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Respiratory Research
Published in: Respiratory Research 1/2012

Open Access 01-12-2012 | Research

Gene expression profiling following NRF2 and KEAP1 siRNA knockdown in human lung fibroblasts identifies CCL11/Eotaxin-1 as a novel NRF2 regulated gene

Authors: Jimmy Fourtounis, I-Ming Wang, Marie-Claude Mathieu, David Claveau, Tenneille Loo, Aimee L Jackson, Mette A Peters, Alex G Therien, Yves Boie, Michael A Crackower

Published in: Respiratory Research | Issue 1/2012

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Abstract

Background

Oxidative Stress contributes to the pathogenesis of many diseases. The NRF2/KEAP1 axis is a key transcriptional regulator of the anti-oxidant response in cells. Nrf2 knockout mice have implicated this pathway in regulating inflammatory airway diseases such as asthma and COPD. To better understand the role the NRF2 pathway has on respiratory disease we have taken a novel approach to define NRF2 dependent gene expression in a relevant lung system.

Methods

Normal human lung fibroblasts were transfected with siRNA specific for NRF2 or KEAP1. Gene expression changes were measured at 30 and 48 hours using a custom Affymetrix Gene array. Changes in Eotaxin-1 gene expression and protein secretion were further measured under various inflammatory conditions with siRNAs and pharmacological tools.

Results

An anti-correlated gene set (inversely regulated by NRF2 and KEAP1 RNAi) that reflects specific NRF2 regulated genes was identified. Gene annotations show that NRF2-mediated oxidative stress response is the most significantly regulated pathway, followed by heme metabolism, metabolism of xenobiotics by Cytochrome P450 and O-glycan biosynthesis. Unexpectedly the key eosinophil chemokine Eotaxin-1/CCL11 was found to be up-regulated when NRF2 was inhibited and down-regulated when KEAP1 was inhibited. This transcriptional regulation leads to modulation of Eotaxin-1 secretion from human lung fibroblasts under basal and inflammatory conditions, and is specific to Eotaxin-1 as NRF2 or KEAP1 knockdown had no effect on the secretion of a set of other chemokines and cytokines. Furthermore, the known NRF2 small molecule activators CDDO and Sulphoraphane can also dose dependently inhibit Eotaxin-1 release from human lung fibroblasts.

Conclusions

These data uncover a previously unknown role for NRF2 in regulating Eotaxin-1 expression and further the mechanistic understanding of this pathway in modulating inflammatory lung disease.
Appendix
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Literature
1.
Cho HY, Reddy SP, Kleeberger SR: Nrf2 defends the lung from oxidative stress. Antioxid Redox Signal. 2006, 8: 76-87. 10.1089/ars.2006.8.76.PubMedCrossRef
2.
Rahman I, Biswas SK, Kode A: Oxidant and antioxidant balance in the airways and airway diseases. Eur J Pharmacol. 2006, 533: 222-239. 10.1016/j.ejphar.2005.12.087.PubMedCrossRef
3.
Pope CA: Air pollution and health - good news and bad. N Engl J Med. 2004, 351: 1132-1134. 10.1056/NEJMe048182.PubMedCrossRef
4.
Emelyanov A, Fedoseev G, Abulimity A, Rudinski K, Fedoulov A, Karabanov A, et al: Elevated concentrations of exhaled hydrogen peroxide in asthmatic patients. Chest. 2001, 120: 1136-1139. 10.1378/chest.120.4.1136.PubMedCrossRef
5.
Smith LJ, Shamsuddin M, Sporn PH, Denenberg M, Anderson J: Reduced superoxide dismutase in lung cells of patients with asthma. Free Radic Biol Med. 1997, 22: 1301-1307. 10.1016/S0891-5849(96)00550-3.PubMedCrossRef
6.
Gerritsen WB, Asin J, Zanen P, van den Bosch JM, Haas FJ: Markers of inflammation and oxidative stress in exacerbated chronic obstructive pulmonary disease patients. Respir Med. 2005, 99: 84-90. 10.1016/j.rmed.2004.04.017.PubMedCrossRef
7.
Quinlan GJ, Evans TW, Gutteridge JM: 4-hydroxy-2-nonenal levels increase in the plasma of patients with adult respiratory distress syndrome as linoleic acid appears to fall. Free Radic Res. 1994, 21: 95-106. 10.3109/10715769409056561.PubMedCrossRef
8.
Roumen RM, Hendriks T, de Man BM, Goris RJ: Serum lipofuscin as a prognostic indicator of adult respiratory distress syndrome and multiple organ failure. Br J Surg. 1994, 81: 1300-1305. 10.1002/bjs.1800810913.PubMedCrossRef
9.
Abdala-Valencia H, Earwood J, Bansal S, Jansen M, Babcock G, Garvy B, et al: Nonhematopoietic NADPH oxidase regulation of lung eosinophilia and airway hyperresponsiveness in experimentally induced asthma. Am J Physiol Lung Cell Mol Physiol. 2007, 292: L1111-L1125. 10.1152/ajplung.00208.2006.PubMedPubMedCentralCrossRef
10.
Ciencewicki J, Trivedi S, Kleeberger SR: Oxidants and the pathogenesis of lung diseases. J Allergy Clin Immunol. 2008, 122: 456-468. 10.1016/j.jaci.2008.08.004.PubMedPubMedCentralCrossRef
11.
Diaz-Sanchez D, Jyrala M, Ng D, Nel A, Saxon A: In vivo nasal challenge with diesel exhaust particles enhances expression of the CC chemokines rantes, MIP-1alpha, and MCP-3 in humans. Clin Immunol. 2000, 97: 140-145. 10.1006/clim.2000.4921.PubMedCrossRef
12.
Hao M, Comier S, Wang M, Lee JJ, Nel A: Diesel exhaust particles exert acute effects on airway inflammation and function in murine allergen provocation models. J Allergy Clin Immunol. 2003, 112: 905-914. 10.1016/j.jaci.2003.07.005.PubMedCrossRef
13.
Kirkham P, Rahman I: Oxidative stress in asthma and COPD: antioxidants as a therapeutic strategy. Pharmacol Ther. 2006, 111: 476-494. 10.1016/j.pharmthera.2005.10.015.PubMedCrossRef
14.
Li N, Hao M, Phalen RF, Hinds WC, Nel AE: Particulate air pollutants and asthma. A paradigm for the role of oxidative stress in PM-induced adverse health effects. Clin Immunol. 2003, 109: 250-265. 10.1016/j.clim.2003.08.006.PubMedCrossRef
15.
Nel AE, Diaz-Sanchez D, Ng D, Hiura T, Saxon A: Enhancement of allergic inflammation by the interaction between diesel exhaust particles and the immune system. J Allergy Clin Immunol. 1998, 102: 539-554. 10.1016/S0091-6749(98)70269-6.PubMedCrossRef
16.
Papaiahgari S, Yerrapureddy A, Reddy SR, Reddy NM, Dodd O, Crow MT, et al: Genetic and pharmacologic evidence links oxidative stress to ventilator-induced lung injury in mice. Am J Respir Crit Care Med. 2007, 176: 1222-1235. 10.1164/rccm.200701-060OC.PubMedPubMedCentralCrossRef
17.
Whitekus MJ, Li N, Zhang M, Wang M, Horwitz MA, Nelson SK, et al: Thiol antioxidants inhibit the adjuvant effects of aerosolized diesel exhaust particles in a murine model for ovalbumin sensitization. J Immunol. 2002, 168: 2560-2567.PubMedCrossRef
18.
Adcock IM, Barnes PJ: Molecular mechanisms of corticosteroid resistance. Chest. 2008, 134: 394-401. 10.1378/chest.08-0440.PubMedCrossRef
19.
Nguyen T, Sherratt PJ, Pickett CB: Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annu Rev Pharmacol Toxicol. 2003, 43: 233-260. 10.1146/annurev.pharmtox.43.100901.140229.PubMedCrossRef
20.
Kobayashi M, Itoh K, Suzuki T, Osanai H, Nishikawa K, Katoh Y, et al: Identification of the interactive interface and phylogenic conservation of the Nrf2-Keap1 system. Genes Cells. 2002, 7: 807-820. 10.1046/j.1365-2443.2002.00561.x.PubMedCrossRef
21.
Kobayashi M, Yamamoto M: Nrf2-Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. Adv Enzyme Regul. 2006, 46: 113-140. 10.1016/j.advenzreg.2006.01.007.PubMedCrossRef
22.
Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, et al: Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol Cell Biol. 2004, 24: 7130-7139. 10.1128/MCB.24.16.7130-7139.2004.PubMedPubMedCentralCrossRef
23.
Kobayashi A, Kang MI, Watai Y, Tong KI, Shibata T, Uchida K, et al: Oxidative and electrophilic stresses activate Nrf2 through inhibition of ubiquitination activity of Keap1. Mol Cell Biol. 2006, 26: 221-229. 10.1128/MCB.26.1.221-229.2006.PubMedPubMedCentralCrossRef
24.
Kobayashi M, Yamamoto M: Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation. Antioxid Redox Signal. 2005, 7: 385-394. 10.1089/ars.2005.7.385.PubMedCrossRef
25.
Kobayashi M, Li L, Iwamoto N, Nakajima-Takagi Y, Kaneko H, Nakayama Y, et al: The antioxidant defense system Keap1-Nrf2 comprises a multiple sensing mechanism for responding to a wide range of chemical compounds. Mol Cell Biol. 2009, 29: 493-502. 10.1128/MCB.01080-08.PubMedPubMedCentralCrossRef
26.
Wakabayashi N, Itoh K, Wakabayashi J, Motohashi H, Noda S, Takahashi S, et al: Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Nat Genet. 2003, 35: 238-245. 10.1038/ng1248.PubMedCrossRef
27.
Pierrou S, Broberg P, O’Donnell RA, Pawlowski K, Virtala R, Lindqvist E, et al: Expression of genes involved in oxidative stress responses in airway epithelial cells of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007, 175: 577-586. 10.1164/rccm.200607-931OC.PubMedCrossRef
28.
Malhotra D, Thimmulappa R, Navas-Acien A, Sandford A, Elliott M, Singh A, et al: Decline in NRF2-regulated antioxidants in chronic obstructive pulmonary disease lungs due to loss of its positive regulator, DJ-1. Am J Respir Crit Care Med. 2008, 178: 592-604. 10.1164/rccm.200803-380OC.PubMedPubMedCentralCrossRef
29.
Adair-Kirk TL, Atkinson JJ, Griffin GL, Watson MA, Kelley DG, DeMello D, et al: Distal airways in mice exposed to cigarette smoke: Nrf2-regulated genes are increased in Clara cells. Am J Respir Cell Mol Biol. 2008, 39: 400-411. 10.1165/rcmb.2007-0295OC.PubMedPubMedCentralCrossRef
30.
Rangasamy T, Guo J, Mitzner WA, Roman J, Singh A, Fryer AD, et al: Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice. J Exp Med. 2005, 202: 47-59. 10.1084/jem.20050538.PubMedPubMedCentralCrossRef
31.
Iizuka T, Ishii Y, Itoh K, Kiwamoto T, Kimura T, Matsuno Y, et al: Nrf2-deficient mice are highly susceptible to cigarette smoke-induced emphysema. Genes Cells. 2005, 10: 1113-1125. 10.1111/j.1365-2443.2005.00905.x.PubMedCrossRef
32.
Rangasamy T, Cho CY, Thimmulappa RK, Zhen L, Srisuma SS, Kensler TW, et al: Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. J Clin Invest. 2004, 114: 1248-1259.PubMedPubMedCentralCrossRef
33.
Cho HY, Jedlicka AE, Reddy SP, Kensler TW, Yamamoto M, Zhang LY, et al: Role of NRF2 in protection against hyperoxic lung injury in mice. Am J Respir Cell Mol Biol. 2002, 26: 175-182.PubMedCrossRef
34.
Cho HY, Imani F, Miller-DeGraff L, Walters D, Melendi GA, Yamamoto M, et al: Antiviral activity of Nrf2 in a murine model of respiratory syncytial virus disease. Am J Respir Crit Care Med. 2009, 179: 138-150.PubMedPubMedCentralCrossRef
35.
Sussan TE, Rangasamy T, Blake DJ, Malhotra D, El Haddad H, Bedja D, et al: Targeting Nrf2 with the triterpenoid CDDO-imidazolide attenuates cigarette smoke-induced emphysema and cardiac dysfunction in mice. Proc Natl Acad Sci U S A. 2009, 106: 250-255. 10.1073/pnas.0804333106.PubMedPubMedCentralCrossRef
36.
Cho HY, Reddy SP, Debiase A, Yamamoto M, Kleeberger SR: Gene expression profiling of NRF2-mediated protection against oxidative injury. Free Radic Biol Med. 2005, 38: 325-343. 10.1016/j.freeradbiomed.2004.10.013.PubMedCrossRef
37.
Lee JM, Calkins MJ, Chan K, Kan YW, Johnson JA: Identification of the NF-E2-related factor-2-dependent genes conferring protection against oxidative stress in primary cortical astrocytes using oligonucleotide microarray analysis. J Biol Chem. 2003, 278: 12029-12038. 10.1074/jbc.M211558200.PubMedCrossRef
38.
Nair S, Xu C, Shen G, Hebbar V, Gopalakrishnan A, Hu R, et al: Toxicogenomics of endoplasmic reticulum stress inducer tunicamycin in the small intestine and liver of Nrf2 knockout and C57BL/6J mice. Toxicol Lett. 2007, 168: 21-39. 10.1016/j.toxlet.2006.10.012.PubMedPubMedCentralCrossRef
39.
Purdom-Dickinson SE, Lin Y, Dedek M, Morrissy S, Johnson J, Chen QM: Induction of antioxidant and detoxification response by oxidants in cardiomyocytes: evidence from gene expression profiling and activation of Nrf2 transcription factor. J Mol Cell Cardiol. 2007, 42: 159-176. 10.1016/j.yjmcc.2006.09.012.PubMedPubMedCentralCrossRef
40.
Thompson CA, Burcham PC: Genome-Wide Transcriptional Responses to Acrolein. Chem Res Toxicol. 2008, 21: 2245-2256. 10.1021/tx8001934.PubMedCrossRef
41.
Zhu L, Pi J, Wachi S, Andersen ME, Wu R, Chen Y: Identification of Nrf2-dependent airway epithelial adaptive response to proinflammatory oxidant-hypochlorous acid challenge by transcription profiling. Am J Physiol Lung Cell Mol Physiol. 2008, 294: L469-L477.PubMedCrossRef
42.
Barve A, Khor TO, Nair S, Lin W, Yu S, Jain MR, et al: Pharmacogenomic profile of soy isoflavone concentrate in the prostate of Nrf2 deficient and wild-type mice. J Pharm Sci. 2008, 97: 4528-4545. 10.1002/jps.21311.PubMedCrossRef
43.
Hu R, Xu C, Shen G, Jain MR, Khor TO, Gopalkrishnan A, et al: Identification of Nrf2-regulated genes induced by chemopreventive isothiocyanate PEITC by oligonucleotide microarray. Life Sci. 2006, 79: 1944-1955. 10.1016/j.lfs.2006.06.019.PubMedCrossRef
44.
Hu R, Xu C, Shen G, Jain MR, Khor TO, Gopalkrishnan A, et al: Gene expression profiles induced by cancer chemopreventive isothiocyanate sulforaphane in the liver of C57BL/6J mice and C57BL/6J/Nrf2 (-/-) mice. Cancer Lett. 2006, 243: 170-192. 10.1016/j.canlet.2005.11.050.PubMedCrossRef
45.
Kwak MK, Wakabayashi N, Itoh K, Motohashi H, Yamamoto M, Kensler TW: Modulation of gene expression by cancer chemopreventive dithiolethiones through the Keap1-Nrf2 pathway. Identification of novel gene clusters for cell survival. J Biol Chem. 2003, 278: 8135-8145. 10.1074/jbc.M211898200.PubMedCrossRef
46.
Reddy NM, Kleeberger SR, Yamamoto M, Kensler TW, Scollick C, Biswal S, et al: Genetic dissection of the Nrf2-dependent redox signaling-regulated transcriptional programs of cell proliferation and cytoprotection. Physiol Genomics. 2007, 32: 74-81. 10.1152/physiolgenomics.00126.2007.PubMedCrossRef
47.
Thimmulappa RK, Mai KH, Srisuma S, Kensler TW, Yamamoto M, Biswal S: Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res. 2002, 62: 5196-5203.PubMed
48.
Baglole CJ, Sime PJ, Phipps RP: Cigarette smoke-induced expression of heme oxygenase-1 in human lung fibroblasts is regulated by intracellular glutathione. Am J Physiol Lung Cell Mol Physiol. 2008, 295: L624-L636. 10.1152/ajplung.90215.2008.PubMedPubMedCentralCrossRef
49.
Al Muhsen S, Johnson JR, Hamid Q: Remodeling in asthma. J Allergy Clin Immunol. 2011, 128: 451-462. 10.1016/j.jaci.2011.04.047.PubMedCrossRef
50.
Johnson PR, Burgess JK: Airway smooth muscle and fibroblasts in the pathogenesis of asthma. Curr Allergy Asthma Rep. 2004, 4: 102-108. 10.1007/s11882-004-0054-9.PubMedCrossRef
51.
Zhou X, Hu H, Balzar S, Trudeau JB, Wenzel SE: MAPK regulation of IL-4/IL-13 receptors contributes to the synergistic increase in CCL11/eotaxin-1 in response to TGF-beta1 and IL-13 in human airway fibroblasts. J Immunol. 2012, 188: 6046-6054. 10.4049/jimmunol.1102760.PubMedPubMedCentralCrossRef
52.
Murata T, Shimada M, Sakakibara S, Yoshino T, Masuda T, Shintani T, et al: Synthesis and structure-activity relationships of novel IKK-beta inhibitors. Part 3: Orally active anti-inflammatory agents. Bioorg Med Chem Lett. 2004, 14: 4019-4022. 10.1016/j.bmcl.2004.05.041.PubMedCrossRef
53.
Honda T, Rounds BV, Bore L, Finlay HJ, Favaloro FG, Suh N, et al: Synthetic oleanane and ursane triterpenoids with modified rings A and C: a series of highly active inhibitors of nitric oxide production in mouse macrophages. J Med Chem. 2000, 43: 4233-4246. 10.1021/jm0002230.PubMedCrossRef
54.
Kittler R, Heninger AK, Franke K, Habermann B, Buchholz F: Production of endoribonuclease-prepared short interfering RNAs for gene silencing in mammalian cells. Nat Methods. 2005, 2: 779-784. 10.1038/nmeth1005-779.PubMedCrossRef
55.
Jackson AL, Bartz SR, Schelter J, Kobayashi SV, Burchard J, Mao M, et al: Expression profiling reveals off-target gene regulation by RNAi. Nat Biotechnol. 2003, 21: 635-637. 10.1038/nbt831.PubMedCrossRef
56.
Rothenberg ME, Hogan SP: The eosinophil. Annu Rev Immunol. 2006, 24: 147-174. 10.1146/annurev.immunol.24.021605.090720.PubMedCrossRef
57.
Li N, Nel AE: Role of the Nrf2-mediated signaling pathway as a negative regulator of inflammation: implications for the impact of particulate pollutants on asthma. Antioxid Redox Signal. 2006, 8: 88-98. 10.1089/ars.2006.8.88.PubMedCrossRef
58.
Li W, Khor TO, Xu C, Shen G, Jeong WS, Yu S, et al: Activation of Nrf2-antioxidant signaling attenuates NFkappaB-inflammatory response and elicits apoptosis. Biochem Pharmacol. 2008, 76: 1485-1489. 10.1016/j.bcp.2008.07.017.PubMedPubMedCentralCrossRef
59.
Huber MA, Denk A, Peter RU, Weber L, Kraut N, Wirth T: The IKK-2/Ikappa Balpha /NF-kappa B pathway plays a key role in the regulation of CCR3 and eotaxin-1 in fibroblasts. A critical link to dermatitis in Ikappa Balpha -deficient mice. J Biol Chem. 2002, 277: 1268-1275. 10.1074/jbc.M109358200.PubMedCrossRef
60.
Nair S, Doh ST, Chan JY, Kong AN, Cai L: Regulatory potential for concerted modulation of Nrf2- and Nfkb1-mediated gene expression in inflammation and carcinogenesis. Br J Cancer. 2008, 99: 2070-2082. 10.1038/sj.bjc.6604703.PubMedPubMedCentralCrossRef
61.
Ziegelbauer K, Gantner F, Lukacs NW, Berlin A, Fuchikami K, Niki T, et al: A selective novel low-molecular-weight inhibitor of IkappaB kinase-beta (IKK-beta) prevents pulmonary inflammation and shows broad anti-inflammatory activity. Br J Pharmacol. 2005, 145: 178-192. 10.1038/sj.bjp.0706176.PubMedPubMedCentralCrossRef
62.
Liby K, Hock T, Yore MM, Suh N, Place AE, Risingsong R, et al: The synthetic triterpenoids, CDDO and CDDO-imidazolide, are potent inducers of heme oxygenase-1 and Nrf2/ARE signaling. Cancer Res. 2005, 65: 4789-4798. 10.1158/0008-5472.CAN-04-4539.PubMedCrossRef
63.
Murray JI, Whitfield ML, Trinklein ND, Myers RM, Brown PO, Botstein D: Diverse and specific gene expression responses to stresses in cultured human cells. Mol Biol Cell. 2004, 15: 2361-2374. 10.1091/mbc.E03-11-0799.PubMedPubMedCentralCrossRef
64.
Pickett G, Seagrave J, Boggs S, Polzin G, Richter P, Tesfaigzi Y: Effects of 10 cigarette smoke condensates on primary human airway epithelial cells by comparative gene and cytokine expression studies. Toxicol Sci. 2010, 114: 79-89. 10.1093/toxsci/kfp298.PubMedPubMedCentralCrossRef
65.
Ammous Z, Hackett NR, Butler MW, Raman T, Dolgalev I, O’Connor TP, et al: Variability in small airway epithelial gene expression among normal smokers. Chest. 2008, 133: 1344-1353. 10.1378/chest.07-2245.PubMedPubMedCentralCrossRef
66.
Chen XL, Dodd G, Thomas S, Zhang X, Wasserman MA, Rovin BH, et al: Activation of Nrf2/ARE pathway protects endothelial cells from oxidant injury and inhibits inflammatory gene expression. Am J Physiol Heart Circ Physiol. 2006, 290: H1862-H1870. 10.1152/ajpheart.00651.2005.PubMedCrossRef
67.
Osburn WO, Yates MS, Dolan PD, Chen S, Liby KT, Sporn MB, et al: Genetic or pharmacologic amplification of nrf2 signaling inhibits acute inflammatory liver injury in mice. Toxicol Sci. 2008, 104: 218-227. 10.1093/toxsci/kfn079.PubMedPubMedCentralCrossRef
68.
Thimmulappa RK, Scollick C, Traore K, Yates M, Trush MA, Liby KT, et al: Nrf2-dependent protection from LPS induced inflammatory response and mortality by CDDO-Imidazolide. Biochem Biophys Res Commun. 2006, 351: 883-889. 10.1016/j.bbrc.2006.10.102.PubMedPubMedCentralCrossRef
69.
Jayaprakasam B, Doddaga S, Wang R, Holmes D, Goldfarb J, Li XM: Licorice Flavonoids Inhibit Eotaxin-1 Secretion by Human Fetal Lung Fibroblasts in Vitro. J Agric Food Chem. 2009, 57: 820-825. 10.1021/jf802601j.PubMedPubMedCentralCrossRef
70.
Nakajima T, Imanishi M, Yamamoto K, Cyong JC, Hirai K: Inhibitory effect of baicalein, a flavonoid in Scutellaria Root, on eotaxin production by human dermal fibroblasts. Planta Med. 2001, 67: 132-135. 10.1055/s-2001-11532.PubMedCrossRef
71.
Nam NH: Naturally occurring NF-kappaB inhibitors. Mini Rev Med Chem. 2006, 6: 945-951. 10.2174/138955706777934937.PubMedCrossRef
72.
Rahman I, Biswas SK, Kirkham PA: Regulation of inflammation and redox signaling by dietary polyphenols. Biochem Pharmacol. 2006, 72: 1439-1452. 10.1016/j.bcp.2006.07.004.PubMedCrossRef
73.
Garcia-Zepeda EA, Rothenberg ME, Ownbey RT, Celestin J, Leder P, Luster AD: Human eotaxin is a specific chemoattractant for eosinophil cells and provides a new mechanism to explain tissue eosinophilia. Nat Med. 1996, 2: 449-456. 10.1038/nm0496-449.PubMedCrossRef
74.
Minshall EM, Hamid QA: Fibroblasts: a cell type central to eosinophil recruitment?. Clin Exp Allergy. 2000, 30: 301-303. 10.1046/j.1365-2222.2000.00753.x.PubMedCrossRef
75.
Richter A, Puddicombe SM, Lordan JL, Bucchieri F, Wilson SJ, Djukanovic R, et al: The contribution of interleukin (IL)-4 and IL-13 to the epithelial-mesenchymal trophic unit in asthma. Am J Respir Cell Mol Biol. 2001, 25: 385-391.PubMedCrossRef
76.
Sabatini F, Silvestri M, Sale R, Scarso L, Defilippi AC, Risso FM, et al: Fibroblast-eosinophil interaction: modulation of adhesion molecules expression and chemokine release by human fetal lung fibroblasts in response to IL-4 and TNF-alpha. Immunol Lett. 2002, 84: 173-178. 10.1016/S0165-2478(02)00183-9.PubMedCrossRef
77.
Sato E, Nelson DK, Koyama S, Hoyt JC, Robbins RA: Inflammatory cytokines modulate eotaxin release by human lung fibroblast cell line. Exp Lung Res. 2001, 27: 173-183. 10.1080/019021401750069401.PubMedCrossRef
78.
Terada N, Hamano N, Nomura T, Numata T, Hirai K, Nakajima T, et al: Interleukin-13 and tumour necrosis factor-alpha synergistically induce eotaxin production in human nasal fibroblasts. Clin Exp Allergy. 2000, 30: 348-355. 10.1046/j.1365-2222.2000.00750.x.PubMedCrossRef
79.
Wenzel SE, Trudeau JB, Barnes S, Zhou X, Cundall M, Westcott JY, et al: TGF-beta and IL-13 synergistically increase eotaxin-1 production in human airway fibroblasts. J Immunol. 2002, 169: 4613-4619.PubMedCrossRef
80.
81.
Kang ES, Kim GH, Kim HJ, Woo IS, Ham SA, Jin H, et al: Nrf2 regulates curcumin-induced aldose reductase expression indirectly via nuclear factor-kappaB. Pharmacol Res. 2008, 58: 15-21. 10.1016/j.phrs.2008.05.009.PubMedCrossRef
82.
Shen G, Jeong WS, Hu R, Kong AN: Regulation of Nrf2, NF-kappaB, and AP-1 signaling pathways by chemopreventive agents. Antioxid Redox Signal. 2005, 7: 1648-1663. 10.1089/ars.2005.7.1648.PubMedCrossRef
83.
Yang H, Magilnick N, Lee C, Kalmaz D, Ou X, Chan JY, et al: Nrf1 and Nrf2 regulate rat glutamate-cysteine ligase catalytic subunit transcription indirectly via NF-kappaB and AP-1. Mol Cell Biol. 2005, 25: 5933-5946. 10.1128/MCB.25.14.5933-5946.2005.PubMedPubMedCentralCrossRef
84.
Hein H, Schluter C, Kulke R, Christophers E, Schroder JM, Bartels J: Genomic organization, sequence, and transcriptional regulation of the human eotaxin gene. Biochem Biophys Res Commun. 1997, 237: 537-542. 10.1006/bbrc.1997.7169.PubMedCrossRef
85.
Matsukura S, Stellato C, Plitt JR, Bickel C, Miura K, Georas SN, et al: Activation of eotaxin gene transcription by NF-kappa B and STAT6 in human airway epithelial cells. J Immunol. 1999, 163: 6876-6883.PubMed
86.
Hoeck J, Woisetschlager M: STAT6 mediates eotaxin-1 expression in IL-4 or TNF-alpha-induced fibroblasts. J Immunol. 2001, 166: 4507-4515.PubMedCrossRef
87.
Matsui S, Sonoda Y, Sekiya T, Aizu-Yokota E, Kasahara T: Glycyrrhizin derivative inhibits eotaxin 1 production via STAT6 in human lung fibroblasts. Int Immunopharmacol. 2006, 6: 369-375. 10.1016/j.intimp.2005.08.025.PubMedCrossRef
88.
Mandal D, Fu P, Levine AD: REDOX regulation of IL-13 signaling in intestinal epithelial cells: usage of alternate pathways mediates distinct gene expression patterns. Cell Signal. 2010, 22: 1485-1494. 10.1016/j.cellsig.2010.05.017.PubMedPubMedCentralCrossRef
Metadata
Title
Gene expression profiling following NRF2 and KEAP1 siRNA knockdown in human lung fibroblasts identifies CCL11/Eotaxin-1 as a novel NRF2 regulated gene
Authors
Jimmy Fourtounis
I-Ming Wang
Marie-Claude Mathieu
David Claveau
Tenneille Loo
Aimee L Jackson
Mette A Peters
Alex G Therien
Yves Boie
Michael A Crackower
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2012
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/1465-9921-13-92

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Letter to the Editor

Airway protease/antiprotease imbalance in atopic asthmatics contributes to increased Influenza A virus cleavage and replication

Research

Surfactant Protein D modulates allergen particle uptake and inflammatory response in a human epithelial airway model

Research

Comparison of the variability of the annual rates of change in FEV1 determined from serial measurements of the pre- versus post-bronchodilator FEV1 over 5 years in mild to moderate COPD: Results of the lung health study

Research

Differential effects of formoterol on thrombin- and PDGF-induced proliferation of human pulmonary arterial vascular smooth muscle cells

Research

Lipoteichoic acid induces surfactant protein-A biosynthesis in human alveolar type II epithelial cells through activating the MEK1/2-ERK1/2-NF-κB pathway

Research

Rituximab therapy in pulmonary alveolar proteinosis improves alveolar macrophage lipid homeostasis
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits