Release of nitric oxide during the T cell-independent pathway of macrophage activation. Its role in resistance to Listeria monocytogenes.

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Abstract
Immunodeficient mice are remarkably resistant to Listeria monocytogenes (LM) infection. We examined the role that nitric oxide (NO.) plays in the CB-17/lcr SCID (SCID) response to LM. SCID spleen cells produced large quantities of NO. (as measured by nitrite formation) when incubated in the presence of heat-killed LM. NO. production was dependent on the release of IFN-gamma by the SCID NK cells. When tested directly, macrophages produced large quantities of nitrite in response to LM, but only in the presence of IFN-gamma. The production of NO. induced by LM was not affected by neutralizing antibodies to TNF or IL-1. The production of NO. was inhibited by addition of either of two inhibitors of NO.synthase, NG-monomethyl arginine, or aminoguanidine. In a different situation, NK cells that were stimulated by TNF and Listeria products to release IFN-gamma did not produce NO.. Macrophages cultured with IFN-gamma killed live LM. This increased killing of LM was significantly inhibited by amino-guanidine. In vivo, administration of aminoguanidine resulted in a marked increase in the mortality and spleen bacterial loads of LM-infected SCID or immunocompetent control mice. We conclude that NO. is a critical effector molecule of T cell-independent natural resistance to LM as studied in the SCID mouse, and that the NO.-mediated response is essential for both SCID and immunocompetent host to survive after LM infection.

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