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.