title: An NF-κB-independent and Erk1/2-dependent mechanism controls CXCL8/IL-8 responses of airway epithelial cells to cadmium.
abstract: Airway epithelial cells in the lung are the first line of defense against pathogens and environmental pollutants. Inhalation of the environmental pollutant cadmium has been linked to the development of lung cancer and chronic obstructive pulmonary disease, which are diseases characterized by chronic inflammation. To address the role of airway epithelial cells in cadmium-induced lung inflammation, we investigated how cadmium regulates secretion of interleukin 8 (IL-8) by airway epithelial cells. We show that exposure of human airway epithelial cells to subtoxic doses of cadmium in vitro promotes a characteristic inflammatory cytokine response consisting of IL-8, but not IL-1β or tumor necrosis factor-alpha. We also found that intranasal delivery of cadmium increases lung levels of the murine IL-8 homologs macrophage inflammatory protein-2 and keracinocyte-derived chemokine and results in an influx of Gr1+ cells into the lung. We determined that inhibition of the nuclear factor-κB (NF-κB) pathway had no effect on cadmium-induced IL-8 secretion by human airway epithelial cells, suggesting that IL-8 production was mediated through an NF-κB-independent pathway. Mitogen-activated protein kinases (MAPKs) are often involved in proinflammatory signaling. Cadmium could activate the main MAPKs (i.e., p38, JNK, and Erk1/2) in human airway epithelial cells. However, only pharmacological inhibition of Erk1/2 pathway or knockdown of the expression of Erk1 and Erk2 using small interfering RNAs suppressed secretion of IL-8 induced by cadmium. Our findings identify cadmium as a potent activator of the proinflammatory cytokine IL-8 in lung epithelial cells and reveal for the first time the role of an NF-κB-independent but Erk1/2-dependent pathway in cadmium-induced lung inflammation.
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Dorothy M. Davis Heart and Lung Research Institute, Columbus, OH 43210, USA. Estelle.boyaka@osumc.edu
authors.forename: Estelle
authors.initials: E
authors.lastname: Cormet-Boyaka
authors.forename: Kalyn
authors.initials: K
authors.lastname: Jolivette
authors.forename: Astrid
authors.initials: A
authors.lastname: Bonnegarde-Bernard
authors.forename: Jessica
authors.initials: J
authors.lastname: Rennolds
authors.forename: Fatemat
authors.initials: F
authors.lastname: Hassan
authors.forename: Payal
authors.initials: P
authors.lastname: Mehta
authors.forename: Susheela
authors.initials: S
authors.lastname: Tridandapani
authors.forename: Jeanette
authors.initials: J
authors.lastname: Webster-Marketon
authors.forename: Prosper N
authors.initials: PN
authors.lastname: Boyaka
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D001980:Bronchi / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D019187:Cadmium Compounds / Q000633:toxicity*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D019570:Inhalation Exposure; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D011014:Pneumonia / Q000139:chemically induced* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013431:Sulfates / Q000633:toxicity*; D013997:Time Factors; D014162:Transfection
chemical_list: D000393:Air Pollutants; C508606:CXCL8 protein, human; D019187:Cadmium Compounds; C508600:IL6 protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D013431:Sulfates; C037123:cadmium sulfate; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
references.citation: Lung Cancer. 2007 May;56(2):167-74
references.pmid: 17207890
references.citation: Am J Respir Cell Mol Biol. 2011 Aug;45(2):189-201
references.pmid: 21330463
references.citation: Nat Immunol. 2010 May;11(5):373-84
references.pmid: 20404851
references.citation: Int J Environ Res Public Health. 2009 Jul;6(7):1930-46
references.pmid: 19742163
references.citation: J Biol Chem. 2003 Dec 26;278(52):53035-44
references.pmid: 14565959
references.citation: Respir Res. 2005 Oct 12;6:116
references.pmid: 16219107
references.citation: Toxicol Lett. 2010 Sep 15;198(1):56-62
references.pmid: 20435108
references.citation: Clin Rev Allergy Immunol. 2006 Apr;30(2):129-40
references.pmid: 16645224
references.citation: Lymphokine Cytokine Res. 1993 Dec;12(6):421-8
references.pmid: 8123758
references.citation: Environ Res. 1989 Aug;49(2):197-207
references.pmid: 2753006
references.citation: Cell Signal. 2004 Mar;16(3):343-53
references.pmid: 14687664
references.citation: Scand J Work Environ Health. 1998;24 Suppl 1:1-51
references.pmid: 9569444
references.citation: Eur Respir J. 1997 Sep;10(9):2139-46
references.pmid: 9311517
references.citation: Contrib Microbiol. 2008;15:147-163
references.pmid: 18511860
references.citation: J Allergy Clin Immunol. 1998 Nov;102(5):714-8
references.pmid: 9867498
references.citation: J Pharmacol Exp Ther. 2001 Sep;298(3):1199-205
references.pmid: 11504821
references.citation: Curr Allergy Asthma Rep. 2007 Sep;7(5):357-62
references.pmid: 17697644
references.citation: Am J Respir Cell Mol Biol. 2002 Mar;26(3):266-8
references.pmid: 11867332
references.citation: EMBO J. 1999 Sep 15;18(18):4969-80
references.pmid: 10487749
references.citation: J Immunol. 2003 Jun 15;170(12):6257-65
references.pmid: 12794158
references.citation: Curr Opin Immunol. 2007 Dec;19(6):711-20
references.pmid: 17928212
references.citation: Chemosphere. 2003 Aug;52(6):959-66
references.pmid: 12781229
references.citation: Mol Immunol. 2008 Mar;45(6):1665-73
references.pmid: 17997161
references.citation: Am J Physiol Lung Cell Mol Physiol. 2006 May;290(5):L1028-35
references.pmid: 16373669
references.citation: Toxicol Appl Pharmacol. 1980 Jun 15;54(1):156-60
references.pmid: 7394784
references.citation: Semin Respir Crit Care Med. 2010 Jun;31(3):257-66
references.pmid: 20496295
references.citation: J Air Waste Manag Assoc. 2009 May;59(5):560-7
references.pmid: 19583156
references.citation: Pediatr Pulmonol. 2008 Jan;43(1):11-9
references.pmid: 18041080
references.citation: J Biol Chem. 2008 Jan 11;283(2):833-9
references.pmid: 17932045
references.citation: Chemosphere. 2009 Jul;76(3):300-5
references.pmid: 19403155
references.citation: J Leukoc Biol. 2002 Nov;72(5):847-55
references.pmid: 12429706
references.citation: Toxicol Appl Pharmacol. 2000 Mar 15;163(3):231-9
references.pmid: 10702362
references.citation: Toxicol Lett. 2010 Apr 1;193(3):252-60
references.pmid: 20105457
references.citation: Toxicol Appl Pharmacol. 2010 Feb 15;243(1):46-54
references.pmid: 19914270
references.citation: Environ Geochem Health. 2010 Feb;32(1):1-12
references.pmid: 19688602
references.citation: Am J Respir Med. 2002;1(1):19-25
references.pmid: 14720072
references.citation: Chest. 2002 Mar;121(3 Suppl):70S-75S
references.pmid: 11893692
references.citation: Toxicol Sci. 2010 Jul;116(1):349-58
references.pmid: 20363832
references.citation: Lancet. 1988 Feb 27;1(8583):477
references.pmid: 2893902
references.citation: Crit Care Res Pract. 2010;2010:
references.pmid: 20948883
references.citation: J Inflamm (Lond). 2009 Jun 12;6:19
references.pmid: 19523218
references.citation: Am J Respir Cell Mol Biol. 1998 Sep;19(3):498-506
references.pmid: 9730878
references.citation: Am J Respir Crit Care Med. 1999 Nov;160(5 Pt 2):S38-43
references.pmid: 10556168
references.citation: J Immunol. 2007 May 15;178(10):6504-13
references.pmid: 17475880
references.citation: Am J Pathol. 2005 Dec;167(6):1621-30
references.pmid: 16314475
references.citation: Toxicol Appl Pharmacol. 2004 Apr 15;196(2):258-65
references.pmid: 15081272
references.citation: Lancet Oncol. 2006 Feb;7(2):119-26
references.pmid: 16455475
references.citation: Mol Cell Biol. 1999 Oct;19(10):6742-53
references.pmid: 10490613
references.citation: Lancet Infect Dis. 2010 May;10(5):360-6
references.pmid: 20417418
references.citation: Curr Drug Targets Inflamm Allergy. 2005 Dec;4(6):619-25
references.pmid: 17305518
references.citation: Cytokine. 2007 Jan;37(1):26-34
references.pmid: 17391980
references.citation: Cell Signal. 2002 Apr;14(4):327-40
references.pmid: 11858940
references.citation: Toxicology. 2005 Jul 1;211(1-2):36-48
references.pmid: 15863246
references.citation: Crit Rev Immunol. 2010;30(1):53-67
references.pmid: 20370620
references.citation: Curr Drug Targets Inflamm Allergy. 2005 Dec;4(6):607-18
references.pmid: 17305517
references.citation: Toxicol Appl Pharmacol. 1998 Aug;151(2):359-66
references.pmid: 9707512
references.citation: Environ Technol. 2002 Dec;23(12):1425-33
references.pmid: 12523513
references.citation: Adv Exp Med Biol. 2009;653:15-34
references.pmid: 19799109
references.citation: Toxicology. 2004 May 3;197(3):213-28
references.pmid: 15033544
references.citation: Clin Respir J. 2008 Oct;2 Suppl 1:84-7
references.pmid: 20298355
references.citation: J Biol Inorg Chem. 2010 Nov;15(8):1275-83
references.pmid: 20632048
references.citation: IARC Sci Publ. 1992;(118):133-48
references.pmid: 1303936
references.citation: FASEB J. 2003 Jul;17(10):1319-21
references.pmid: 12832293