Inherited IL-12 unresponsiveness contributes to the high LPS resistance of the Lps(d) C57BL/10ScCr mouse.
LPS(d) mouse strains are characterized by the presence of a defective LPS/tlr4 gene that make them refractory to the biological activity of LPS. One of the mouse strains commonly used to study LPS defects is the C57BL/10ScCr (Cr) strain. However, unlike other LPS(d) strains, the Cr strain also has a heavily impaired IFN-gamma response to micro-organisms. As a consequence, unlike other LPS(d) mouse strains, they do not acquire a partial LPS susceptibility when treated with sensitizing bacteria. Because IL-12 is important for the microbial induction of IFN-gamma, we investigated whether the production or function of IL-12 might be defective in Cr mice. IL-12 mRNA (p35 and p40) was present in the spleen of untreated Cr mice, IL-12p40 mRNA was inducible in mice injected with live or killed Salmonella typhimurium, and IL-12 (p70) was inducible in macrophages by bacteria. Thus, Cr mice exhibit normal IL-12 responses. In functional tests, splenocytes of untreated or of S. typhimurium-infected mice failed to produce IFN-gamma when stimulated with murine rIL-12 or with a combination of IL-12 and murine rIL-18 or Con A. Furthermore, Cr mice were identical with IL-12p35/p40 and IL-12 receptor beta(1) knockout mice in their impaired in vivo and in vitro IFN-gamma responses to bacteria. Thus, Cr mice carry a second genetic defect unrelated to the Lps/tlr4 mutation that underlies the IL-12 unresponsiveness and contributes to the LPS resistance and impaired innate immune response in this strain.
Merlin
T
T
Max Planck Institut für Immunbiologie, Freiburg, Germany.
Sing
A
A
Nielsen
P J
PJ
Galanos
C
C
Freudenberg
M A
MA
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D007108:Immune Tolerance / Q000235:genetics*; D007113:Immunity, Innate / Q000235:genetics; D007275:Injections, Intravenous; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D018664:Interleukin-12 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D020382:Interleukin-18 / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides / Q000008:administration & dosage* / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL / Q000235:genetics* / Q000276:immunology*; D018345:Mice, Knockout; D011425:Propionibacterium acnes / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D012481:Salmonella Infections, Animal / Q000235:genetics / Q000276:immunology; D012486:Salmonella typhimurium / Q000276:immunology; D013045:Species Specificity; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic / Q000276:immunology
D020382:Interleukin-18; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D018664:Interleukin-12; D007371:Interferon-gamma