Inhibition of leukotriene biosynthesis abrogates the host control of Mycobacterium tuberculosis.
Leukotrienes produced from arachidonic acid by the action of 5-lipoxygenase (5-LO) are classical mediators of inflammatory responses. Recently, it has been demonstrated that leukotrienes also play an important role in host defense against microorganisms. In vitro studies have shown that leukotrienes augmented the anti-mycobacterial activity of neutrophils. In this study, we examined the role of leukotrienes in regulating host response and cytokine generation in a murine model of tuberculosis. Administration of the 5-LO pathway inhibitor MK 886, which reduced lung levels of both the leukotriene B(4) and the anti-inflammatory substance lipoxin A(4) by approximately 50%, increased 60-day mortality from 14% to approximately 57% in Mycobacterium tuberculosis-infected mice, and increased lung bacterial burden by approximately 15-fold. Although MK 886-treated animals exhibited no reduction in pulmonary leukocyte accumulation, they did manifest reduced levels of nitric oxide generation and of the protective type 1 cytokines interleukin-12 and gamma interferon. Together our results demonstrate that 5-LO pathway product(s) - presumably leukotrienes - positively regulate protective Th1 responses against mycobacterial infection in vivo. Moreover, the immunosuppressive phenotype in infected mice observed with MK 886 is most consistent with inhibition of an activator (LTB(4)) rather than a suppressor (LXA(4)) of antimicrobial defense, suggesting the major effect of leukotrienes.
Peres
Camila M
CM
Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo (USP), Av. do Cafe s/n, Ribeirao Preto, São Paulo 14040-903, Brazil.
de Paula
Lúcia
L
Medeiros
Alexandra I
AI
Sorgi
Carlos A
CA
Soares
Edson G
EG
Carlos
Daniela
D
Peters-Golden
Marc
M
Silva
Célio L
CL
Faccioli
Lúcia H
LH
D000818:Animals; D016207:Cytokines / Q000276:immunology; D005260:Female; D007211:Indoles / Q000494:pharmacology*; D007962:Leukocytes / Q000276:immunology; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D015289:Leukotrienes / Q000096:biosynthesis* / Q000276:immunology* / Q000378:metabolism; D044045:Lipoxins / Q000096:biosynthesis / Q000276:immunology / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000254:growth & development* / Q000276:immunology; D009569:Nitric Oxide / Q000096:biosynthesis / Q000097:blood; D018417:Th1 Cells / Q000276:immunology; D014376:Tuberculosis / Q000188:drug therapy / Q000276:immunology* / Q000382:microbiology; D002722:Chlorobenzenes
D016207:Cytokines; D007211:Indoles; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D044045:Lipoxins; D016859:Lipoxygenase Inhibitors; D009569:Nitric Oxide; C040527:lipoxin A4; C060893:MK-886; D002722:Chlorobenzenes