Journal
JOURNAL OF IMMUNOLOGY
Volume 170, Issue 5, Pages 2621-2628Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.170.5.2621
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The phagolysosomal compartment is crucial for the defense against infection with intracellular pathogens. Within this compartment, the TNF- and IFN-gamma-responsive acid sphingomyelinase (ASMase) generates the signaling molecule ceramide, resulting in the activation of proteases like cathepsin D. To investigate the possible role of ASMase as a mediator of the antibacterial effects of TNF and IFN-gamma, ASMase(-/-) mice were infected with Listeria monocytogenes. ASMase(-/-) mice showed a dramatically increased susceptibility to L. monocytogenes (LD50 similar to100 CFU) when compared with syngeneic wild-type mice (LD50 similar to10,000 CFU). In L. monocytogenes-challenged ASMase(-/-) mice, IFN-gamma serum levels as well as IL-1beta and IL-6 secretion by macrophages were similar to those observed in wild-type C57BL/6 mice. Although macrophages and granulocytes from ASMase(-/-) mice showed intact production of reactive nitrogen intermediates and oxidative burst, ASMase(-/-) macrophages proved completely incapable of restricting the growth of L monocytogenes in vitro. The results of this study suggest that ASMase is crucially required for the intracellular control of L monocytogenes in macrophages and granulocytes by nonoxidative mechanisms.
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