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© The Rockefeller University Press, 0022-1007/1997/4/1231/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 7, April 7, 1997 1231-1240

Article

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

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-{gamma} (IFN-{gamma}) gene knockout (GKO) mice infected with Leishmania donovani proceeded to reduce liver parasite burdens by 50% by week 12. This late-developing IFN-{gamma}–independent antileishmanial mechanism appeared to be dependent largely on endogenous tumor necrosis factor-{alpha} (TNF-{alpha}): L. donovani infection induced TNF-{alpha} mRNA expression in parasitized GKO livers and neutralization of TNF-{alpha} 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-{gamma}–independent effects. The action of IL-12 against L. donovani was TNF-{alpha} dependent and required the activity of inducible nitric oxide synthase. These results point to the presence of an IFN-{gamma}–independent antimicrobial mechanism, mediated by TNF-{alpha}, 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.

Address correspondence to Dr. H.W. Murray, Department of Medicine, Box 130, 525 East 68th St., New York 10021.

1Abbreviations used in this paper: AG, aminoguanidine; GKO, gene knockout mice; iNOS, inducible nitric oxide synthase; LDU, Leishman-Donovan units; NO, nitric oxide; RT, reverse transcriptase.


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