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Respiratory Research
Published in: Respiratory Research 1/2006

Open Access 01-12-2006 | Research

Arsenic trioxide, a potent inhibitor of NF-κB, abrogates allergen-induced airway hyperresponsiveness and inflammation

Authors: Lin-Fu Zhou, Yi Zhu, Xue-Fan Cui, Wei-Ping Xie, Ai-Hua Hu, Kai-Sheng Yin

Published in: Respiratory Research | Issue 1/2006

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Abstract

Background

Overactivation of nuclear factor κB (NF-κB) orchestrates airway eosinophilia, but does not dampen airway hyperresponsiveness in asthma. NF-κB repression by arsenic trioxide (As2O3) contributes to apoptosis of eosinophils (EOS) in airways. Here we provide evidence that As2O3 abrogates allergen (OVA)-induced airway eosinophilia by modulating the expression of IκBα, an NF-κB inhibitory protein, and decreases the airway hyperresponsiveness.

Methods

Using a murine model of asthma, the airway hyperresponsiveness was conducted by barometric whole-body plethysmography. Airway eosinophilia, OVA-specific IgE in serum, and chemokine eotaxin and RANTES (regulated upon activation, normal T cell expressed and secreted) in bronchoalveolar lavage fluid were measured by lung histology, Diff-Quick staining, and ELISA. Chemokine-induced EOS chemotactic activity was evaluated using EOS chemotaxis assay. Electrophoretic mobility shift assay and Western blot analysis were performed to assess pulmonary NF-κB activation and IκBα expression, respectively.

Results

As2O3 attenuated the allergen-induced serum IgE, chemokine expression of eotaxin and RANTES, and the EOS recruitment in bronchoalveolar lavage fluid, which is associated with an increased IκBα expression as well as a decreased NF-κB activation. Also, As2O3 suppressed the chemotaxis of EOS dose-dependently in vitro. Additionally, As2O3 significantly ameliorated the allergen-driven airway hyperresponsiveness, the cardinal feature underlying asthma.

Conclusion

These findings demonstrate an essential role of NF-κB in airway eosinophilia, and illustrate a potential dissociation between airway inflammation and hyperresponsiveness. As2O3 likely exerts its broad anti-inflammatory effects by suppression of NF-κB activation through augmentation of IκBα expression in asthma.
Literature
1.
Zhou LF, Zhang MS, Yin KS, Ji Y, Xie WP, Cui XF, Ji XH: Effects of adenoviral gene transfer of mutated IκBα, a novel inhibitor of NF-κB, on human monocyte-derived dendritic cells. Acta Pharmacol Sin 2006, 27:609–616.CrossRefPubMed
2.
Trautmann A, Schmid-Grendelmeier P, Kruger K, Crameri R, Akids M, Akkaya A, Brocker EB, Blaser K, Akdis CA: T cells and eosinophils cooperate in the induction of bronchial epithelial cell apoptosis in asthma. J Allergy Clin Immunol 2002, 109:329–337.CrossRefPubMed
3.
Fujihara S, Ward C, Dransfield I, Hay RT, Uings IJ, Hayes B, Farrow SN, Haslett C, Rossi AG: Inhibition of nuclear factor-κB activation un-masks the ability of TNF-α to induce human eosinophil apoptosis. Eur J Immunol 2002, 32:457–466.CrossRefPubMed
4.
Hart L, Lim S, Adcock I, Barnes PJ, Chung KF: Effects of inhaled corticosteroid therapy on expression and DNA-binding activity of nuclear factor κB in asthma. Am J Respir Crit Care Med 2000, 161:224–231.CrossRefPubMed
5.
Chen F, Castranova V, Li Z, Karin M, Shi X: Inhibitor of nuclear factor kappaB kinase deficiency enhances oxidative stress and prolongs c-Jun NH2-terminal kinase activation induced by arsenic. Cancer Res 2003, 63:7689–7693.PubMed
6.
Yang G, Abate A, George AG, Weng YH, Dennery PA: Maturational differences in lung NF-κB activation and their role in tolerance to hyperoxia. J Clin Invest 2004, 114:669–678.CrossRefPubMedPubMedCentral
7.
Cui XF, Imaizumi T, Yoshida H, Tangji K, Matsumiya T, Sato K: Lipopolysaccharide induces the expression of cellular inhibitor of apoptosis protein-2 in human macrophages. Biochim Biophys Acta 2000, 1524:178–182.CrossRefPubMed
8.
Zheng PZ, Wang KK, Zhang QY, Huang QH, Du YZ, Zhang QH, Xiao DK, Shen SH, Imbeaud S, Eveno E, Zhao CJ, Chen YL, Fan HY, Waxman S, Auffray C, Jin G, Chen SJ, Chen Z, Zhang J: Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci USA 2005, 102:7653–7658.CrossRefPubMedPubMedCentral
9.
Christman JW, Sadikot RT, Blackwell TS: The role of nuclear factor-κB in pulmonary diseases. Chest 2000, 117:1482–1487.CrossRefPubMed
10.
Zhu Z, Zheng T, Homer RJ, Kim YK, Chen NY, Cohn L, Hamid Q, Elias JA: Acidic mammalian chitinase in asthmatic Th2 inflammation and IL-13 pathway activation. Science 2004, 304:1678–1682.CrossRefPubMed
11.
E1 Bakkouri K, Wullaert A, Haegman M, Heyninck K, Beyaert R: Adenoviral gene transfer of the NF-κB inhibitory protein ABIN-1 decreases allergic airway inflammation in a murine asthma model. J Biol Chem 2005, 280:17938–17944.CrossRef
12.
Shan X, Hu A, Veler H, Fatma S, Grunstein JS, Chuang S, Grunstein MM: Regulation of Toll-like receptor 4-induced pro-asthmatic changes in airway smooth muscle function by opposing actions of ERK1/2 and p38 MAPK signaling. Am J Physiol Lung Cell Mol Physiol 2006, 291:L324-L333.CrossRefPubMed
13.
Zhou LF, Yin KS: Inhibition of nuclear factor κB overexpression by arsenic trioxide contributes to apoptosis of pulmonary eosinophils in asthmatic guinea-pigs. Zhonghua Jie He He Hu Xi Za Zhi 2002, 25:439. Chinese
14.
Zhou LF, Yin KS, Zhou ZM: Role of low dosage arsenic trioxide on pulmonary dendritic cells in asthmatic mice. Chin J Integr Med 2003, 9:281–284.CrossRef
15.
Kline JN, Krieg AM, Waldschmidt TJ, Ballas ZK, Jain V, Businga TR: CpG oligodeoxynucleotides do not require TH1 cytokines to prevent eosinophilic airway inflammation in a murine model of asthma. J Allergy Clin Immunol 1999, 104:1258–1264.CrossRefPubMed
16.
Yang L, Cohn L, Zhang DH, Homer R, Ray A, Ray P: Essential role of nuclear factor κB in the induction of eosinophilia in allergic airway inflammation. J Exp Med 1998, 188:1739–1750.CrossRefPubMedPubMedCentral
17.
Chvatchko Y, Proudfoot AEI, Buser R, Juillard P, Alouani S, Kosco-Vibois M, Coyle AJ, Nibbs RJ, Graham G, Offord RE, Wells TNC: Inhibition of airway inflammation by amino-terminally modified RANTES/CC chemokine ligand 5 analogues is not mediated through CCR3. J Immunol 2003, 171:5498–5506.CrossRefPubMed
18.
Zhou LF, Yin KS, Zhu ZL, Zhu Y, Yao X, Mao H, Xie WP, Huang M: Adenovirus-mediated overexpression of novel mutated IκBα inhibits nuclear factor κB activation in endothelial cells. Chin Med J 2005, 118:1422–1428.PubMed
19.
Melgert BN, Postma DS, Kuipers I, Geerlings M, Luinge MA, van der Strate BW, Kerstjens HA, Timens W, Hylkema MN: Female mice are more susceptible to the development of allergic airway inflammation than male mice. Clin Exp Allergy 2005, 35:1496–1503.CrossRefPubMed
20.
21.
Kang BN, Tirumurugaan KG, Deshpande DA, Amrani Y, Panettieri RA, Walseth TF, Kannan MS: Transcriptional regulation of CD38 expression by tumor necrosis factor-alpha in human airway smooth muscle cells: role of NF-kappaB and sensitivity to glucocorticoids. FASEB J 2006, 20:1000–1002.CrossRefPubMed
22.
Grunstein MM, Veler H, Shan X, Larson J, Grunstein JS, Chuang S: Pro-asthmatic effects and mechanisms of action of the dust mite allergen, Der p 1, in airway smooth muscle. J Allergy Clin Immunol 2005, 116:94–101.CrossRefPubMed
23.
Hoffmann A, Levchenko A, Scott ML, Baltimore D: The IκB – NF-κB signaling module: temporal control and selective gene activation. Science 2002, 298:1241–1245.CrossRefPubMed
24.
25.
Kumar A, Lnu S, Malya R, Barron D, Moore J, Corry DB, Boriek AM: Mechanical stretch activates nuclear factor-kappaB, activator protein-1, and mitogen-activated protein kinases in lung parenchyma: implications in asthma. FASEB J 2003, 17:1800–1811.CrossRefPubMed
26.
Bureau F, Delhalle S, Bonizzi G, Fievez L, Dogne S, Kirschvink N, Vanderplasschen A, Merville MP, Bours V, Lekeux P: Mechanisms of persistent NF-kappaB activity in the bronchi of an animal model of asthma. J Immunol 2000, 165:5822–5830.CrossRefPubMed
27.
Hakonarson H, Halapi E, Whelan R, Gulcher J, Stefansson K, Grunstein MM: Association between IL-1beta/TNF-alpha-induced glucocorticoid-sensitive changes in multiple gene expression and altered responsiveness in airway smooth muscle. Am J Respir Cell Mol Biol 2001, 25:761–771.CrossRefPubMed
28.
Das J, Chen CH, Yang L, Cohn P, Ray P, Ray A: A critical role for NF-κB in GATA3 expression and TH2 differentiation in allergic airway inflammation. Nat Immunol 2001, 2:45–50.CrossRefPubMed
29.
Poynter ME, Cloots R, van Woerkom T, Butnor KJ, Vacek P, Taatjes DJ, Irvin CG, Janssen-Heininger YM: NF-κB activation in airways modulates allergic inflammation but not hyperresponsiveness. J Immunol 2004, 173:7003–7009.CrossRefPubMedPubMedCentral
30.
31.
Nishikubo K, Murata Y, Tamaki S, Imanaka-Yoshida K, Yuda N, Kai M, Takamura S, Sebald W, Adachi Y, Yasutomi Y: A single administration of interleukin-4 antagonistic mutant DNA inhibits allergic airway inflammation in a mouse modle of asthma. Gene Ther 2003, 10:2119–2125.CrossRefPubMed
32.
Kierstein S, Poulain FR, Cao Y, Grous M, Matias R, Kierstein G, Beers MF, Salmon M, Panettieri RJ Jr, Haczku A: Susceptibility to ozone-induced airway inflammation is associated with decreased levels of surfactant protein D. Respir Res 2006, 7:85.CrossRefPubMedPubMedCentral
33.
Mathas S, Lietz A, Janz M, Hainz M, Jundt F, Scheidereit C, Bommert K, Dorken B: Inhibition of NF-κB essentially contributes to arsenic-induced apoptosis. Blood 2003, 102:1028–1034.CrossRefPubMed
34.
Miyahara N, Swanson BJ, Takeda K, Taube C, Miyahara S, Kodama T, Dakhama A, Ott VL, Gelfand EW: Effector CD8 + T cells mediate inflammation and airway hyper-responsiveness. Nat Med 2004, 10:865–869.CrossRefPubMed
35.
36.
Boxall C, Holgate ST, Davies DE: The contribution of transforming growth factor-beta and epidermal growth factor signalling to airway remodelling in chronic asthma. Eur Respir J 2006, 27:208–229.CrossRefPubMed
37.
Yamamoto Y, Gaynor RB: Therapeutic potential of inhibition of the NF-κB pathway in the treatment of inflammation and cancer. J Clin Invest 2001, 107:135–142.CrossRefPubMedPubMedCentral
38.
Wong CK, Wang CB, Ip WK, Tian YP, Lam CW: Role of p38 MAPK and NF-κB for chemokine release in coculture of human eosinophils and bronchial epithelial cells. Clin Exp Immunol 2005, 139:90–100.CrossRefPubMedPubMedCentral
39.
Hakonarson H, Kim C, Whelan R, Campbell D, Grunstein MM: Bi-directional activation between human airway smooth muscle cells and T lymphocytes: role in induction of altered airway responsiveness. J Immunol 2001, 166:293–303.CrossRefPubMed
40.
Hu A, Wang F, Sellers JR: Mutations in human nonmuscle myosin IIA found in patients with May-Hegglin anomaly and Fechtner syndrome result in impaired enzymatic function. J Biol Chem 2002, 277:46512–46517.CrossRefPubMed
41.
Xie WP, Wang H, Ding JH, Wang H, Hu G: Effects of iptakalim hydrochloride, a novel K ATP channel opener, on pulmonary vascular remodeling in hypoxic rats. Life Sci 2004, 75:2065–2076.CrossRefPubMed
42.
Chilton PM, Mitchell TC: CD8 T cells require Bcl-3 for maximal gamma interferon production upon secondary exposure to antigen. Infect Immun 2006, 74:4180–4189.CrossRefPubMedPubMedCentral
Metadata
Title
Arsenic trioxide, a potent inhibitor of NF-κB, abrogates allergen-induced airway hyperresponsiveness and inflammation
Authors
Lin-Fu Zhou
Yi Zhu
Xue-Fan Cui
Wei-Ping Xie
Ai-Hua Hu
Kai-Sheng Yin
Publication date
01-12-2006
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2006
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/1465-9921-7-146

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