J. Exp. Med.
© The Rockefeller University Press
0022-1007/97/04/1231/10 $2.00
Volume 185, Number 7, April 7, 1997 1231-1240

Intracellular Antimicrobial Activity in the Absence of Interferon-: Effect of Interleukin-12 in Experimental Visceral Leishmaniasis in Interferon- Gene-disrupted Mice

By Alice P. Taylor, and Henry W. Murray

From the Department of Medicine, Cornell University Medical College, New York 10021

Despite permitting uncontrolled intracellular visceral infection for 8 wk, interferon- (IFN-) gene knockout (GKO) mice infected with Leishmania donovani proceeded to reduce liver parasite burdens by 50% by week 12. This late-developing IFN--independent antileishmanial mechanism appeared to be dependent largely on endogenous tumor necrosis factor- (TNF-): L. donovani infection induced TNF- mRNA expression in parasitized GKO livers and neutralization of TNF- reversed control at week 12. 7 d of treatment of infected GKO mice with interleukin-12 (IL-12) readily induced leishmanicidal activity and also partially restored the near-absent tissue granulomatous response, observations that for the first time expand the antimicrobial repertoire of IL-12 to include IFN--independent effects. The action of IL-12 against L. donovani was TNF- dependent and required the activity of inducible nitric oxide synthase. These results point to the presence of an IFN--independent antimicrobial mechanism, mediated by TNF-, which remains quiescent until activated late in the course of experimental visceral leishmaniasis. However, as judged by the effect of exogenous IL-12 this quiescent mechanism can readily be induced to rapidly yield enhanced intracellular antimicrobial activity.

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