Leukotrienes Enhance the Bactericidal Activity of Alveolar Macrophages Against Klebsiella Pneumoniae Through the Activation of NADPH Oxidase

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2005 Feb 19

PMID 15718414

Citations 81

Authors

Carlos H C Serezani

David M Aronoff

Sonia Jancar

Peter Mancuso

Marc Peters-Golden

Affiliations

Soon will be listed here.

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.

Citing Articles

Zafirlukast induces DNA condensation and has bactericidal effect on replicating .

Niet S, Green K, Schimmel I, Bakker J, Lodder B, Reits E Antimicrob Agents Chemother. 2024; 68(8):e0002924.

PMID: 38990015 PMC: 11304721. DOI: 10.1128/aac.00029-24.

Activation of leukotriene B receptor 1 is a prerequisite for complement receptor 3-mediated antifungal responses of neutrophils.

Xin Y, Xiong S, Zhou L, Lin X Cell Mol Immunol. 2024; 21(3):245-259.

PMID: 38297112 PMC: 10901876. DOI: 10.1038/s41423-024-01130-4.

Leukotrienes in Innate Immunity: Still Underappreciated after All These Years?.

Serezani C, Divangahi M, Peters-Golden M J Immunol. 2023; 210(3):221-227.

PMID: 36649580 PMC: 11749155. DOI: 10.4049/jimmunol.2200599.

Host Immune Response to Clinical Hypervirulent Pulmonary Infections via Transcriptome Analysis.

Lei L, Zhang X, Yang R, Jing H, Yuan Y, Chen Z J Immunol Res. 2022; 2022:5336931.

PMID: 36249423 PMC: 9553456. DOI: 10.1155/2022/5336931.

Toxoplasma gondii Infection Decreases Intestinal 5-Lipoxygenase Expression, while Exogenous LTB Controls Parasite Growth.

Araujo E, Briceno M, Cariaco Y, Oliveira M, Almeida M, de Miranda N Infect Immun. 2022; 90(7):e0002922.

PMID: 35658510 PMC: 9302167. DOI: 10.1128/iai.00029-22.

References

Kita H, Gleich G, OGrady S . Regulation of human eosinophil NADPH oxidase activity: a central role for PKCdelta. J Cell Physiol. 2001; 189(3):306-15. DOI: 10.1002/jcp.10022. View

Kim Y, Jang Y, Han E, Lee C . Depressant effect of ambroxol on stimulated functional responses and cell death in rat alveolar macrophages exposed to silica in vitro. J Pharmacol Exp Ther. 2002; 300(2):629-37. DOI: 10.1124/jpet.300.2.629. View

Woo C, You H, Cho S, Eom Y, Chun J, Yoo Y . Leukotriene B(4) stimulates Rac-ERK cascade to generate reactive oxygen species that mediates chemotaxis. J Biol Chem. 2002; 277(10):8572-8. DOI: 10.1074/jbc.M104766200. View

Mancuso P, Gottschalk A, Phare S, Peters-Golden M, Lukacs N, Huffnagle G . Leptin-deficient mice exhibit impaired host defense in Gram-negative pneumonia. J Immunol. 2002; 168(8):4018-24. DOI: 10.4049/jimmunol.168.8.4018. View

Hickman-Davis J, OReilly P, Davis I, Peti-Peterdi J, Davis G, Young K . Killing of Klebsiella pneumoniae by human alveolar macrophages. Am J Physiol Lung Cell Mol Physiol. 2002; 282(5):L944-56. DOI: 10.1152/ajplung.00216.2001. View

Gordon S, Read R . Macrophage defences against respiratory tract infections. Br Med Bull. 2002; 61:45-61. DOI: 10.1093/bmb/61.1.45. View

Seguchi H, Kobayashi T . Study of NADPH oxidase-activated sites in human neutrophils. J Electron Microsc (Tokyo). 2002; 51(2):87-91. DOI: 10.1093/jmicro/51.2.87. View

Zhao X, Bey E, Wientjes F, Cathcart M . Cytosolic phospholipase A2 (cPLA2) regulation of human monocyte NADPH oxidase activity. cPLA2 affects translocation but not phosphorylation of p67(phox) and p47(phox). J Biol Chem. 2002; 277(28):25385-92. DOI: 10.1074/jbc.M203630200. View

Talvani A, Machado F, SantAna G, Klein A, Barcelos L, Silva J . Leukotriene B(4) induces nitric oxide synthesis in Trypanosoma cruzi-infected murine macrophages and mediates resistance to infection. Infect Immun. 2002; 70(8):4247-53. PMC: 128190. DOI: 10.1128/IAI.70.8.4247-4253.2002. View

10.

Demitsu T, Katayama H, Yaoita H, Nakano M . Phagocytosis and bactericidal action of mouse peritoneal macrophages treated with leukotriene B4. Int J Immunopharmacol. 1989; 11(7):801-8. DOI: 10.1016/0192-0561(89)90134-3. View

11.

Peters-Golden M, McNish R, Hyzy R, Shelly C, Toews G . Alterations in the pattern of arachidonate metabolism accompany rat macrophage differentiation in the lung. J Immunol. 1990; 144(1):263-70. View

12.

PFEFFERKORN L, Guyre P, Fanger M . Functional comparison of the inductions of NADPH oxidase activity and Fc gamma RI in IFN gamma-treated U937 cells. Mol Immunol. 1990; 27(3):263-72. DOI: 10.1016/0161-5890(90)90139-q. View

13.

OFlaherty J, Jacobson D, Redman J, Rossi A . Translocation of protein kinase C in human polymorphonuclear neutrophils. Regulation by cytosolic Ca2(+)-independent and Ca2(+)-dependent mechanisms. J Biol Chem. 1990; 265(16):9146-52. View

14.

Sharma P, Evans A, Parker P, Evans F . NADPH-oxidase activation by protein kinase C-isotypes. Biochem Biophys Res Commun. 1991; 177(3):1033-40. DOI: 10.1016/0006-291x(91)90642-k. View

15.

Peters-Golden M, McNish R, Sporn P, Balazovich K . Basal activation of protein kinase C in rat alveolar macrophages: implications for arachidonate metabolism. Am J Physiol. 1991; 261(6 Pt 1):L462-71. DOI: 10.1152/ajplung.1991.261.6.L462. View

16.

Della Bianca V, Grzeskowiak M, Dusi S, Rossi F . Transmembrane signaling pathways involved in phagocytosis and associated activation of NADPH oxidase mediated by Fc gamma Rs in human neutrophils. J Leukoc Biol. 1993; 53(4):427-38. DOI: 10.1002/jlb.53.4.427. View

17.

Todt J, Hu B, Punturieri A, Sonstein J, Polak T, Curtis J . Activation of protein kinase C beta II by the stereo-specific phosphatidylserine receptor is required for phagocytosis of apoptotic thymocytes by resident murine tissue macrophages. J Biol Chem. 2002; 277(39):35906-14. PMC: 2640489. DOI: 10.1074/jbc.M202967200. View

18.

Ito N, Yokomizo T, Sasaki T, Kurosu H, Penninger J, Kanaho Y . Requirement of phosphatidylinositol 3-kinase activation and calcium influx for leukotriene B4-induced enzyme release. J Biol Chem. 2002; 277(47):44898-904. DOI: 10.1074/jbc.M208051200. View

19.

Hoyal C, Gutierrez A, Young B, Catz S, Lin J, Tsichlis P . Modulation of p47PHOX activity by site-specific phosphorylation: Akt-dependent activation of the NADPH oxidase. Proc Natl Acad Sci U S A. 2003; 100(9):5130-5. PMC: 154310. DOI: 10.1073/pnas.1031526100. View

20.

Chen Q, Powell D, Rane M, Singh S, Butt W, Klein J . Akt phosphorylates p47phox and mediates respiratory burst activity in human neutrophils. J Immunol. 2003; 170(10):5302-8. DOI: 10.4049/jimmunol.170.10.5302. View