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Published online before print August 11, 2003

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(Journal of Leukocyte Biology. 2003;74:889-896.)
© 2003 by Society for Leukocyte Biology

Generation and characterization of mice transgenic for human IL-18-binding protein isoform a

Giamila Fantuzzi^*,1, Nirmal K. Banda, Carla Guthridge, Andrea Vondracek, Soo-Hyun Kim^*, Britta Siegmund^*,2, Tania Azam^*, Joseph A. Sennello^*, Charles A. Dinarello^* and William P. Arend

Divisions of
^* Infectious Diseases and
Rheumatology, Department of Medicine, University of Colorado Health Sciences Center, Denver, CO

¹Correspondence: University of Colorado Health Sciences Center, 4200 East Ninth Avenue B168, Denver, CO 80262. E-mail: Giamila.Fantuzzi{at}UCHSC.edu

Interleukin (IL)-18 binding protein (IL-18BP) is a natural inhibitor of the pleiotropic cytokine IL-18. To study the role of IL-18BP in modulating inflammatory responses in vivo, mice transgenic for human IL-18BP isoform a (IL-18BP-Tg) were generated. The transgene was expressed at high levels in each organ examined. High levels of bioactive human IL-18BPa were detectable in the circulation of IL-18BP-Tg mice, which were viable, fertile, and had no tissue or organ abnormality. The high levels of IL-18BP in the transgenic mice were able to completely neutralize the interferon- (IFN-)-inducing activity of exogenously administered IL-18. Following administration of endotoxin, with or without prior sensitization with heat-inactivated Propionibacterium acnes, IL-18BP-Tg mice produced significantly lower serum levels of IFN- and macrophage-inflammatory protein-2 compared with nontransgenic littermates. Significantly reduced production of IFN- in response to endotoxin was also observed in cultures of IL-18BP-Tg splenocytes. Finally, IL-18BP-Tg mice were completely protected in a model of hepatotoxicity induced by administration of concanavalin A. These results indicate that high endogenous levels of IL-18BP in trangenic mice effectively neutralize IL-18 and are protective in response to different inflammatory stimuli.

Key Words: cytokines • interferon • endotoxin • hepatitis

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