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Respiratory Research
Published in: Respiratory Research 1/2014

Open Access 01-12-2014 | Research

Vitamin D regulating TGF-β induced epithelial-mesenchymal transition

Authors: Kimberly D Fischer, Devendra K Agrawal

Published in: Respiratory Research | Issue 1/2014

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Abstract

Background

Subepithelial fibrosis is a characteristic hallmark of airway remodeling in asthma. A critical regulator of fibrosis, transforming growth factor β (TGF-β), can induce airway remodeling in epithelial cells through induction of epithelial-mesenchymal transition (EMT). Vitamin D has immunomodulatory functions, however, its effect on controlling subepithelial fibrosis is not known.

Methods

Human bronchial epithelial cells (BEAS-2B) were exposed to calcitriol followed by stimulation with TGF-β1 or TGF-β2. The protein expression and mRNA transcripts for E-cadherin, Snail, vimentin, and N-cadherin were analyzed by Western blot and qPCR. An invasion assay and scratch wound assay were performed to identify the migratory properties of the cells following treatments.

Results

TGF-β1 decreased E-cadherin expression and increased protein expression and mRNA transcripts of Snail, vimentin, and N-cadherin together with increased cell invasion and migration. TGF-β2 elicited migratory response similar to TGF-β1 but induced the expression of EMT markers differently from that by TGF-β1. Calcitriol attenuated TGF-β1- and TGF-β2-induced cell motility. Also, calcitriol inhibited the expression of EMT markers in TGF-β1-treated epithelial cells with less effect on TGF-β2.

Conclusions

These data suggest that calcitriol inhibits both migration and invasion induced by TGF-β1 and TGF-β2 in human airway epithelial cells. However, the regulatory effect of vitamin D in epithelial-mesenchymal transition was more effective to TGF-β1-induced changes. Thus, calcitriol could be a potential therapeutic agent in the prevention and management of subepithelial fibrosis and airway remodeling.
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Literature
1.
Morrill MS: The effects of maternal employment on the health of school-age children. J Health Econ. 2011, 30: 240-257. 10.1016/j.jhealeco.2011.01.001.PubMedCrossRef
2.
Kelly MM, O°Connor TM, Leigh R, Otis J, Gwozd C, Gauvreau GM, Gauldie J, O’Byrne PM: Effects of budesonide and formoterol on allergen-induced airway responses, inflammation, and airway remodeling in asthma. J Allergy Clin Immunol. 2010, 125: 349-356. 10.1016/j.jaci.2009.09.011. e13PubMedCrossRef
3.
Haussler MR, Jurutka PW, Mizwicki M, Norman AW: Vitamin D receptor (VDR)-mediated actions of 1α,25(OH)2vitamin D3: genomic and non-genomic mechanisms. Best Pract Res Clin Endocrinol Metab. 2011, 25: 543-559. 10.1016/j.beem.2011.05.010. [Vitamin D: Classical and Novel Actions]PubMedCrossRef
4.
Akinbami LJ, Moorman JE, Bailey C, Zahran HS, King M, Johnson CA, Liu X: Trends in asthma prevalence, health care use, and mortality in the United States, 2001-2010. NCHS Data Brief. 2012, (May; (94)): 1-8.
5.
6.
Krstic G: Asthma prevalence associated with geographical latitude and regional insolation in the United States of America and Australia. PLoS One. 2011, 6: e18492-10.1371/journal.pone.0018492.PubMedPubMedCentralCrossRef
7.
Litonjua AA, Weiss ST: Is vitamin D deficiency to blame for the asthma epidemic?. J Allergy Clin Immunol. 2007, 120: 1031-1035. 10.1016/j.jaci.2007.08.028.PubMedCrossRef
8.
Bener A, Ehlayel MS, Tulic MK, Hamid Q: Vitamin D deficiency as a strong predictor of asthma in children. Int Arch Allergy Immunol. 2012, 157: 168-175. 10.1159/000323941.PubMedCrossRef
9.
Freishtat RJ, Iqbal SF, Pillai DK, Klein CJ, Ryan LM, Benton AS, Teach SJ: High prevalence of Vitamin D deficiency among Inner-City African American Youth with asthma in Washington, DC. J Pediatr. 2010, 156: 948-952. 10.1016/j.jpeds.2009.12.033.PubMedPubMedCentralCrossRef
10.
11.
Majak P, Olszowiec-Chlebna M, Smejda K, Stelmach I: Vitamin D supplementation in children may prevent asthma exacerbation triggered by acute respiratory infection. J Allergy Clin Immunol. 2011, 127: 1294-1296. 10.1016/j.jaci.2010.12.016.PubMedCrossRef
12.
Castro M, King TS, Kunselman SJ, Cabana MD, Denlinger L, Holguin F, Kazani SD, Moore WC, Moy J, Sorkness CA, Avila P, Bacharier LB, Bleecker E, Boushey HA, Chmiel J, Fitzpatrick AM, Gentile D, Hundal M, Israel E, Kraft M, Krishnan JA, LaForce C, Lazarus SC, Lemanske R, Lugogo N, Martin RJ, Mauger DT, Naureckas E, Peters SP, Phipatanakul W, et al: Effect of vitamin d3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin d levels: the vida randomized clinical trial. JAMA. 2014, 311: 2083-2091. 10.1001/jama.2014.5052.PubMedPubMedCentralCrossRef
13.
Bar Yoseph R, Livnat G, Schnapp Z, Hakim F, Dabbah H, Goldbart A, Bentur L: The effect of vitamin D on airway reactivity and inflammation in asthmatic children: a double-blind placebo-controlled trial. Pediatr Pulmonol. 2014, -in press
14.
Foong RE, Shaw NC, Berry LJ, Hart PH, Gorman S, Zosky GR: Vitamin D deficiency causes airway hyperresponsiveness, increases airway smooth muscle mass, and reduces TGF-β expression in the lungs of female BALB/c mice. Physiol Rep. 2014, 2: e00276-10.1002/phy2.276.PubMedPubMedCentralCrossRef
15.
Agrawal T, Gupta GK, Agrawal DK: Calcitriol decreases expression of importin α3 and attenuates RelA translocation in human bronchial smooth muscle cells. J Clin Immunol. 2012, 32: 1093-1103. 10.1007/s10875-012-9696-x.PubMedPubMedCentralCrossRef
16.
Minshall EM, Leung DY, Martin RJ, Song YL, Cameron L, Ernst P, Hamid Q: Eosinophil-associated TGF-beta1 mRNA expression and airways fibrosis in bronchial asthma. Am J Respir Cell Mol Biol. 1997, 17: 326-333. 10.1165/ajrcmb.17.3.2733.PubMedCrossRef
17.
Kim DY, Kwon EY, Hong GU, Lee YS, Lee S-H, Ro JY: Cigarette smoke exacerbates mouse allergic asthma through Smad proteins expressed in mast cells. Respir Res. 2011, 12: 49-10.1186/1465-9921-12-49.PubMedPubMedCentralCrossRef
18.
Bousquet J, Jeffery PK, Busse WW, Johnson M, Vignola AM: Asthma from bronchoconstriction to airways inflammation and remodeling. Am J Respir Crit Care Med. 2000, 161: 1720-1745. 10.1164/ajrccm.161.5.9903102.PubMedCrossRef
19.
Heijink IH, Postma DS, Noordhoek JA, Broekema M, Kapus A: House dust mite-promoted epithelial-to-mesenchymal transition in human bronchial epithelium. Am J Respir Cell Mol Biol. 2010, 42: 69-79. 10.1165/rcmb.2008-0449OC.PubMedCrossRef
20.
Hackett T-L, Warner SM, Stefanowicz D, Shaheen F, Pechkovsky DV, Murray LA, Argentieri R, Kicic A, Stick SM, Bai TR, Knight DA: Induction of epithelial-mesenchymal transition in primary airway epithelial cells from patients with asthma by transforming growth factor-β1. Am J Respir Crit Care Med. 2009, 180: 122-133. 10.1164/rccm.200811-1730OC.PubMedCrossRef
21.
Vincent T, Neve EPA, Johnson JR, Kukalev A, Rojo F, Albanell J, Pietras K, Virtanen I, Philipson L, Leopold PL, Crystal RG, de Herreros AG, Moustakas A, Pettersson RF, Fuxe J: A SNAIL1 sMAD3/4 transcriptional repressor complex promotes TGF-β mediated epithelial-mesenchymal transition. Nat Cell Biol. 2009, 11: 943-950. 10.1038/ncb1905.PubMedPubMedCentralCrossRef
22.
Johnson JR, Roos A, Berg T, Nord M, Fuxe J: Chronic respiratory aeroallergen exposure in mice induces epithelial-mesenchymal transition in the large airways. PLoS One. 2011, 6: e16175-10.1371/journal.pone.0016175.PubMedPubMedCentralCrossRef
23.
Balzar S, Chu HW, Silkoff P, Cundall M, Trudeau JB, Strand M, Wenzel S: Increased TGF-beta2 in severe asthma with eosinophilia. J Allergy Clin Immunol. 2005, 115: 110-117. 10.1016/j.jaci.2004.09.034.PubMedCrossRef
24.
Torrego A, Hew M, Oates T, Sukkar M, Fan Chung K: Expression and activation of TGF-beta isoforms in acute allergen-induced remodelling in asthma. Thorax. 2007, 62: 307-313. 10.1136/thx.2006.063487.PubMedPubMedCentralCrossRef
25.
Loughlin DT, Artlett CM: Modification of collagen by 3-Deoxyglucosone alters wound healing through differential regulation of p38 MAP kinase. PLoS One. 2011, 6: e18676-10.1371/journal.pone.0018676.PubMedPubMedCentralCrossRef
26.
Ito I, Waku T, Aoki M, Abe R, Nagai Y, Watanabe T, Nakajima Y, Ohkido I, Yokoyama K, Miyachi H, Shimizu T, Murayama A, Kishimoto H, Nagasawa K, Yanagisawa J: A nonclassical vitamin D receptor pathway suppresses renal fibrosis. J Clin Invest. 2013, 123: 4579-4594. 10.1172/JCI67804.PubMedPubMedCentralCrossRef
27.
28.
Micallef L, Vedrenne N, Billet F, Coulomb B, Darby IA, Desmoulière A: The myofibroblast, multiple origins for major roles in normal and pathological tissue repair. Fibrogenesis Tissue Repair. 2012, 5 (Suppl 1 Proceedings of Fibroproliferative disorders: from biochemical analysis to targeted therapiesPetro E Petrides and David Brenner): S5-PubMedPubMedCentral
29.
Pain M, Bermudez O, Lacoste P, Royer P-J, Botturi K, Tissot A, Brouard S, Eickelberg O, Magnan A: Tissue remodelling in chronic bronchial diseases: from the epithelial to mesenchymal phenotype. Eur Respir Rev. 2014, 23: 118-130. 10.1183/09059180.00004413.PubMedCrossRef
30.
Câmara J, Jarai G: Epithelial-mesenchymal transition in primary human bronchial epithelial cells is Smad-dependent and enhanced by fibronectin and TNF-alpha. Fibrogenesis Tissue Repair. 2010, 3: 2-10.1186/1755-1536-3-2.PubMedPubMedCentralCrossRef
31.
Thevenot PT, Saravia J, Jin N, Giaimo JD, Chustz RE, Mahne S, Kelley MA, Hebert VY, Dellinger B, Dugas TR, Demayo FJ, Cormier SA: Radical-containing ultrafine particulate matter initiates epithelial-to-mesenchymal transitions in airway epithelial cells. Am J Respir Cell Mol Biol. 2013, 48: 188-197. 10.1165/rcmb.2012-0052OC.PubMedPubMedCentralCrossRef
32.
33.
Makinde T, Murphy RF, Agrawal DK: The regulatory role of TGF-β in airway remodeling in asthma. Immunol Cell Biol. 2007, 85: 348-356. 10.1038/sj.icb.7100044.PubMedCrossRef
34.
Bradding P, Roberts JA, Britten KM, Montefort S, Djukanovic R, Mueller R, Heusser CH, Howarth PH, Holgate ST: Interleukin-4, −5, and −6 and tumor necrosis factor-alpha in normal and asthmatic airways: evidence for the human mast cell as a source of these cytokines. Am J Respir Cell Mol Biol. 1994, 10: 471-480. 10.1165/ajrcmb.10.5.8179909.PubMedCrossRef
35.
McGee HS, Stallworth AL, Agrawal T, Shao Z, Lorence L, Agrawal DK: Fms-like tyrosine kinase 3 ligand decreases T helper type 17 cells and suppressors of cytokine signaling proteins in the lung of house dust mite-sensitized and -challenged mice. Am J Respir Cell Mol Biol. 2010, 43: 520-529. 10.1165/rcmb.2009-0241OC.PubMedPubMedCentralCrossRef
36.
Halwani R, Al-Muhsen S, Al-Jahdali H, Hamid Q: Role of transforming growth factor-β in airway remodeling in asthma. Am J Respir Cell Mol Biol. 2011, 44: 127-133. 10.1165/rcmb.2010-0027TR.PubMedCrossRef
37.
Batra V, Musani AI, Hastie AT, Khurana S, Carpenter KA, Zangrilli JG, Peters SP: Bronchoalveolar lavage fluid concentrations of transforming growth factor (TGF)-β1, TGF-β2, interleukin (IL)-4 and IL-13 after segmental allergen challenge and their effects on β-smooth muscle actin and collagen III synthesis by primary human lung fibroblasts. Clin Exp Allergy. 2004, 34: 437-444. 10.1111/j.1365-2222.2004.01885.x.PubMedCrossRef
38.
Bottoms SE, Howell JE, Reinhardt AK, Evans IC, McAnulty RJ: TGF-β isoform specific regulation of airway inflammation and remodelling in a murine model of asthma. PLoS One. 2010, 5: e9674-10.1371/journal.pone.0009674.PubMedPubMedCentralCrossRef
39.
Holgate ST, Davies DE, Puddicombe S, Richter A, Lackie P, Lordan J, Howarth P: Mechanisms of airway epithelial damage: epithelial-mesenchymal interactions in the pathogenesis of asthma. Eur Respir J. 2003, 22 (44 suppl): 24s-29s. 10.1183/09031936.03.00000803.CrossRef
40.
Doerner AM, Zuraw BL: TGF-β1 induced epithelial to mesenchymal transition (EMT) in human bronchial epithelial cells is enhanced by IL-1β but not abrogated by corticosteroids. Respir Res. 2009, 10: 100-10.1186/1465-9921-10-100.PubMedPubMedCentralCrossRef
41.
Zhang M, Zhang Z, Pan H-Y, Wang D-X, Deng Z-T, Ye X-L: TGF-beta1 induces human bronchial epithelial cell-to-mesenchymal transition in vitro. Lung. 2009, 187: 187-194. 10.1007/s00408-009-9139-5.PubMedCrossRef
42.
Ramirez AM, Wongtrakool C, Welch T, Steinmeyer A, Zügel U, Roman J: Vitamin D inhibition of pro-fibrotic effects of transforming growth factor β1 in lung fibroblasts and epithelial cells. J Steroid Biochem Mol Biol. 2010, 118: 142-150. 10.1016/j.jsbmb.2009.11.004.PubMedPubMedCentralCrossRef
43.
Banerjee A, Damera G, Bhandare R, Gu S, Lopez-Boado YS, Panettieri RA, Tliba O: Vitamin D and glucocorticoids differentially modulate chemokine expression in human airway smooth muscle cells. Br J Pharmacol. 2008, 155: 84-92. 10.1038/bjp.2008.232.PubMedPubMedCentralCrossRef
44.
Muehleisen B, Gallo RL: Vitamin D in allergic disease: shedding light on a complex problem. J Allergy Clin Immunol. 2013, 131: 324-329. 10.1016/j.jaci.2012.12.1562.PubMedCrossRef
45.
Boxall C, Holgate ST, Davies DE: The contribution of transforming growth factor-β and epidermal growth factor signalling to airway remodelling in chronic asthma. Eur Respir J. 2006, 27: 208-229. 10.1183/09031936.06.00130004.PubMedCrossRef
46.
Agrawal T, Gupta GK, Agrawal DK: Vitamin D supplementation reduces airway hyperresponsiveness and allergic airway inflammation in a murine model. Clin Exp Allergy J Br Soc Allergy Clin Immunol. 2013, 43: 672-683.
47.
Hansdottir S, Monick MM, Hinde SL, Lovan N, Look DC, Hunninghake GW: Respiratory epithelial cells convert inactive vitamin D to its active form: potential effects on host defense. J Immunol Baltim Md 1950. 2008, 181: 7090-7099.
48.
Bernabeu C, Lopez-Novoa JM, Quintanilla M: The emerging role of TGF-β superfamily coreceptors in cancer. Biochim Biophys Acta BBA - Mol Basis Dis. 2009, 1792: 954-973. 10.1016/j.bbadis.2009.07.003.CrossRef
49.
Johnson JR, Nishioka M, Chakir J, Risse P-A, Almaghlouth I, Bazarbashi AN, Plante S, Martin JG, Eidelman D, Hamid Q: IL-22 contributes to TGF-β1-mediated epithelial-mesenchymal transition in asthmatic bronchial epithelial cells. Respir Res. 2013, 14: 118-10.1186/1465-9921-14-118.PubMedPubMedCentralCrossRef
50.
Ji X, Li J, Xu L, Wang W, Luo M, Luo S, Ma L, Li K, Gong S, He L, Zhang Z, Yang P, Zhou Z, Xiang X, Wang C-Y: IL4 and IL-17A provide a Th2/Th17-polarized inflammatory milieu in favor of TGF-β1 to induce bronchial epithelial-mesenchymal transition (EMT). Int J Clin Exp Pathol. 2013, 6: 1481-1492.PubMedPubMedCentral
51.
Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat M-L, Gabbiani G: The myofibroblast: one function, multiple origins. Am J Pathol. 2007, 170: 1807-1816. 10.2353/ajpath.2007.070112.PubMedPubMedCentralCrossRef
52.
Wang W-C, Kuo C-Y, Tzang B-S, Chen H-M, Kao S-H: IL-6 augmented motility of airway epithelial cell BEAS-2B via Akt/GSK-3β signaling pathway. J Cell Biochem. 2012, 113: 3567-3575. 10.1002/jcb.24235.PubMedCrossRef
53.
Zhou B, Liu Y, Kahn M, Ann DK, Han A, Wang H, Nguyen C, Flodby P, Zhong Q, Krishnaveni MS, Liebler JM, Minoo P, Crandall ED, Borok Z: Interactions between β-catenin and transforming growth factor-β signaling pathways mediate epithelial-mesenchymal transition and are dependent on the transcriptional co-activator cAMP-response element-binding protein (CREB)-binding protein (CBP). J Biol Chem. 2012, 287: 7026-7038. 10.1074/jbc.M111.276311.PubMedPubMedCentralCrossRef
54.
Chow JYC, Ban M, Wu HL, Nguyen F, Huang M, Chung H, Dong H, Carethers JM: TGF-beta downregulates PTEN via activation of NF-kappaB in pancreatic cancer cells. Am J Physiol Gastrointest Liver Physiol. 2010, 298: G275-G282. 10.1152/ajpgi.00344.2009.PubMedPubMedCentralCrossRef
55.
Agrawal T, Gupta GK, Agrawal DK: Vitamin D deficiency decreases the expression of VDR and prohibitin in the lungs of mice with allergic airway inflammation. Exp Mol Pathol. 2012, 93: 74-81. 10.1016/j.yexmp.2012.04.004.PubMedPubMedCentralCrossRef
56.
57.
Wu S, Xia Y, Liu X, Sun J: Vitamin D receptor deletion leads to reduced level of IκBα protein through protein translation, protein-protein interaction, and post-translational modification. Int J Biochem Cell Biol. 2010, 42: 329-10.1016/j.biocel.2009.11.012.PubMedPubMedCentralCrossRef
Metadata
Title
Vitamin D regulating TGF-β induced epithelial-mesenchymal transition
Authors
Kimberly D Fischer
Devendra K Agrawal
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2014
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/s12931-014-0146-6

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