IFN-gamma-independent production of IL-12 during murine endotoxemia.
We examined whether IFN-gamma deficiency alters the in vivo IL-12 response occurring in the mouse model of acute endotoxemia. C57BL/6 IFN-gamma knockout mice (IFN-gamma 0/0) produced as much circulating IL-12 p40 and IL-12 p70 as did IFN-gamma +/+ mice following injection with S. enteritidis LPS, despite sustaining 11-fold reductions in circulating TNF-alpha. Pretreatment of IFN-gamma 0/0 mice with recombinant mouse IFN-gamma (rIFN-gamma) enhanced circulating TNF-alpha by as much as sixfold, but serum IL-12 p40 and IL-12 p70 responses increased by only twofold or less. Compared with IFN-gamma +/+ mice, the spleens of endotoxemic IFN-gamma 0/0 mice generated two- to threefold fewer IL-12 p40-secreting cells following in vitro or in vivo exposure to endotoxin. The addition of rIFN-gamma to IFN-gamma 0/0 splenocyte culture restored normal levels of LPS-stimulated IL-12 p40 production. Removal of Mac-1+ or F4/80+ cells from endotoxin-stimulated spleen reduced both TNF-alpha and IL-12 p40 production, but 33D1+ dendritic cell removal only affected IL-12 synthesis. These data suggest that the aggregate IL-12 p40 and p70 response to endotoxemia in vivo is IFN-gamma-independent and distinct from IFN-gamma-dependent serum TNF-alpha and splenic IL-12 responses. The cellular and/or cytokine basis for the unexpected preservation of IL-12 production in IFN-gamma-deficient mice may be relevant to normal and pathologic immune responses.
Division of Geographic Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
F P
FP
Heinzel
R M
RM
Rerko
F
F
Ahmed
A M
AM
Hujer
D000818:Animals; D019446:Endotoxemia / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D007371:Interferon-gamma / Q000494:pharmacology*; D018664:Interleukin-12 / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000494:pharmacology; D013154:Spleen / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000187:drug effects
D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma