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Generation and characterization of mice transgenic for human IL‐18‐binding protein isoform a
Author(s) -
Fantuzzi Giamila,
Banda Nirmal K.,
Guthridge Carla,
Vondracek Andrea,
Kim SooHyun,
Siegmund Britta,
Azam Tania,
Sennello Joseph A.,
Dinarello Charles A.,
Arend William P.
Publication year - 2003
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0503230
Subject(s) - transgene , biology , genetically modified mouse , gene isoform , cytokine , splenocyte , microbiology and biotechnology , immunology , immune system , biochemistry , gene
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.