Release of nitric oxide during the T cell-independent pathway of macrophage activation. Its role in resistance to Listeria monocytogenes.
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.
Beckerman
K P
KP
Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110.
Rogers
H W
HW
Corbett
J A
JA
Schreiber
R D
RD
McDaniel
M L
ML
Unanue
E R
ER
D000594:Amino Acid Oxidoreductases / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D006146:Guanidines / Q000494:pharmacology; D007371:Interferon-gamma / Q000502:physiology; D008088:Listeriosis / Q000276:immunology*; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase; D013154:Spleen / Q000378:metabolism; D013601:T-Lymphocytes / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D006146:Guanidines; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; C004479:pimagedine