resistant to infection (38). Similarly, we would predict that in the absence of PGES, mice are more susceptible to infec- tion. WT and PGES / mice were infected by the aerosol route with 100 virulent Mtb per lung. Similar numbers of bacteria were found in the lungs of both WT and PGES / mice on day 1 after infection (n = 4/group). The bacterial burden in WT and PGES / mice was not different 2 wk after infection (unpublished data). However, after 5 wk WT mice controlled the infection more efficiently compared with the PGES / mice, whose lungs contained more bac- teria ( log 10 = 0.97; P = 0.0079; Fig. 6). This difference was not observed in the spleen (unpublished data). To assess whether the balance between PGE2 and LXA4 is changed during the course of a mycobacterial infection in vivo, we next measured the levels of PGE2 and LXA4 in sera from WT mice infected with either virulent Erdmann strain or avirulent H37Ra. As it was observed in vitro, virulent bac- teria induced remarkably more LXA4 after 7 d of infection, whereas avirulent H37Ra induced more PGE2. This indi- cates that PGE2 significantly contributes in vivo to protec- tive responses against mycobacterial infection in the lung. DISCUSSION The central finding of this study is that in the local environ- ment of an Mtb infection, M infected with virulent Mtb pref- erentially synthesize LXA4 and little, if any, PGE2. In contrast, M infected with avirulent H37Ra produce mainly pros- tanoids, including PGE2, and only small amounts of LXA4. Figure 6. Mycobacterial burden of PGES / and WT M in vitro and in vivo. (A) Mycobacterial burden after 4 h (inoculum), 4 d, and 7 d of PGES / and WT M in vitro infected with H37Rv (MOI 10:1). The dif- ference in the bacterial burden was significant at 4 and 7 d after infection (*, P < 0.03). (B) 5 wk after aerosol infection, CFUs were determined by plating of homogenized lung tissue as indicated on the ordinate. The difference in mycobacterial burden in the lungs of PGES / versus WT mice is statistically significant (*, P = 0.002; five mice per group). (C and D) Induction of LXA4 and PGE2 production during the course of mycobacterial infection. WT mice were infected by aerosol exposure with virulent (Erdmann) or avirulent (H37Ra). LXA4 (C) and PGE2 (D) measured by ELISA in the sera at 7, 14, and 35 d after infection (*, P < 0.01; three mice per time points). These results are representative of two independent experiments. The error bars represent SE. JEM VOL. 205, November 24, 2008 A RT I C L E Our results demonstrate hitherto unappreciated disparate roles for LXA4 and PGE2 in the regulation of induction of host M necrosis, a cell death leading to cytolysis. M infected with virulent Mtb that produce LXA4 and reduced amounts of PGE2 undergo necrosis. In contrast, prevention of necrosis and con- comitant induction of M apoptosis is associated with in- creased PGE2 production. Thus, the induction of LXA4 and the resulting inhibition of PGE2 production contribute to the virulence of Mtb and enhance its capacity to evade killing by the innate immune system. Indeed, the failure of PGES / M to control H37Rv replication in vitro and the observation that PGES / mice have a 10-fold higher Mtb burden in their lungs compared with WT mice demonstrate the protective ef- fect of PGE2 against virulent Mtb. Preferential synthesis of ei- ther LXA4 or of prostanoids is a critical branch point for the innate antimycobacterial response of the infected M (Fig. 7). Lipoxins are best described as potent negative regulators of acute inflammatory processes (55), in part via inhibition of DC mobilization, inhibition of IL12 production (56), and PMN- induced inflammation in vivo. LXA4 activities are multifold and include inhibition of PMN entry to sites of inflammation, reduction of vascular permeability, promotion of monocyte infiltration, and ingestion of apoptotic cells, perhaps including infected M by phagocytes (39). Moreover, lipid mediators that resolve inflammatory events, including LXA4, stimulate phagocytosis of zymosan and of microbial organisms leading to de novo infection of phagocytes (56). The results suggest that the action of LXA4 in reducing prostanoid production as part of the inflammation-resolving program of LXA4 is exploited by Mtb in the local environment. Thus, although temporally regulated dampening of the inflammatory response is generally highly beneficial to the host, our studies uncover a novel sce- nario wherein LXA4-driven reduction of “proinflammatory” PGE2 synthesis functionally acts as an efficient mechanism used by pathogenic Mtb. More specifically, LXA4 counteracts the Figure 7. Infection of M with the virulent H37Rv predominantly induces LXA4 production and block of COX2 and PGE2 production, which might lead to necrotic cell lysis and spread of the infection. In contrast, M infected with avirulent H37Ra produce larger amounts of PGE2 which blocks LXA4 production and supports M apoptosis and con- tainment of the Mtb. Predominant production of either PGE2 or LXA4 by M infected with H37Ra or H37Rv, respectively, is supported by the fact that PGE2 inhibits LXA4 production and vice versa. 2797