Impact of ozone exposure on the response to glucocorticoid in a mouse model of asthma: involvements of p38 MAPK and MKP-1

Respiratory Research

Xin Zhou¹  Pengyu Zhang¹  Yuqing Chen¹  Min Zhang¹  Feng Li¹  Aihua Bao¹ 

[1] Department of Respiratory Medicine, Shanghai First People’s Hospital, Shanghai Jiao tong University, 100 Haining Road, Shanghai 200080China

关键词: Asthma;    IL-17;    MKP-1;    p38 MAPK;    Glucocorticoids insensitivity;    Ozone;   

Others  :  1137256
DOI  :  10.1186/s12931-014-0126-x

 received in 2014-03-29, accepted in 2014-10-02,  发布年份 2014

【 摘 要 】

Background

Molecular mechanisms involved in the oxidative stress induced glucocorticoids insensitivity remain elusive. The mitogen-activated protein kinase phosphatase (MKP) 1 mediates a part of glucocorticoids action and can be modified by exogenous oxidants. Whether oxidant ozone (O₃) can affect the function of MKP-1 and hence blunt the response to corticotherapy is not clear.

Methods

Here we employed a murine model of asthma established with ovalbumin (OVA) sensitization and challenge to evaluate the influence of O₃ on the inhibitory effect of dexamethasone on AHR and airway inflammation, and by administration of SB239063, a selective p38 MAPK inhibitor, to explore the underlying involvements of the activation of p38 MAPK and the expression of MKP-1.

Results

Ozone exposure not only aggravated the pulmonary inflammation and AHR, but also decreased the inhibitory effects of dexamethasone, accompanied by the elevated oxidative stress, airway neutrophilia, enhanced phosphorylation of p38 MAPK, and upregulated expression of IL-17. Administration of SB239063 caused significant inhibition of the p38 MAPK phosphorylation, alleviation of the airway neutrophilia, and decrement of the ozone-induced IL-17 expression, and partly restored the ozone-impaired effects of dexamethasone. Ozone exposure not only decreased the protein expression of MKP-1, but also diminished the dexamethasone-mediated induction process of MKP-1 mRNA and protein expression.

Conclusions

The glucocorticoids insensitivity elicited by ozone exposure on current asthma model may involve the enhanced phosphorylation of p38 MAPK and disturbed expression of MKP-1.

【 授权许可】

   
2014 Bao et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]Barnes PJ, Adcock IM: Glucocorticoid resistance in inflammatory diseases. Lancet 2009, 373(9678):1905-1917.
• [2]King EM, Chivers JE, Rider CF, Minnich A, Giembycz MA, Newton R: Glucocorticoid repression of inflammatory gene expression shows differential responsiveness by transactivation- and transrepression-dependent mechanisms. PLoS One 2013, 8(1):e53936.
• [3]Andrew R, Clark JRSM, Tchen CR: Role of dual specificity phosphatases in biological responses to glucocorticoids. J Biol Chem 2008, 283(38):25765-25769.
• [4]Furst R, Schroeder T, Eilken HM, Bubik MF, Kiemer AK, Zahler S, Vollmar AM: MAPK phosphatase-1 represents a novel anti-inflammatory target of glucocorticoids in the human endothelium. FASEB J 2007, 21(1):74-80.
• [5]Maier JV, Brema S, Tuckermann J, Herzer U, Klein M, Stassen M, Moorthy A, Cato AC: Dual specificity phosphatase 1 knockout mice show enhanced susceptibility to anaphylaxis but are sensitive to glucocorticoids. Mol Endocrinol 2007, 21(11):2663-2671.
• [6]Abraham SM, Lawrence T, Kleiman A, Warden P, Medghalchi M, Tuckermann J, Saklatvala J, Clark AR: Antiinflammatory effects of dexamethasone are partly dependent on induction of dual specificity phosphatase 1. J Exp Med 2006, 203(8):1883-1889.
• [7]Li F, Zhang M, Hussain F, Triantaphyllopoulos K, Clark AR, Bhavsar PK, Zhou X, Chung KF: Inhibition of p38 MAPK-dependent bronchial contraction after ozone by corticosteroids. Eur Respir J 2011, 37(4):933-942.
• [8]Maneechotesuwan K, Yao X, Ito K, Jazrawi E, Usmani OS, Adcock IM, Barnes PJ: Suppression of GATA-3 nuclear import and phosphorylation: a novel mechanism of corticosteroid action in allergic disease. PLoS Med 2009, 6(5):e1000076.
• [9]Furst R, Zahler S, Vollmar AM: Dexamethasone-induced expression of endothelial mitogen-activated protein kinase phosphatase-1 involves activation of the transcription factors activator protein-1 and 3′,5′-cyclic adenosine 5′-monophosphate response element-binding protein and the generation of reactive oxygen species. Endocrinology 2008, 149(7):3635-3642.
• [10]Barnes PJ: Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease. J Allergy Clin Immunol 2013, 131(3):636-645.
• [11]Committee of the Environmental and Occupational Health Assembly of the American Thoracic Society Am J Respir Crit Care Med 1996, 153(1):3-50.
• [12]Bao A, Liang L, Li F, Min Z, Zhou X: Effects of acute ozone exposure on lung peak allergic inflammation of mice. Front Biosci 2013, 18:838-851.
• [13]Liang L, Li F, Bao A, Zhang M, Chung KF, Zhou X: Activation of p38 mitogen-activated protein kinase in ovalbumin and ozone-induced mouse model of asthma. Respirology 2013, 18(Supplement S3):20-29.
• [14]Stenfors N, Bosson J, Helleday R, Behndig AF, Pourazar J, Tornqvist H, Kelly FJ, Frew AJ, Sandstrom T, Mudway IS, Blomberg A: Ozone exposure enhances mast-cell inflammation in asthmatic airways despite inhaled corticosteroid therapy. Inhal Toxicol 2010, 22(2):133-139.
• [15]Williams AS, Issa R, Durham A, Leung SY, Kapoun A, Medicherla S, Higgins LS, Adcock IM, Chung KF: Role of p38 mitogen-activated protein kinase in ozone-induced airway hyperresponsiveness and inflammation. Eur J Pharmacol 2008, 600(1-3):117-122.
• [16]Wang JM, Denis M, Fournier M, Laviolette M: Cyclosporin A increases the pulmonary eosinophilia induced by inhaled Aspergillus antigen in mice. Clin Exp Immunol 1993, 93(3):323-330.
• [17]Pichavant M, Goya S, Meyer EH, Johnston RA, Kim HY, Matangkasombut P, Zhu M, Iwakura Y, Savage PB, DeKruyff RH, Shore SA, Umetsu DT: Ozone exposure in a mouse model induces airway hyperreactivity that requires the presence of natural killer T cells and IL-17. J Exp Med 2008, 205(2):385-393.
• [18]Hamelmann E, Schwarze J, Takeda K, Oshiba A, Larsen GL, Irvin CG, Gelfand EW: Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography. Am J Respir Crit Care Med 1997, 156(3 Pt 1):766-775.
• [19]Zhou LF, Zhu Y, Cui XF, Xie WP, Hu AH, Yin KS: Arsenic trioxide, a potent inhibitor of NF-kappaB, abrogates allergen-induced airway hyperresponsiveness and inflammation. Respir Res 2006, 7:146. BioMed Central Full Text
• [20]Lee KS, Lee HK, Hayflick JS, Lee YC, Puri KD: Inhibition of phosphoinositide 3-kinase delta attenuates allergic airway inflammation and hyperresponsiveness in murine asthma model. FASEB J 2006, 20(3):455-465.
• [21]Hulo S, Tiesset H, Lancel S, Edme JL, Viollet B, Sobaszek A, Neviere R: AMP-activated protein kinase deficiency reduces ozone-induced lung injury and oxidative stress in mice. Respir Res 2011, 12:64. BioMed Central Full Text
• [22]Dolezych B, Szulinska E: Selenium modifies glutathione peroxidase activity and glutathione concentration in mice exposed to ozone-provoked oxidative stress. J Trace Elem Med Biol 2003, 17(2):133-137.
• [23]Brondello JM, Pouyssegur J, McKenzie FR: Reduced MAP kinase phosphatase-1 degradation after p42/p44MAPK-dependent phosphorylation. Science 1999, 286(5449):2514-2517.
• [24]Sohaskey ML, Ferrell JE Jr: Activation of p42 mitogen-activated protein kinase (MAPK), but not c-Jun NH(2)-terminal kinase, induces phosphorylation and stabilization of MAPK phosphatase XCL100 in Xenopus oocytes. Mol Biol Cell 2002, 13(2):454-468.
• [25]Mihaescu A, Santen S, Jeppsson B, Thorlacius H: p38 Mitogen-activated protein kinase signalling regulates vascular inflammation and epithelial barrier dysfunction in an experimental model of radiation-induced colitis. Br J Surg 2010, 97(2):226-234.
• [26]Kim SR, Lee KS, Park SJ, Jeon MS, Lee YC: Inhibition of p38 MAPK reduces expression of vascular endothelial growth factor in allergic airway disease. J Clin Immunol 2012, 32(3):574-586.
• [27]Kim SR, Lee KS, Park SJ, Min KH, Lee MH, Lee KA, Bartov O, Atlas D, Lee YC: A novel dithiol amide CB3 attenuates allergic airway disease through negative regulation of p38 mitogen-activated protein kinase. Am J Respir Crit Care Med 2011, 183(8):1015-1024.
• [28]Larsen ST, Matsubara S, McConville G, Poulsen SS, Gelfand EW: Ozone increases airway hyperreactivity and mucus hyperproduction in mice previously exposed to allergen. J Toxicol Environ Health A 2010, 73(11):738-747.
• [29]Kierstein S, Krytska K, Sharma S, Amrani Y, Salmon M, Panettieri RA Jr, Zangrilli J, Haczku A: Ozone inhalation induces exacerbation of eosinophilic airway inflammation and hyperresponsiveness in allergen-sensitized mice. Allergy 2008, 63(4):438-446.
• [30]Schleimer RP: Glucocorticoids suppress inflammation but spare innate immune responses in airway epithelium. Proc Am Thorac Soc 2004, 1(3):222-230.
• [31]Ordonez CL, Shaughnessy TE, Matthay MA, Fahy JV: Increased neutrophil numbers and IL-8 levels in airway secretions in acute severe asthma: Clinical and biologic significance. Am J Respir Crit Care Med 2000, 161(4 Pt 1):1185-1190.
• [32]Ito K, Herbert C, Siegle JS, Vuppusetty C, Hansbro N, Thomas PS, Foster PS, Barnes PJ, Kumar RK: Steroid-resistant neutrophilic inflammation in a mouse model of an acute exacerbation of asthma. Am J Respir Cell Mol Biol 2008, 39(5):543-550.
• [33]Hirsch G, Lavoie-Lamoureux A, Beauchamp G, Lavoie JP: Neutrophils are not less sensitive than other blood leukocytes to the genomic effects of glucocorticoids. PLoS One 2012, 7(9):e44606.
• [34]Onda K, Nagashima M, Kawakubo Y, Inoue S, Hirano T, Oka K: Mitogen-activated protein kinase kinase 1/extracellular signal-regulated kinase (MEK-1/ERK) inhibitors sensitize reduced glucocorticoid response mediated by TNFalpha in human epidermal keratinocytes (HaCaT). Biochem Biophys Res Commun 2006, 351(1):266-272.
• [35]Van Bogaert T, Vandevyver S, Dejager L, Van Hauwermeiren F, Pinheiro I, Petta I, Engblom D, Kleyman A, Schutz G, Tuckermann J, Libert C: Tumor necrosis factor inhibits glucocorticoid receptor function in mice: a strong signal toward lethal shock. J Biol Chem 2011, 286(30):26555-26567.
• [36]Goleva E, Li LB, Leung DY: IFN-gamma reverses IL-2- and IL-4-mediated T-cell steroid resistance. Am J Respir Cell Mol Biol 2009, 40:223-230.
• [37]Bhavsar P, Khorasani N, Hew M, Johnson M, Chung KF: Effect of p38 MAPK inhibition on corticosteroid suppression of cytokine release in severe asthma. Eur Respir J 2010, 35:750-756.
• [38]Mercado N, Hakim A, Kobayashi Y, Meah S, Usmani OS, Chung KF, Barnes PJ, Ito K: Restoration of corticosteroid sensitivity by p38 mitogen activated protein kinase inhibition in peripheral blood mononuclear cells from severe asthma. PLoS One 2012, 7:e41582.
• [39]Irusen E, Matthews JG, Takahashi A, Barnes PJ, Chung KF, Adcock IM: p38 Mitogen-activated protein kinase-induced glucocorticoid receptor phosphorylation reduces its activity: role in steroid-insensitive asthma. J Allergy Clin Immunol 2002, 109:649-657.
• [40]Kasahara DI, Kim HY, Williams AS, Verbout NG, Tran J, Si H, Wurmbrand AP, Jastrab J, Hug C, Umetsu DT, Shore SA: Pulmonary inflammation induced by subacute ozone is augmented in adiponectin-deficient mice: role of IL-17A. J Immunol 2012, 188(9):4558-4567.
• [41]Zhou S, Potts EN, Cuttitta F, Foster WM, Sunday ME: Gastrin-releasing peptide blockade as a broad-spectrum anti-inflammatory therapy for asthma. Proc Natl Acad Sci U S A 2011, 108:2100-2105.
• [42]Gulen MF, Kang Z, Bulek K, Youzhong W, Kim TW, Chen Y, Altuntas CZ, Sass Bak-Jensen K, McGeachy MJ, Do JS, Xiao H, Delgoffe GM, Min B, Powell JD, Tuohy VK, Cua DJ, Li X: The receptor SIGIRR suppresses Th17 cell proliferation via inhibition of the interleukin-1 receptor pathway and mTOR kinase activation. Immunity 2010, 32(1):54-66.
• [43]Commodaro AG, Bombardieri CR, Peron JP, Saito KC, Guedes PM, Hamassaki DE, Belfort RN, Rizzo LV, Belfort R Jr, de Camargo MM: p38{alpha} MAP kinase controls IL-17 synthesis in vogt-koyanagi-harada syndrome and experimental autoimmune uveitis. Invest Ophthalmol Vis Sci 2010, 51:3567-3574.
• [44]McKinley L, Alcorn JF, Peterson A, Dupont RB, Kapadia S, Logar A, Henry A, Irvin CG, Piganelli JD, Ray A, Kolls JK: TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice. J Immunol 2008, 181(6):4089-4097.
• [45]Zijlstra GJ, Ten Hacken NH, Hoffmann RF, van Oosterhout AJ, Heijink IH: Interleukin-17A induces glucocorticoid insensitivity in human bronchial epithelial cells. Eur Respir J 2012, 39(2):439-445.
• [46]Vazquez-Tello A, Halwani R, Hamid Q, Al-Muhsen S: Glucocorticoid receptor-beta up-regulation and steroid resistance induction by IL-17 and IL-23 cytokine stimulation in peripheral mononuclear cells. J Clin Immunol 2013, 33(2):466-478.
• [47]Newton R, King EM, Gong W, Rider CF, Staples KJ, Holden NS, Bergmann MW: Glucocorticoids inhibit IL-1beta-induced GM-CSF expression at multiple levels: roles for the ERK pathway and repression by MKP-1. Biochem J 2010, 427(1):113-124.
• [48]Lasa M, Abraham SM, Boucheron C, Saklatvala J, Clark AR: Dexamethasone causes sustained expression of mitogen-activated protein kinase (MAPK) phosphatase 1 and phosphatase-mediated inhibition of MAPK p38. Mol Cell Biol 2002, 22(22):7802-7811.
• [49]Quante T, Ng YC, Ramsay EE, Henness S, Allen JC, Parmentier J, Ge Q, Ammit AJ: Corticosteroids reduce IL-6 in ASM cells via up-regulation of MKP-1. Am J Respir Cell Mol Biol 2008, 39(2):208-217.
• [50]Li J, Gorospe M, Hutter D, Barnes J, Keyse SM, Liu Y: Transcriptional induction of MKP-1 in response to stress is associated with histone H3 phosphorylation-acetylation. Mol Cell Biol 2001, 21(23):8213-8224.
• [51]Xu Q, Konta T, Nakayama K, Furusu A, Moreno-Manzano V, Lucio-Cazana J, Ishikawa Y, Fine LG, Yao J, Kitamura M: Cellular defense against H2O2-induced apoptosis via MAP kinase-MKP-1 pathway. Free Radic Biol Med 2004, 36(8):985-993.
• [52]Kuwano Y, Kim HH, Abdelmohsen K, Pullmann R Jr, Martindale JL, Yang X, Gorospe M: MKP-1 mRNA stabilization and translational control by RNA-binding proteins HuR and NF90. Mol Cell Biol 2008, 28(14):4562-4575.
• [53]Kim HS, Ullevig SL, Zamora D, Lee CF, Asmis R: Redox regulation of MAPK phosphatase 1 controls monocyte migration and macrophage recruitment. Proc Natl Acad Sci U S A 2012, 109(41):E2803-E2812.
• [54]Lin YW, Chuang SM, Yang JL: ERK1/2 achieves sustained activation by stimulating MAPK phosphatase-1 degradation via the ubiquitin-proteasome pathway. J Biol Chem 2003, 278(24):21534-21541.