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Infection and Immunity, December 2000, p. 6932-6938, Vol. 68, No. 12
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Interleukin-18 (IL-18) Enhances Innate IL-12-Mediated Resistance to Toxoplasma gondii

Guifang Cai,1 Robert Kastelein,2 and Christopher A. Hunter1,*

Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania,1 and Department of Molecular Biology, DNAX Research Institute, Palo Alto, California2

Received 17 March 2000/Returned for modification 10 May 2000/Accepted 28 August 2000

Innate resistance to Toxoplasma gondii is dependent on the ability of interleukin-12 (IL-12) to stimulate natural killer (NK) cell production of gamma interferon (IFN-gamma ). Since IL-18 is a potent enhancer of IL-12-induced production of IFN-gamma by NK cells, SCID mice (which lack an adaptive immune response) were used to assess the role of IL-18 in innate resistance to T. gondii. Administration of anti-IL-18 to SCID mice infected with T. gondii resulted in an early reduction in serum levels of IFN-gamma but did not significantly decrease resistance to this infection. In contrast, administration of exogenous IL-18 to infected SCID mice resulted in increased production of IFN-gamma , reduced parasite burden, and a delay in time to death. The protective effects of IL-18 treatment correlated with increased NK cell numbers and cytotoxic activity at the local site of administration and with elevated levels of inducible nitrous oxide synthose in the spleens of treated mice. In addition, in vivo depletion studies demonstrated that the ability of exogenous IL-18 to enhance resistance to T. gondii was dependent on IL-12, IFN-gamma , and NK cells. Together, these studies demonstrate that although endogenous IL-18 appears to have a limited role in innate resistance to T. gondii, treatment with IL-18 can augment NK cell-mediated immunity to this pathogen.

* Corresponding author. Mailing address: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce St., Philadelphia, PA 19104-6008. Phone: (215) 573-7772. Fax: (215) 573-7023. E-mail: chunter{at}phl.vet.upenn.edu.

Infection and Immunity, December 2000, p. 6932-6938, Vol. 68, No. 12
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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