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Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814
Macrophages derived from IFN-regulatory factor-1 (IRF-1) and IRF-2
knockout (-/-) and wild-type (+/+) mice were utilized to examine the
role of these transcription factors in the regulation of IL-12 mRNA and
protein expression. Induction of IL-12 p40 mRNA by LPS was markedly
diminished in both IRF-1-/- and IRF-2-/-
macrophages. In contrast, IRF-1-/-, but not
IRF-2-/-, macrophages exhibited impaired LPS-induced
IL-12 p35 mRNA expression. The ability of IFN-
to augment
LPS-induced IL-12 p40 mRNA further when both stimuli were present
simultaneously was significantly diminished in both
IRF-1-/- and IRF-2-/- macrophages, with the
most profound impairment observed for IRF-1-/-
macrophages. Reductions in IL-12 mRNA expression after stimulation with
LPS or LPS plus IFN- were accompanied by substantial reductions in
IL-12 p40 and IL-12 p70 protein in both IRF-1-/- and
IRF-2-/- macrophages. Priming IRF-1-/- and
IRF-2-/- macrophages with IFN- for 24 h before
LPS treatment partially restored impaired IL-12 mRNA and protein
production in both IRF-1-/- and IRF-2-/-
macrophages. Depressed IL-12 levels were paralleled by significant
reductions in IFN- mRNA expression in IRF-1-/- and
IRF-2-/- macrophages. These results indicate that both
IRF-1 and IRF-2 are critical transcription factors in the regulation of
macrophage IL-12 and consequently IFN-
production.
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