title: Leukotrienes enhance the bactericidal activity of alveolar macrophages against Klebsiella pneumoniae through the activation of NADPH oxidase.
abstract: Leukotrienes (LTs) are lipid mediators that participate in inflammatory diseases and innate immune function. We sought to investigate the importance of LTs in regulating the microbicidal activity of alveolar macrophages (AMs) and the molecular mechanisms by which this occurs. The role of LTs in enhancing AM microbicidal activity was evaluated pharmacologically and genetically using in vitro challenge with Klebsiella pneumoniae. Exogenous LTs increased AM microbicidal activity in a dose- and receptor-dependent manner, and endogenous production of LTs was necessary for optimal killing. Leukotriene B4 (LTB4) was more potent than cysteinyl LTs. An important role for nicotinamide adenine dinucleotide (NADPH) oxidase in LT-induced microbicidal activity was indicated by the fact that bacterial killing was abrogated by the NADPH oxidase inhibitor diphenyleneiodonium (DPI; 10 microM) and in AMs derived from gp91phox-deficient mice. By contrast, LT-induced microbicidal activity was independent of the generation of nitric oxide. LTs increased H2O2 production, and LTB4 was again the more potent agonist. Both classes of LTs elicited translocation of p47phox to the cell membrane, and LTB4 induced phosphorylation of p47phox in a manner dependent on protein kinase C-delta (PKC-delta) activity. In addition, the enhancement of microbicidal activity by LTs was also dependent on PKC-delta activity. Our results demonstrate that LTs, especially LTB4, enhanceAM microbicidal activity through the PKC-delta-dependent activation of NADPH oxidase.
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109-0642, USA.
authors.forename: Carlos H C
authors.initials: CH
authors.lastname: Serezani
authors.forename: David M
authors.initials: DM
authors.lastname: Aronoff
authors.forename: Sonia
authors.initials: S
authors.lastname: Jancar
authors.forename: Peter
authors.initials: P
authors.lastname: Mancuso
authors.forename: Marc
authors.initials: M
authors.lastname: Peters-Golden
mesh_terms: D000818:Animals; D004789:Enzyme Activation; D007113:Immunity, Innate / Q000187:drug effects*; D007711:Klebsiella pneumoniae / Q000276:immunology*; D015289:Leukotrienes / Q000494:pharmacology*; D016676:Macrophages, Alveolar / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D019255:NADPH Oxidases / Q000276:immunology*; D010587:Phagocytosis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats
chemical_list: D015289:Leukotrienes; D019255:NADPH Oxidases; D019869:Phosphatidylinositol 3-Kinases
references.citation: J Cell Physiol. 2001 Dec;189(3):306-15
references.pmid: 11748588
references.citation: J Pharmacol Exp Ther. 2002 Feb;300(2):629-37
references.pmid: 11805226
references.citation: J Biol Chem. 2002 Mar 8;277(10):8572-8
references.pmid: 11756405
references.citation: J Immunol. 2002 Apr 15;168(8):4018-24
references.pmid: 11937559
references.citation: Am J Physiol Lung Cell Mol Physiol. 2002 May;282(5):L944-56
references.pmid: 11943658
references.citation: Br Med Bull. 2002;61:45-61
references.pmid: 11997298
references.citation: J Electron Microsc (Tokyo). 2002;51(2):87-91
references.pmid: 12005167
references.citation: J Biol Chem. 2002 Jul 12;277(28):25385-92
references.pmid: 12101222
references.citation: Infect Immun. 2002 Aug;70(8):4247-53
references.pmid: 12117933
references.citation: Int J Immunopharmacol. 1989;11(7):801-8
references.pmid: 2557289
references.citation: J Immunol. 1990 Jan 1;144(1):263-70
references.pmid: 2104888
references.citation: Mol Immunol. 1990 Mar;27(3):263-72
references.pmid: 2160604
references.citation: J Biol Chem. 1990 Jun 5;265(16):9146-52
references.pmid: 2160959
references.citation: Biochem Biophys Res Commun. 1991 Jun 28;177(3):1033-40
references.pmid: 2059195
references.citation: Am J Physiol. 1991 Dec;261(6 Pt 1):L462-71
references.pmid: 1662919
references.citation: J Leukoc Biol. 1993 Apr;53(4):427-38
references.pmid: 8482923
references.citation: J Biol Chem. 2002 Sep 27;277(39):35906-14
references.pmid: 12114511
references.citation: J Biol Chem. 2002 Nov 22;277(47):44898-904
references.pmid: 12244116
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5130-5
references.pmid: 12704229
references.citation: J Immunol. 2003 May 15;170(10):5302-8
references.pmid: 12734380
references.citation: J Immunol. 2003 Jun 15;170(12):6273-9
references.pmid: 12794160
references.citation: Prostaglandins Leukot Essent Fatty Acids. 2003 Aug-Sep;69(2-3):99-109
references.pmid: 12895592
references.citation: Prostaglandins Leukot Essent Fatty Acids. 2003 Aug-Sep;69(2-3):117-22
references.pmid: 12895594
references.citation: Prostaglandins Leukot Essent Fatty Acids. 2003 Aug-Sep;69(2-3):123-34
references.pmid: 12895595
references.citation: Blood. 2003 Sep 1;102(5):1877-83
references.pmid: 12730109
references.citation: Natl Vital Stat Rep. 2003 Sep 18;52(3):1-115
references.pmid: 14570230
references.citation: Microbes Infect. 2003 Nov;5(14):1307-15
references.pmid: 14613774
references.citation: Infect Immun. 2004 Mar;72(3):1637-44
references.pmid: 14977971
references.citation: Biochem Biophys Res Commun. 2004 Apr 9;316(3):720-30
references.pmid: 15033459
references.citation: J Infect Dis. 2004 Jun 1;189(11):2001-9
references.pmid: 15143466
references.citation: Prostaglandins Leukot Essent Fatty Acids. 2004 Sep;71(3):185-90
references.pmid: 15253889
references.citation: J Immunol. 2004 Nov 1;173(9):5730-8
references.pmid: 15494525
references.citation: Eur J Pharmacol. 1983 Jul 15;91(1):159-60
references.pmid: 6311572
references.citation: J Immunol. 1985 Mar;134(3):1989-93
references.pmid: 2857187
references.citation: Mol Biochem Parasitol. 1985 Apr;15(1):1-10
references.pmid: 2859521
references.citation: J Clin Invest. 1985 May;75(5):1740-3
references.pmid: 2987311
references.citation: J Immunol Methods. 1985 Sep 3;82(1):131-40
references.pmid: 3928761
references.citation: Annu Rev Immunol. 1984;2:283-318
references.pmid: 6100475
references.citation: J Biol Chem. 1987 Sep 5;262(25):12048-53
references.pmid: 3040727
references.citation: Biochem J. 1988 May 1;251(3):887-91
references.pmid: 2843166
references.citation: Eur J Haematol. 1989 Jul;43(1):67-77
references.pmid: 2548892
references.citation: J Pharmacol Exp Ther. 1994 Feb;268(2):922-9
references.pmid: 8114006
references.citation: Biochem Biophys Res Commun. 1994 Feb 28;199(1):93-8
references.pmid: 8123051
references.citation: J Biol Chem. 1994 Sep 23;269(38):23431-6
references.pmid: 8089108
references.citation: J Exp Med. 1994 Nov 1;180(5):1637-48
references.pmid: 7964451
references.citation: Nature. 1994 Nov 10;372(6502):179-82
references.pmid: 7969451
references.citation: Cell Immunol. 1995 Jan;160(1):115-22
references.pmid: 7842477
references.citation: Nat Genet. 1995 Feb;9(2):202-9
references.pmid: 7719350
references.citation: Biochem J. 1995 Sep 15;310 ( Pt 3):795-806
references.pmid: 7575412
references.citation: Am J Physiol. 1996 Oct;271(4 Pt 1):C1278-84
references.pmid: 8897835
references.citation: Arch Biochem Biophys. 1996 Oct 15;334(2):395-400
references.pmid: 8900416
references.citation: J Immunol. 1996 Dec 15;157(12):5221-4
references.pmid: 8955165
references.citation: Biochem J. 1997 Feb 1;321 ( Pt 3):561-71
references.pmid: 9032437
references.citation: Infect Immun. 1997 May;65(5):1870-5
references.pmid: 9125574
references.citation: Lancet. 1997 May 3;349(9061):1269-76
references.pmid: 9142060
references.citation: Am J Physiol. 1997 Nov;273(5 Pt 1):L1042-7
references.pmid: 9374733
references.citation: J Immunol. 1998 May 1;160(9):4526-34
references.pmid: 9574559
references.citation: Mem Inst Oswaldo Cruz. 1997;92 Suppl 2:115-23
references.pmid: 9698923
references.citation: Am J Physiol. 1998 Aug;275(2 Pt 1):L389-97
references.pmid: 9700101
references.citation: J Clin Invest. 1998 Aug 15;102(4):663-70
references.pmid: 9710433
references.citation: Infect Immun. 1998 Nov;66(11):5140-6
references.pmid: 9784515
references.citation: J Lab Clin Med. 1998 Oct;132(4):251-7
references.pmid: 9794695
references.citation: Blood. 1999 Feb 15;93(4):1399-405
references.pmid: 9949184
references.citation: Tuber Lung Dis. 1997;78(5-6):237-46
references.pmid: 10209678
references.citation: Am J Trop Med Hyg. 1999 Apr;60(4):668-73
references.pmid: 10348246
references.citation: J Immunol. 1999 Nov 15;163(10):5505-11
references.pmid: 10553077
references.citation: Biochem J. 1999 Dec 15;344 Pt 3:859-66
references.pmid: 10585874
references.citation: J Exp Med. 2000 Jul 17;192(2):227-36
references.pmid: 10899909
references.citation: J Immunol. 2000 Nov 1;165(9):5238-44
references.pmid: 11046057
references.citation: Am J Respir Cell Mol Biol. 2000 Dec;23(6):727-33
references.pmid: 11104724
references.citation: Infect Immun. 2001 Jan;69(1):24-33
references.pmid: 11119485
references.citation: J Leukoc Biol. 2001 Jan;69(1):158-60
references.pmid: 11200060
references.citation: J Immunol. 2001 Mar 15;166(6):4059-64
references.pmid: 11238654
references.citation: Infect Immun. 2001 Apr;69(4):2011-6
references.pmid: 11254552
references.citation: J Biol Chem. 2001 Feb 2;276(5):3090-7
references.pmid: 11060300
references.citation: J Biol Chem. 2001 Jul 6;276(27):24743-50
references.pmid: 11328812
references.citation: J Leukoc Biol. 2001 Aug;70(2):163-70
references.pmid: 11493607
references.citation: Br J Pharmacol. 2001 Oct;134(4):797-806
references.pmid: 11606320
references.citation: J Neuroimmunol. 2001 Nov 1;120(1-2):94-102
references.pmid: 11694324
references.citation: J Exp Med. 2001 Nov 5;194(9):1231-42
references.pmid: 11696589