fischer, M.J. Nieuwenhuijsen, B. Brunekreef, W.W. Xun, K. Katsouyanni, K. Dimakopoulou, J. Sommar, B. Forsberg, L. Modig, A. Oudin, B. Oftedal, P.E. Schwarze, P. Nafstad, U. de Faire, N.L. Pedersen, C.G. Östenson, L. Fratiglioni, J. Penell, M. Korek, G. Pershagen, K.T. Eriksen, M. Sørensen, A. Tjønneland, T. Ellermann, M. Eeftens, P.H. Peeters, K. Meliefste, M. Wang, B. Bueno-de-Mesquita, T.J. Key, K. de Hoogh, H. Concin, G. Nagel, A. Vilier, S. Grioni, V. Krogh, M.Y. Tsai, F. Ricceri, C. Sacerdote, C. Galassi, E. Migliore, A. Ranzi, G. Cesaroni, C. Badaloni, F. Forastiere, I. Tamayo, P. Amiano, M. Dorronsoro, A. Trichopoulou, C. Bamia, P. Vineis, and G. Hoek. 2013. Air pollution and lung cancer incidence in 17 European cohorts: Prospective analyses from the European Study of Cohorts for Air Pollution Effects (ESCAPE). The Lancet Oncology 14: 813–822.CrossRefGoogle Scholar
  9. 9.
    Wang, P., J.J. Cao, Z.X. Shen, Y.M. Han, S.C. Lee, Y. Huang, C.S. Zhu, Q.Y. Wang, H.M. Xu, and R.J. Huang. 2015. Spatial and seasonal variations of PM2.5 mass and species during 2010 in Xi’an, China. Sci Total Environ 508: 477–487.CrossRefGoogle Scholar
  10. 10.
    Pope, C.A., III, R.T. Burnett, D. Krewski, M. Jerrett, Y. Shi, E.E. Calle, and M.J. Thun. 2009. Cardiovascular mortality and exposure to airborne fine particulate matter and cigarette smoke: Shape of the exposure-response relationship. Circulation 120: 941–948.CrossRefGoogle Scholar
  11. 11.
    Rusconi, F., D. Catelan, G. Accetta, M. Peluso, R. Pistelli, F. Barbone, E. di Felice, A. Munnia, P. Murgia, L. Paladini, A. Serci, and A. Biggeri. 2011. Asthma symptoms, lung function, and markers of oxidative stress and inflammation in children exposed to oil refinery pollution. The Journal of Asthma 48: 84–90.CrossRefGoogle Scholar
  12. 12.
    Baroja-Mazo, A., F. Martin-Sanchez, A.I. Gomez, et al. 2014. The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nature Immunology 15: 738–748.CrossRefGoogle Scholar
  13. 13.
    Sayan, M., and B.T. Mossman. 2016. The NLRP3 inflammasome in pathogenic particle and fibre-associated lung inflammation and diseases. Particle and Fibre Toxicology 13: 51.CrossRefGoogle Scholar
  14. 14.
    Jo, E.K., J.K. Kim, D.M. Shin, and C. Sasakawa. 2016. Molecular mechanisms regulating NLRP3 inflammasome activation. Cellular & Molecular Immunology 13: 148–159.CrossRefGoogle Scholar
  15. 15.
    He, M., T. Ichinose, S. Yoshida, T. Ito, C. He, Y. Yoshida, K. Arashidani, H. Takano, G. Sun, and T. Shibamoto. 2017. PM2.5-induced lung inflammation in mice: Differences of inflammatory response in macrophages and type II alveolar cells. Journal of Applied Toxicology 37: 1203–1218.CrossRefGoogle Scholar
  16. 16.
    Scaranti, M.C., Gde Júnior, and A.O. Hoff. 2016. Vitamin D and cancer: Does it really matter? Current Opinion in Oncology 28: 205–209.CrossRefGoogle Scholar
  17. 17.
    Hewison, M. 2012. Vitamin D and immune function: An overview. The Proceedings of the Nutrition Society 71: 50–61.CrossRefGoogle Scholar
  18. 18.
    Uberti, F., D. Lattuada, V. Morsanuto, U. Nava, G. Bolis, G. Vacca, D.F. Squarzanti, C. Cisari, and C. Molinari. 2014. Vitamin D protects human endothelial cells from oxidative stress through the autophagic and survival pathways. The Journal of Clinical Endocrinology and Metabolism 99: 1367–1374.CrossRefGoogle Scholar
  19. 19.
    Hansdottir, S., M.M. Monick, N. Lovan, L. Powers, A. Gerke, and G.W. Hunninghake. 2010. Vitamin D decreases respiratory syncytial virus induction of NF-κB-linked chemokines and cytokines in airway epithelium while maintaining the antiviral state. Journal of Immunology 184: 965–974.CrossRefGoogle Scholar
  20. 20.
    Zhang, Y., D.Y. Leung, B.N. Richers, et al. 2012. Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. Journal of Immunology 188: 2127–2135.CrossRefGoogle Scholar
  21. 21.
    Korf, H., M. Wenes, B. Stijlemans, T. Takiishi, S. Robert, M. Miani, D.L. Eizirik, C. Gysemans, and C. Mathieu. 2012. 1,25-Dihydroxyvitamin D3 curtails the inflammatory and T cell stimulatory capacity of macrophages through an IL-10-dependent mechanism. Immunobiology 217: 1292–1300.CrossRefGoogle Scholar
  22. 22.
    McNally, P., C. Coughlan, G. Bergsson, M. Doyle, C. Taggart, L. Adorini, M.R. Uskokovic, B. el-Nazir, P. Murphy, P. Greally, C.M. Greene, and N.G. McElvaney. 2011. Vitamin D receptor agonists inhibit pro-inflammatory cytokine production from the respiratory epithelium in cystic fibrosis. Journal of Cystic Fibrosis 10: 428–434.CrossRefGoogle Scholar
  23. 23.
    Hansdottir, S., M.M. Monick, S.L. Hinde, N. Lovan, D.C. Look, and G.W. Hunninghake. 2008. Respiratory epithelial cells convert inactive vitamin D to its active form: Potential effects on host defense. Journal of Immunology 181: 7090–7099.CrossRefGoogle Scholar
  24. 24.
    Kennel, K.A., M.T. Drake, and D.L. Hurley. 2010. Vitamin D deficiency in adults: When to test and how to treat. Mayo Clinic Proceedings 85: 752–757 quiz 757-758.CrossRefGoogle Scholar
  25. 25.
    Breysse, C., P. Guillot, and G. Berrut. 2015. Study of vitamin D supplementation in people over 65 years in primary care. Geriatrie et psychologie neuropsychiatrie du vieillissement 13: 123–132.Google Scholar
  26. 26.
    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.CrossRefGoogle Scholar
  27. 27.
    Afzal, S., P. Lange, S.E. Bojesen, J.J. Freiberg, and B.G. Nordestgaard. 2014. Plasma 25-hydroxyvitamin D, lung function and risk of chronic obstructive pulmonary disease. Thorax 69: 24–31.CrossRefGoogle Scholar
  28. 28.
    Ginde, A.A., J.M. Mansbach, and Jr. Camargo CA. 2009. Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Archives of Internal Medicine 169: 384–390.CrossRefGoogle Scholar
  29. 29.
    Brehm, J.M., J.C. Celedón, M.E. Soto-Quiros, L. Avila, G.M. Hunninghake, E. Forno, D. Laskey, J.S. Sylvia, B.W. Hollis, S.T. Weiss, and A.A. Litonjua. 2009. Serum vitamin D levels and markers of severity of childhood asthma in Costa Rica. American Journal of Respiratory and Critical Care Medicine 179: 765–771.CrossRefGoogle Scholar
  30. 30.
    Peeters, P.M., I.M. Eurlings, T.N. Perkins, et al. 2014. Silica-induced NLRP3 inflammasome activation in vitro and in rat lungs. Particle and Fibre Toxicology 11: 58.CrossRefGoogle Scholar
  31. 31.
    Xin, L., J. Wang, L.W. Zhang, B. Che, G. Dong, G. Fan, and K. Cheng. 2016. Development of HSPA1A promoter-driven luciferase reporter gene assays in human cells for assessing the oxidative damage induced by silver nanoparticles. Toxicology and Applied Pharmacology 304: 9–17.CrossRefGoogle Scholar
  32. 32.
    Nakayama Wong, L.S., H.H. Aung, M.W. Lamé, T.C. Wegesser, and D.W. Wilson. 2011. Fine particulate matter from urban ambient and wildfire sources from California's San Joaquin Valley initiate differential inflammatory, oxidative stress, and xenobiotic responses in human bronchial epithelial cells. Toxicology In Vitro 25: 1895–1905.CrossRefGoogle Scholar
  33. 33.
    Deweirdt, J., J.F. Quignard, B. Crobeddu, A. Baeza-Squiban, J. Sciare, A. Courtois, S. Lacomme, E. Gontier, B. Muller, J.P. Savineau, R. Marthan, C. Guibert, and I. Baudrimont. 2017. Involvement of oxidative stress and calcium signaling in airborne particulate matter - induced damages in human pulmonary artery endothelial cells. Toxicology In Vitro 45: 340–350.CrossRefGoogle Scholar
  34. 34.
    Crobeddu, B., L. Aragao-Santiago, L.C. Bui, S. Boland, and A. Baeza Squiban. 2017. Oxidative potential of particulate matter 2.5 as predictive indicator of cellular stress. Environmental Pollution 230: 125–133.CrossRefGoogle Scholar
  35. 35.
    Nel, A.E., D. Diaz-Sanchez, and N. Li. 2001. The role of particulate pollutants in pulmonary inflammation and asthma: Evidence for the involvement of organic chemicals and oxidative stress. Current Opinion in Pulmonary Medicine 7: 20–26.CrossRefGoogle Scholar
  36. 36.
    Shi, T., R.P. Schins, A.M. Knaapen, et al. 2003. Hydroxyl radical generation by electron paramagnetic resonance as a new method to monitor ambient particulate matter composition. Journal of Environmental Monitoring 5: 550–556.CrossRefGoogle Scholar
  37. 37.
    Perret, A., and D. Pompon. 1998. Electron shuttle between membrane-bound cytochrome P450 3A4 and b 5 rules uncoupling mechanisms. Biochemistry 37: 11412–11424.CrossRefGoogle Scholar
  38. 38.
    Ng, D., N. Kokot, T. Hiura, et al. 1998. Macrophage activation by polycyclic aromatic hydrocarbons: Evidence for the involvement of stress-activated protein kinases, activator protein-1, and antioxidant response elements. Journal of Immunology 161: 942–951.Google Scholar
  39. 39.
    Li, R., L. Zhao, J. Tong, Y. Yan, and C. Xu. 2017. Fine particulate matter and sulfur dioxide coexposures induce rat lung pathological injury and inflammatory responses via TLR4/p38/NF-κB pathway. International Journal of Toxicology 36: 165–173.CrossRefGoogle Scholar
  40. 40.
    Zhang, Y., S. Wang, J. Zhu, C. Li, T. Zhang, H. Liu, Q. Xu, X. Ye, L. Zhou, and L. Ye. 2018. Effect of atmospheric PM2.5 on expression levels of NF-κB genes and inflammatory cytokines regulated by NF-κB in human macrophage. Inflammation 41: 784–794.CrossRefGoogle Scholar
  41. 41.
    Bömmel, H., M. Haake, P. Luft, J. Horejs-Hoeck, H. Hein, J. Bartels, C. Schauer, U. Pöschl, M. Kracht, and A. Duschl. 2003. The diesel exhaust component pyrene induces expression of IL-8 but not of eotaxin. International Immunopharmacology 3: 1371–1379.CrossRefGoogle Scholar
  42. 42.
    Li, N., M. Hao, R.F. Phalen, et al. 2003. Particulate air pollutants and asthma. A paradigm for the role of oxidative stress in PM-induced adverse health effects. Clinical Immunology 109: 250–265.CrossRefGoogle Scholar
  43. 43.
    Totlandsdal, A.I., F.R. Cassee, P. Schwarze, M. Refsnes, and M. Låg. 2010. Diesel exhaust particles induce CYP1A1 and pro-inflammatory responses via differential pathways in human bronchial epithelial cells. Particle and Fibre Toxicology 7: 41.CrossRefGoogle Scholar
  44. 44.
    Adams, J.S., and M. Hewison. 2010. Update in vitamin D. The Journal of Clinical Endocrinology and Metabolism 95: 471–478.CrossRefGoogle Scholar
  45. 45.
    Cantorna, M.T., L. Snyder, Y.D. Lin, and L.L. Yang. 2015. Vitamin D and 1,25(OH)2D regulation of T cells. Nutrients 7: 3011–3021.CrossRefGoogle Scholar
  46. 46.
    Haas, M.J., M. Jafri, K.R. Wehmeier, L.M. Onstead-Haas, and A.D. Mooradian. 2016. Inhibition of endoplasmic reticulum stress and oxidative stress by vitamin D in endothelial cells. Free Radical Biology & Medicine 99: 1–10.CrossRefGoogle Scholar
  47. 47.
    Tak, P.P., and G.S. Firestein. 2001. NF-κB: A key role in inflammatory diseases. The Journal of Clinical Investigation 107: 7–11.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.School of Public HealthMedical College of Soochow UniversitySuzhouChina
  2. 2.Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public HealthSoochow UniversitySuzhouChina
  3. 3.Suzhou Center for Disease Prevention and ControlSuzhouChina
  4. 4.Suzhou Industrial Park Centers for Disease Control and PreventionSuzhouChina
  5. 5.School for Radiological and Interdisciplinary Sciences (RAD-X)Soochow UniversitySuzhouChina
  6. 6.Institute of Environmental Pollution and HealthShanghai UniversityShanghaiChina

Personalised recommendations