Inhibition of leukotriene biosynthesis abrogates the host control of Mycobacterium tuberculosis

Abstract

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 leukotriene B 4 and the anti-inflammatory substance lipoxin A 4 by ~50%, increased 60-day mortality from 14% to ~57% in Mycobacterium tuberculosis-infected mice, and increased lung bacterial burden by ~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.

Leukotrienes are not essential for the efficacy of a heterologous vaccine against Mycobacterium tuberculosis infection

“…In the present study, we confirmed the results of Peres et al (6), who provided evidence for the importance of LT in the immune response against M. tuberculosis infection. We also confirmed that mice treated with MK-886 were more susceptible to M. tuberculosis infection.…”

“…We also confirmed that mice treated with MK-886 were more susceptible to M. tuberculosis infection. This higher susceptibility was associated with the impaired influx of leukocytes to the lungs after infection and with decreased concentrations of IFN-γ in the lungs, as previously reported by Peres et al (6). Our results, together with those reported by Peres et al (6), suggest that LT can modulate soluble factors related to protection, such as IFN-γ and nitrite, and can stimulate the recruitment of leukocytes to the site of infection.…”

“…This higher susceptibility was associated with the impaired influx of leukocytes to the lungs after infection and with decreased concentrations of IFN-γ in the lungs, as previously reported by Peres et al (6). Our results, together with those reported by Peres et al (6), suggest that LT can modulate soluble factors related to protection, such as IFN-γ and nitrite, and can stimulate the recruitment of leukocytes to the site of infection. In a similar manner, treatment of BALB/c mice with MK-886 increased their susceptibility to infection with H. capsulatum (8).…”

“…M. tuberculosis-infected mice treated with the inhibitor of LT synthesis, MK-886, showed an increase in lung bacterial burden and a decrease in IFN-γ, IL-12 and nitrite secretion. In addition, the influx of neutrophils and mononuclear cells to the lungs of MK-886-treated mice was reduced (6).…”

“…Furthermore, during a secondary immune response against infection by Histoplasma capsulatum, LT play a role by recruiting memory CD4+ and CD8+ cells to the lung (7). The activity of LT as powerful leukotropic and proinflammatory mediators involved in host defenses in a variety of infectious diseases (6,8,9), including mycobacterial infections (6), led us to suggest that LT might be involved in the protective immune response generated by heterologous prime-boost immunization with Bacille Calmette-Guérin (BCG) prime/DNA-HSP65 booster against M. tuberculosis infection.…”