Generation and characterization of mice transgenic for human IL-18-binding protein isoform a.
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-gamma (IFN-gamma)-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-gamma and macrophage-inflammatory protein-2 compared with nontransgenic littermates. Significantly reduced production of IFN-gamma 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.
Fantuzzi
Giamila
G
Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA. Giamila.Fantuzzi@UCHSC.edu
Banda
Nirmal K
NK
Guthridge
Carla
C
Vondracek
Andrea
A
Kim
Soo-Hyun
SH
Siegmund
Britta
B
Azam
Tania
T
Sennello
Joseph A
JA
Dinarello
Charles A
CA
Arend
William P
WP
D000818:Animals; D001483:Base Sequence; D054426:Chemokine CXCL2; D018925:Chemokines / Q000235:genetics; D017931:DNA Primers; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007371:Interferon-gamma / Q000037:antagonists & inhibitors; D020382:Interleukin-18 / Q000037:antagonists & inhibitors; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms / Q000235:genetics
D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D017931:DNA Primers; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D008070:Lipopolysaccharides; D020033:Protein Isoforms; C118370:interleukin-18 binding protein; D007371:Interferon-gamma