title: Regulation of pro-inflammatory responses by lipoxygenases via intracellular reactive oxygen species in vitro and in vivo.
abstract: Reactive oxygen species (ROS) performs a pivotal function as a signaling mediator in receptor-mediated signaling. However, the sources of ROS in this signaling have yet to be determined, but may include lipoxygenases (LOXs) and NADPH oxidase. The stimulation of lymphoid cells with TNF-alpha, IL-1beta, and LPS resulted in significant ROS production and NF-kappaB activation. Intriguingly, these responses were markedly abolished via treatment with the LOXs inhibitor nordihydroguaiaretic acid (NDGA). We further examined in vivo anti-inflammatory effects of NDGA in allergic airway inflammation. Both intraperitoneal and intravenous NDGA administration attenuated ovalbumin (OVA)-induced influx into the lungs of total leukocytes, as well as IL-4, IL-5, IL-13, and TNF-alpha levels. NDGA also significantly reduced serum levels of OVA-specific IgE and suppressed OVA-induced airway hyperresponsiveness to inhaled methacholine. The results of our histological studies and flow cytometric analyses showed that NDGA inhibits OVA-induced lung inflammation and the infiltration of CD11b+ macrophages into the lung. Collectively, our findings indicate that LOXs performs an essential function in pro-inflammatory signaling via the regulation of ROS regulation, and also that the inhibition of LOXs activity may have therapeutic potential with regard to the treatment of allergic airway inflammation.
authors.affiliation: Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine Suwon 440-746, Korea.
authors.forename: So Yong
authors.initials: SY
authors.lastname: Kim
authors.forename: Tae-Bum
authors.initials: TB
authors.lastname: Kim
authors.forename: Keun-ai
authors.initials: KA
authors.lastname: Moon
authors.forename: Tae Jin
authors.initials: TJ
authors.lastname: Kim
authors.forename: Dongwoo
authors.initials: D
authors.lastname: Shin
authors.forename: You Sook
authors.initials: YS
authors.lastname: Cho
authors.forename: Hee-Bom
authors.initials: HB
authors.lastname: Moon
authors.forename: Ki-Young
authors.initials: KY
authors.lastname: Lee
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001249:Asthma / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy / Q000473:pathology; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism; D019169:Jurkat Cells; D008084:Lipoxygenase / Q000502:physiology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009637:Masoprocol / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D017382:Reactive Oxygen Species / Q000009:adverse effects* / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D016859:Lipoxygenase Inhibitors; D017382:Reactive Oxygen Species; D009637:Masoprocol; D008084:Lipoxygenase
references.citation: Pharmacol Ther. 2006 Aug;111(2):476-94
references.pmid: 16458359
references.citation: Curr Opin Immunol. 2006 Dec;18(6):718-26
references.pmid: 17029937
references.citation: Exp Mol Med. 2007 Dec 31;39(6):756-68
references.pmid: 18160846
references.citation: J Clin Invest. 2003 Feb;111(3):291-7
references.pmid: 12569150
references.citation: Pulm Pharmacol Ther. 2001;14(6):409-20
references.pmid: 11782121
references.citation: Biochemistry. 1994 Nov 29;33(47):14144-55
references.pmid: 7947826
references.citation: Life Sci. 2004 Sep 24;75(19):2341-51
references.pmid: 15350831
references.citation: Int J Mol Med. 2003 Jan;11(1):27-32
references.pmid: 12469213
references.citation: FEBS Lett. 1999 Apr 16;449(1):7-11
references.pmid: 10225417
references.citation: Mol Pharmacol. 2007 Feb;71(2):454-60
references.pmid: 17105871
references.citation: J Biol Chem. 1995 Jul 21;270(29):17273-8
references.pmid: 7615527
references.citation: Mol Pharmacol. 2004 Sep;66(3):592-600
references.pmid: 15322251
references.citation: Antioxid Redox Signal. 2003 Dec;5(6):781-8
references.pmid: 14588151
references.citation: Blood. 1999 Mar 1;93(5):1464-76
references.pmid: 10029572
references.citation: Am Rev Respir Dis. 1992 Sep;146(3):768-74
references.pmid: 1519861
references.citation: J Immunol. 1997 Apr 1;158(7):3401-7
references.pmid: 9120300
references.citation: Free Radic Biol Med. 1990;9(3):235-43
references.pmid: 2272532
references.citation: J Allergy Clin Immunol. 1991 Oct;88(4):561-71
references.pmid: 1918723
references.citation: Antioxid Redox Signal. 2006 Jul-Aug;8(7-8):1113-20
references.pmid: 16910759
references.citation: J Immunol. 2002 Nov 1;169(9):5294-9
references.pmid: 12391249
references.citation: Pharmacol Rev. 1998 Dec;50(4):515-96
references.pmid: 9860804
references.citation: Curr Top Med Chem. 2007;7(3):265-75
references.pmid: 17305569
references.citation: N Engl J Med. 2006 Nov 23;355(21):2226-35
references.pmid: 17124020
references.citation: J Allergy Clin Immunol. 2004 Aug;114(2):429-35
references.pmid: 15316528
references.citation: Eur Respir J. 2000 Sep;16(3):534-54
references.pmid: 11028671
references.citation: Oncogene. 1999 Nov 1;18(45):6104-11
references.pmid: 10557101
references.citation: J Biol Chem. 2004 Oct 1;279(40):41975-84
references.pmid: 15280382
references.citation: J Biol Chem. 1999 Oct 15;274(42):29812-8
references.pmid: 10514459
references.citation: J Am Soc Nephrol. 2003 Aug;14(8 Suppl 3):S211-5
references.pmid: 12874433
references.citation: IUBMB Life. 1999 Jul;48(1):41-7
references.pmid: 10791914
references.citation: J Clin Pathol. 2002 Aug;55(8):561-8
references.pmid: 12147646
references.citation: Cell. 2005 Jun 3;121(5):667-70
references.pmid: 15935753
references.citation: Am J Physiol Lung Cell Mol Physiol. 2000 Dec;279(6):L1047-57
references.pmid: 11076794
references.citation: J Biochem Mol Biol. 2003 Jan 31;36(1):95-109
references.pmid: 12542980
references.citation: Thorax. 2000 Oct;55 Suppl 2:S51-3
references.pmid: 10992559
references.citation: Free Radic Biol Med. 2003 Aug 1;35(3):213-25
references.pmid: 12885584
references.citation: Nat Rev Immunol. 2003 Sep;3(9):745-56
references.pmid: 12949498
references.citation: Free Radic Res. 2006 Jun;40(6):619-30
references.pmid: 16753840
references.citation: Mol Pharmacol. 1999 Jul;56(1):116-23
references.pmid: 10385691
references.citation: Ann N Y Acad Sci. 2004 Apr;1011:86-100
references.pmid: 15126287
references.citation: Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):11239-43
references.pmid: 7479972
references.citation: J Biol Chem. 1999 Jun 18;274(25):18100-6
references.pmid: 10364264
references.citation: Science. 1983 May 6;220(4597):568-75
references.pmid: 6301011
references.citation: Chest. 1997 Feb;111(2 Suppl):27S-34S
references.pmid: 9042024
references.citation: Immunology. 1980 Aug;40(4):709-19
references.pmid: 6776039
references.citation: J Biol Chem. 1999 Jul 9;274(28):19792-8
references.pmid: 10391922
references.citation: Cell Signal. 2002 Nov;14(11):879-97
references.pmid: 12220615
references.citation: Thorax. 2005 Dec;60(12):1012-8
references.pmid: 16166100
references.citation: Exp Cell Res. 2003 Oct 1;289(2):335-41
references.pmid: 14499634
references.citation: J Neurochem. 2004 Oct;91(1):133-43
references.pmid: 15379894
references.citation: Curr Opin Immunol. 2006 Dec;18(6):727-32
references.pmid: 17010591
references.citation: Circ Res. 1999 Sep 17;85(6):562-3
references.pmid: 10488060
references.citation: Breast Cancer Res Treat. 2005 Nov;94(1):37-46
references.pmid: 16142439
references.citation: J Cell Physiol. 2005 Mar;202(3):874-9
references.pmid: 15389564
references.citation: Exp Mol Med. 2006 Jun 30;38(3):217-29
references.pmid: 16819280
references.citation: Mol Cell Biol. 1999 Mar;19(3):1950-60
references.pmid: 10022882
references.citation: J Exp Med. 2000 Aug 7;192(3):455-62
references.pmid: 10934234
references.citation: J Immunol. 2002 Nov 1;169(9):5287-93
references.pmid: 12391248
references.citation: Arch Gerontol Geriatr. 2004 May-Jun;38(3):201-12
references.pmid: 15066307
references.citation: Am J Physiol. 1999 Dec;277(6):L1067-88
references.pmid: 10600876
references.citation: N Engl J Med. 1990 Sep 6;323(10):645-55
references.pmid: 2166915
references.citation: J Exp Med. 2006 Oct 2;203(10):2377-89
references.pmid: 17000866
references.citation: EMBO J. 1995 Aug 1;14(15):3731-40
references.pmid: 7641692