Transforming growth factor β1 genotypes in relation to TGFβ1, interleukin-8, and tumor necrosis factor alpha in induced sputum and blood in cystic fibrosis

O Eickmeier, L v D Boom, F Schreiner, M J Lentze, D NGampolo, R Schubert, S Zielen, S Schmitt-Grohé, O Eickmeier, L v D Boom, F Schreiner, M J Lentze, D NGampolo, R Schubert, S Zielen, S Schmitt-Grohé

Abstract

Background: High-producer TGFβ1 genotypes are associated with severe lung disease in cystic fibrosis (CF), but studies combining IL-8, TNFα-, and TGFβ1(+genotype) levels and their impact on CF lung disease are scarce.

Aim: Assessing the relationship between TGF β 1, IL-8, and TNF- α and lung disease in CF in an exacerbation-free interval.

Methods: Twenty four patients delta F508 homozygous (median age 20.5 y, Shwachman score 75, FEV1(%) 83) and 8 controls (median age 27.5 y) were examined. TGF β 1 was assessed in serum and induced sputum (IS) by ELISA, for IL-8 and TNF- α by chemiluminescence in IS and whole blood. Genotyping was performed for TGF β 1 C-509T and T+869C utilizing RFLP.

Results: TGF β 1 in IS (CF/controls median 76.5/59.1 pg/mL, P < 0.074) was higher in CF. There was a negative correlation between TGF β 1 in serum and lung function (LF) (FEV1 (r = -0.488, P = 0.025), MEF 25 (r = -0.425, P = 0.055), and VC (r = -0.572, P = 0.007)). Genotypes had no impact on TGF β 1 in IS, serum, and LF. In IS TGF β 1 correlated with IL-8 (r = 0.593, P < 0.007) and TNF- α (r = 0.536, P < 0.018) in patients colonized by bacteria with flagellin.

Conclusion: TGF β 1 in serum not in IS correlates with LF. In patients colonized by bacteria with flagellin, TGF β 1 correlates with IL-8 and TNF- α in IS.

Figures

Figure 1
Figure 1
Log 10 TGFβ1 (pg/mL) in induced sputum in CF patients colonized by either P. aeruginosa, S. aureus, or S. maltophilia plotted as a function of Log 10 IL-8 with linear regression line (r = 0.593, P < 0.007).
Figure 2
Figure 2
Log 10 TGFβ1 (pg/mL) in induced sputum in CF patients colonized by either P. aeruginosa, S. aureus, or S. maltophilia plotted as a function of Log 10 TNF-alpha with linear regression line (r = 0.536, P < 0.018).
Figure 3
Figure 3
Log 10 TGFβ1 (pg/mL) in serum in CF patients plotted as a function of Log FEV1 (%) with linear regression line (r = −0.488, P < 0.025).
Figure 4
Figure 4
Log 10 TGFβ1 (pg/mL) in serum in CF patients plotted as a function of Log 10 MEF 25 (%) with linear regression line (r = −0.425, P < 0.055).
Figure 5
Figure 5
Log 10 TGFβ1 (pg/mL) in serum in CF patients plotted as a function of Log VC (%) with linear regression line (r = −0.572, P < 0.007).

References

    1. Arkwright PD, Laurie S, Super M, et al. TGF-β1 genotype and accelerated decline in lung function of patients with cystic fibrosis. Thorax. 2000;55(6):459–462.
    1. Arkwright PD, Pravica V, Geraghty PJ, et al. End-organ dysfunction in cystic fibrosis: association with angiotensin I converting enzyme and cytokine gene polymorphisms. The American Journal of Respiratory and Critical Care Medicine. 2003;167(3):384–389.
    1. Drumm ML, Konstan MW, Schluchter MD, et al. Genetic modifiers of lung disease in cystic fibrosis. The New England Journal of Medicine. 2005;353(14):1443–1453.
    1. Corvol H, Boelle P, Brouard J, et al. Genetic variations in inflammatory mediators influence lung disease progression in cystic fibrosis. Pediatric Pulmonology. 2008;43(12):1224–1232.
    1. Epstein FH. Role of transforming growth factor β in human disease. The New England Journal of Medicine. 2000;342(18):1350–1358.
    1. Pittet JF, Griffiths MJD, Geiser T, et al. TGF-β is a critical mediator of acute lung injury. Journal of Clinical Investigation. 2001;107(12):1537–1544.
    1. Sheppard D. Transforming growth factor β: a central modulator of pulmonary and airway inflammation and fibrosis. Proceedings of the American Thoracic Society. 2006;3(5):413–417.
    1. Schwarz KB, Rosensweig J, Sharma S, et al. Plasma markers of platelet activation in cystic fibrosis liver and lung disease. Journal of Pediatric Gastroenterology and Nutrition. 2003;37(2):187–191.
    1. Peterson-Carmichael SL, Harris WT, Goel R, et al. Association of lower airway inflammation with physiologic findings in young children with cystic fibrosis. Pediatric Pulmonology. 2009;44(5):503–511.
    1. Harris WT, Muhlebach MS, Oster RA, Knowles MR, Noah TL. Transforming growth factor-β1 in bronchoalveolar lavage fluid from children with cystic fibrosis. Pediatric Pulmonology. 2009;44(11):1057–1064.
    1. Harris WT, Muhlebach MS, Oster RA, Knowles MR, Clancy JP, Noah TL. Plasma TGF-β1 in pediatric cystic fibrosis: potential biomarker of lung disease and response to therapy. Pediatric Pulmonology. 2011;46(7):688–695.
    1. Yang J, Wang D, Sun T. Flagellin of Pseudomonas aeruginosa induces transforming growth factor β 1 expression in normal bronchial epithelial cells through mitogen activated protein kinase cascades. Chinese Medical Journal. 2011;124(4):599–605.
    1. Snodgrass SM, Cihil KM, Cornuet P, Myerburg MM, Swiatecka-Urban A. TGF-β1 inhibits CFTR biogenesis and prevents functional rescue of delF08-CFTR in primary differentiated human bronchial epithelial cells. PLoS ONE. 2013;8(5)e63167
    1. Schmitt-Grohé S, Naujoks C, Bargon J, et al. Interleukin-8 in whole blood and clinical status in cystic fibrosis. Cytokine. 2005;29(1):18–23.
    1. Schmitt-Grohé S, Stüber F, Book M, et al. TNF-α promoter polymorphism in relation to TNF-α production and clinical status in cystic fibrosis. Lung. 2006;184(2):99–104.
    1. Holz O, Jörres RA, Koschyk S, Speckin P, Welker L, Magnussen H. Changes in sputum composition during sputum induction in healthy and asthmatic subjects. Clinical and Experimental Allergy. 1998;28(3):284–292.
    1. Munger JS, Huang X, Kawakatsu H, et al. The integrin αvβ6 binds and activates latent TGFβ1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell. 1999;96(3):319–328.
    1. Mu D, Cambier S, Fjellbirkeland L, et al. The integrin ανβ8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-β1. Journal of Cell Biology. 2002;157(3):493–507.
    1. Abbas AR, Baldwin D, Ma Y, et al. Immune response in silico (IRIS): immune-specific genes identified from a compendium of microarray expression data. Genes and Immunity. 2005;6(4):319–331.
    1. Guo W, Dong Z, Guo Y, et al. Polymorphisms of transforming growth factor-β1 associated with increased risk of gastric cardia adenocarcinoma in North China. International Journal of Immunogenetics. 2011;38(3):215–224.
    1. Parker D, Prince A. Epithelial uptake of flagella initiates proinflammatory signaling. PLoS ONE. 2013;8(3)e59932
    1. Shaykhiev R, Behr J, Bals R. Microbial patterns signaling via toll-like receptors 2 and 5 contribute to epithelial repair, growth and survival. PLoS ONE. 2008;3(1)e1393
    1. Zgair AK, Chhibber S. Stenotrophomonas maltophilia flagellin induces compartmentalized innate immune response in mouse lung. Journal of Medical Microbiology. 2010;59(8):913–919.
    1. Hartl D, Latzin P, Hordijk P, et al. Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease. Nature Medicine. 2007;13(12):1423–1430.
    1. Pollard HB, Eidelman O, Glasman M, et al. IL-8 promoter’omics in CF lung epithelial cells. Pediatric Pulmonology. 2006;(supplement 29):p. 249.
    1. Sagel SD, Wagner BD, Anthony MM, Emmett P, Zemanick ET. Sputum biomarkers of inflammation and lung function decline in children with cystic fibrosis. The American Journal of Respiratory and Critical Care Medicine. 2012;186(9):857–865.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir