Bafica, A. et al. Host control of Mycobacterium tuberculosis is regulated by 5-lipoxygenase-dependent lipoxin production. J. Clin. Invest. 115, 1601-1606

Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 07/2005; 115(6):1601-6. DOI: 10.1172/JCI23949
Source: PubMed


Th1 type cytokine responses are critical in the control of Mycobacterium tuberculosis infection. Recent findings indicate that 5-lipoxygenase-dependent (5-LO-dependent) lipoxins regulate host IL-12 production in vivo. Here, we establish lipoxins as key chemical mediators in resistance to M. tuberculosis infection. High levels of lipoxin A4 (LXA4) were detected in sera from infected WT but not infected 5-LO-deficient mice. Moreover, lungs from M. tuberculosis-infected 5-lo-/- animals showed increased IL-12, IFN-gamma, and NO synthase 2 (NOS2) mRNA levels compared with the same tissues in WT mice. Similarly, splenocyte recall responses were enhanced in mycobacteria-infected 5-lo-/- versus WT mice. Importantly, bacterial burdens in 5-lo-/- lungs were significantly lower than those from WT mice, and this enhancement in the resistance of the 5-lo-/- animals to M. tuberculosis was completely prevented by administration of a stable LXA4 analog. Together our results demonstrate that lipoxins negatively regulate protective Th1 responses against mycobacterial infection in vivo and suggest that the inhibition of lipoxin biosynthesis could serve as a strategy for enhancing host resistance to M. tuberculosis.

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    • "The enzymes cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO) or 12/15-lipoxygenase (12/15-LO) compete with each other for arachidonic acid to generate COX-dependent prostaglandins or LO-dependent lipoxins and leukotrienes. Mice deficient in 5-LO are resistant to Mtb infection, while Ptgs2 À/À mice are susceptible to TB, suggesting that the balance of lipid mediators may affect the outcome of disease [10] [102] [103]. Accordingly, the avirulent H37Ra Mtb strain stimulates the release of large amounts of PGE2 by infected macrophages, while the virulent H37Rv Mtb strain induces less PGE2 and more lipoxin A4 (LXA4) [103] [104]. "
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    • "However, in our model, 5-LO−/− T. cruzi infected mice exhibited an increased capacity to produce IL-12 and IFN-γ. A similar result was obtained in other infection models using 5-LO−/− mice [22, 29, 30], and this capacity was found to be essential to achieving protective immunity against pathogens in these mice [22, 47]. Previous studies have demonstrated that the quality and quantity of inflammatory mediators such as IL-12, IFN-γ, and IL-10 released during the first two weeks of infection are critical to driving the generation of parasite-specific effector T cells [48] and we suggest that early IL-12 and IFN-γ production during infection was regulated by LTs. "
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    ABSTRACT: In the present work we examine the contribution of 5-lipoxygenase- (5-LO-) derived lipid mediators to immune responses during the acute phase of Trypanosoma cruzi infection in 5-LO gene knockout (5-LO(-/-)) mice and wild-type (WT) mice. Compared with WT mice, the 5-LO(-/-) mice developed less parasitemia/tissue parasitism, less inflammatory cell infiltrates, and a lower mortality. This resistance of 5-LO(-/-) mice correlated with several differences in the immune response to infection, including reduced PGE2 synthesis; sustained capacity of splenocytes to produce high levels of interleukin (IL)-12 early in the infection; enhanced splenocyte production of IL-1β, IL-6, and IFN-γ; rapid T-cell polarization to secrete high quantities of IFN-γ and low quantities of IL-10; and greater numbers of CD8(+)CD44(high)CD62L(low) memory effector T cells at the end of the acute phase of infection. The high mortality in WT mice was associated with increased production of LTB4/LTC4, T cell bias to produce IFN-γ, high levels of serum nitrite, and marked protein extravasation into the peritoneal cavity, although survival was improved by treatment with a cys-LT receptor 1 antagonist. These data also provide evidence that 5-LO-derived mediators negatively affect host survival during the acute phase of T. cruzi infection.
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    • "The host cell production of the eicosanoids, PGE 2 versus LXA 4 , is of critical importance for the induction of apoptosis or necrosis, respectively (Behar et al. 2010). Mice deficient in 5- lipoxygenase cannot make LXA 4 and thus are more resistant to Mtb infections (Bafica et al. 2005). On the other hand, mice deficient in prostaglandin E synthase (PTGES) cannot produce PGE 2 and these animals are more susceptible to Mtb infections (Divangahi et al. 2009). "
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