Inhibition of leukotriene biosynthesis abrogates the host control of Mycobacterium tuberculosis

Autor(es)

Peres, Camila M. ; Paula, Lúcia de ; Medeiros, Alexandra I. ; Sorgi, Carlos A. ; Soares, Edson G. ; Carlos, Daniela ; Peters-Golden, Marc ; Silva, Célio L. ; Faccioli, Lúcia H. ^[9]

• Tipo de documento: Artigo Científico
• Fonte: Microbes and Infection; v. 9, n. 4, p. 483-489, Apr. 2007.
• Área do conhecimento: Ciências Biológicas - Imunologia
• Assunto(s): Fatores imunológicos Doenças respiratórias Pneumonia Citocinas Bactérias Mycobacterium tuberculosis

Resumo

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 B4 and the anti-inflammatory substance lipoxin A4 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 (LTB4) rather than a suppressor (LXA4) of antimicrobial defense, suggesting the major effect of leukotrienes. (AU)

• Processo FAPESP: 01/12400-6 - Participacao de prostaglandinas e leucotrienos na fase aguda da tuberculose experimental.
• Beneficiário: Camila Peres Buzalaf
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 00/09663-2 - Estudos de novas vacinas e terapia gênica contra tuberculose
• Beneficiário: Celio Lopes Silva
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 02/12856-2 - Modulação das respostas imunes inata e adquirida por leucotrienos e prostaglandinas
• Beneficiário: Lúcia Helena Faccioli
• Modalidade de apoio: Auxílio à Pesquisa - Temático