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

Journal of Leukocyte Biology

Britta Siegmund¹  Joseph A. Sennello¹  Charles A. Dinarello¹  Tania Azam¹  William P. Arend²  Giamila Fantuzzi¹  Andrea Vondracek²  Soo-Hyun Kim¹  Carla Guthridge²  Nirmal K. Banda² 

[1] Infectious Diseases and Infectious Diseases and Infectious Diseases and;Rheumatology, Department of Medicine, University of Colorado Health Sciences Center, Denver, CO Rheumatology, Department of Medicine, University of Colorado Health Sciences Center, Denver, CO Rheumatology, Department of Medicine, University of Colorado Health Sciences Center, Denver, CO

关键词: cytokines;    interferon;    endotoxin;    hepatitis;   

DOI  :  10.1189/jlb.0503230

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

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-γ (IFN-γ)-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-γ and macrophage-inflammatory protein-2 compared with nontransgenic littermates. Significantly reduced production of IFN-γ 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.

【 授权许可】

Unknown