Endotoxin fails to induce IFN-gamma in endotoxin-tolerant mice: deficiencies in both IL-12 heterodimer production and IL-12 responsiveness.
Mice exposed to sublethal endotoxemia develop short-term endotoxin tolerance, a state characterized by decreased monokine production and enhanced protection against endotoxic lethality. We confirmed that TNF-alpha production is markedly impaired in endotoxin-tolerant mice and additionally found 2- to 6-fold decreases in serum IFN-gamma in these animals following endotoxin challenge. The IFN-gamma deficiency of endotoxin tolerance correlated with 8-fold decreases in the bioactive p40/p35 heterodimeric form of IL-12. In contrast, total circulating IL-12 p40 was reduced by only 30-50%. Endotoxin-tolerant mice were less responsive to IL-12 than control mice, as evidenced by 3-fold lower levels of IFN-gamma inducible in vivo when rIL-12 was administered at the time of endotoxin challenge. Similarly, spleen cell cultures of endotoxin-tolerant mice produced 3-fold less IFN-gamma in the presence of optimal concentrations of both IL-12 and IL-18. Finally, levels of IL-12R beta 2 subunit mRNA and the percent composition of NK lymphocytes in the spleen were both decreased in endotoxin-tolerant mice relative to controls. We conclude that endotoxin-tolerant mice are profoundly impaired in their ability to produce IFN-gamma in response to endotoxin and that this is associated with acquired defects in both the production of circulating IL-12 heterodimer response and the response to IL-12 by NK cells.
Balkhy
H H
HH
Cleveland Citywide Pediatric Infectious Diseases Program, Case Western Reserve University School of Medicine, OH 44106, USA.
Heinzel
F P
FP
D000818:Animals; D002478:Cells, Cultured; D019281:Dimerization; D004361:Drug Tolerance; D004731:Endotoxins / Q000008:administration & dosage*; D005260:Female; D007106:Immune Sera / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007369:Interferon Inducers / Q000008:administration & dosage*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D016753:Interleukin-10 / Q000276:immunology; D018664:Interleukin-12 / Q000008:administration & dosage* / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D020382:Interleukin-18 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage; D018655:Lymphocyte Count; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000235:genetics; D053707:Receptors, Interleukin-12; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000494:pharmacology
D004731:Endotoxins; D007106:Immune Sera; D007369:Interferon Inducers; D020382:Interleukin-18; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma