Leukotriene B₄Induces Nitric Oxide Synthesis inTrypanosoma cruzi-Infected Murine Macrophages and Mediates Resistance to Infection

Abstract

. Finally, daily treatment of infected mice with CP-105,696 was accompanied by a significantly higher level of blood parasitemia, but not lethality, than that seen in vehicle-treated animals. In conclusion, our results suggest a role for LTB 4 during experimental T. cruzi infection. Chemoattractant molecules such as LTB 4 not only may play a major role in leukocyte migration into sites of inflammation in vivo but also, in the event of an infection, may play a relevant role in the activation of recruited leukocytes to kill the invading microorganism in an NO-dependent manner.Chagas' disease is a protozoan infection caused by Trypanosoma cruzi and is an important public health problem in much of Latin America. The murine model of Chagas' disease has been used to understand the pathophysiological mechanisms underlying the disease and host protection. In this model, host resistance developed against parasites is dependent on the production of inflammatory cytokines, especially interleukin-12, which triggers the production of gamma interferon (IFN-␥) by NK or T cells, and tumor necrosis factor alpha (TNF-␣) (1, 5-7). These cytokines can in turn activate macrophages to produce nitric oxide (NO), the main effector molecule that controls intracellular parasite replication (5, 10, 15, 31). In macrophages, NO is generated from the guanidino nitrogen atom of L-arginine by an inducible NADPH-dependent enzyme called inducible NO synthase (iNOS) (19,22). More recently, it was shown that chemoattractant molecules which act on G protein-coupled serpentine receptors, such as chemokines and platelet-activating factor (PAF), may also participate in the cascade of events leading to NO production and parasite killing (2, 3). On the other hand, interleukin-10 and transforming growth factor ␤ appear to modulate negatively the production of NO and T. cruzi killing induced by proinflammatory cytokines (28,29).Leukotrienes are metabolites of arachidonic acid and have been shown to induce leukocyte activation and/or recruitment in several models of inflammation (9, 14). Leukotriene B 4 (LTB 4 ) acts via G protein-coupled receptors and is enzymatically produced through the 5-lipoxygenase pathway (8,33). A previous study demonstrated the ability of LTB 4 to induce the uptake and killing of T. cruzi by murine macrophages (32). However, the mechanisms underlying LTB 4 -induced killing and whether this was relevant in vivo were not evaluated. Here we investigated the ability of LTB 4 to induce the production of NO and whether NO mediated LTB 4 -induced parasite killing by peritoneal macrophages infected with T. cruzi in vitro. As the actions of LTB 4 may be partially dependent on the release of secondary mediators, such as PAF (13,16,18,24), we also evaluated whether LTB 4 -induced NO production and parasite killing were PAF dependent. Finally, we investigated whether endogenous production of LTB 4 played a relevant role in the infection of mice with T. cruzi in vivo.

Leukotrienes Are Essential for the Control ofLeishmania amazonensisInfection and Contribute to Strain Variation in Susceptibility

“…Moreover, treatment of macrophages with LTB 4 induces iNOS expression and NO production in both strains of mice. Our results are in line with the findings of Talvani et al (14) that showed a synergism between infection with T. cruzi and treatment with LTB 4 .…”

“…However, some persistent leishmanicidal activities of LTB 4 -treated macrophages even in the presence of L-NAME suggest that other mechanisms independent of NO may be operative. Talvani et al (14) demonstrated that NO is the molecule involved 6 stationary phase promastigotes of L. amazonensis in the left hind footpad at time 0, and were treated or not from days 1-7 with the 5-LO inhibitor zileuton (1 mg/kg i.p. daily).…”

“…The IFN-␥-mediated killing of Toxoplasma gondii by human monocytes was shown to be dependent on LT biosynthesis (13). In addition, Talvani et al (14) showed that during T. cruzi infection, LTB 4 is able to promote NO release and thereby kill this parasite.…”

Leukotriene B4 Modulates P2X7 Receptor–MediatedLeishmania amazonensisElimination in Murine Macrophages

“…Many studies have shown the involvement of 5-LO during murine Chagas' disease. Literature data show that LTB 4 leads to an increase in NO synthesis, which participates in the resistance to the infection (41). However, Clark and coworkers (36) demonstrated in vivo that 5-LO KO mice have increased NO and IL-6 levels in plasma with a concomitant decrease in the expression of iNOS in cardiac tissue 12 d postinfection with T. cruzi.…”

Leukotriene B4 Potentiates CpG Signaling for Enhanced Cytokine Secretion by Human Leukocytes

“…In such mice, infection with all of the aforementioned pathogens was facilitated by the absence of TLR9. LTB 4 has also shown antimicrobial activities against Klebsiella pneumoniae (42), Trypanosoma cruzi (43), and Leishmania amazonensis (44). Moreover, we previously demonstrated the antiviral properties of LTB 4 against different viruses such as human and murine CMV and HSV-1 as well as the influenza virus (20 -22).…”