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in Endotoxin-Tolerant Mice: Deficiencies in Both IL-12 Heterodimer Production and IL-12 Responsiveness1
*
Cleveland Citywide Pediatric Infectious Diseases Program, Case Western Reserve University School of Medicine, Cleveland, OH, 44106; and
Division of Geographic Medicine, Case Western Reserve University School of Medicine and Medical Research Services, Veterans Affairs Medical Center, Cleveland OH 44106
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-
production is markedly impaired in endotoxin-tolerant mice and
additionally found 2- to 6-fold decreases in serum IFN-
in these
animals following endotoxin challenge. The IFN- 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- 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- in the presence of
optimal concentrations of both IL-12 and IL-18. Finally, levels of
IL-12R ß2 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- 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.
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