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Infection and Immunity, June 2000, p. 3502-3508, Vol. 68, No. 6
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Role of Interleukin-18 (IL-18) during Lethal Shock: Decreased Lipopolysaccharide Sensitivity but Normal Superantigen Reaction in IL-18-Deficient Mice

Peter Hochholzer, Grayson B. Lipford, Hermann Wagner, Klaus Pfeffer, and Klaus Heeg*

Institute of Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Munich, Germany

Received 9 September 1999/Returned for modification 26 October 1999/Accepted 29 February 2000

Lethal shock can be associated with excessive secretion of cytokines such as tumor necrosis factor (TNF) and gamma interferon (IFN-gamma ). IFN-gamma mediates macrophage activation and appears to be controlled by interleukin (IL)-12 and IL-18. To investigate the role of IL-18 in vivo, we generated IL-18-deficient mice by gene targeting. IL-18-/- mice showed decreased sensitivity towards lipopolysaccharide (LPS)-induced shock. LPS-induced IFN-gamma production was abrogated, yet induction of IL-12 and TNF was not affected. Both wild-type and IL-18-deficient mice succumbed to LPS-induced lethal shock after sensitization with D-galactosamine. However, in marked contrast to LPS, the bacterial superantigen Staphylococcus aureus enterotoxin B (SEB) induced comparable serum levels of IFN-gamma in IL-18+/+ and IL-18-/- mice, accompanied by an upregulation of cell surface markers CD14, CD122 (IL-2Rbeta ), and CD132 (IL-2Rgamma ) on peritoneal macrophages. Moreover, SEB injection rendered IL-18-deficient mice sensitive for subsequent challenge with LPS. The degree of sensitization was comparable to that in wild-type controls with respect to lethality. However, LPS-induced TNF levels in serum were significantly reduced in SEB-sensitized IL-18-deficient mice. These results imply that IL-18 plays an important role in induction of IFN-gamma and lethality in response to LPS.

* Corresponding author. Present address (mailing address): Institut für Medizinische Mikrobiologie und Krankenhaushygiene, Philipps University of Marburg, Pilgrimstein 2, D-35037 Marburg, Germany. Phone: 49-6421-28-66453. Fax: 49-6421-28-66420. E-mail: heeg{at}post.med.uni-marburg.de.

Infection and Immunity, June 2000, p. 3502-3508, Vol. 68, No. 6
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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