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Production in IFN Regulatory Factor-1 Knockout Mice During Endotoxemia Is Secondary to a Loss of Both IL-12 and IL-12 Receptor Expression1
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814
Mice with a targeted mutation in the gene that encodes the
transcription factor IFN regulatory factor-1 (IRF-1) were used to
assess the contribution of IRF-1 to IL-12-dependent and
IL-12-independent pathways of IFN-
production. In response to LPS,
IRF-1-/- mice produced less IL-12 p40, IL-12 p35, and
IFN- mRNA in the liver than IRF-1+/+ mice. While
pulmonary IFN- mRNA levels were also mitigated in
IRF-1-/- mice, pulmonary IL-12 p40 and IL-12 p35 mRNA
were not dysregulated. Circulating IL-12 p70 and IFN- levels were
profoundly attenuated in LPS-challenged IRF-1-/- mice.
Further analysis revealed a major deficiency in hepatic IL-12Rß1 and
IL-12Rß2 mRNA expression as well as pulmonary IL-12Rß1 mRNA
expression in LPS-challenged IRF-1-/- mice. In vitro,
IFN- up-regulated IL-12Rß1 mRNA in macrophages from
IRF-1+/+, but not IRF-1-/-, mice.
IFN--induced IL-12Rß2 mRNA expression was also diminished in
macrophages from IRF-1-/- mice. In contrast to
IRF-1+/+ mice, administration of exogenous IL-12 to
IRF-1-/- mice resulted in reduced serum IFN- and
hepatic and pulmonary IFN- mRNA, demonstrating that loss of IL-12R
results in diminished IL-12 responsiveness. While LPS-challenged
IRF-1-/- mice also had reduced IL-15 mRNA levels, serum
IL-18 responses were intact. Finally, induction of IRF-1 mRNA by LPS in
livers of IFN- knockout mice were markedly attenuated, suggesting a
feedback amplification loop. These studies indicate that IRF-1
deficiency disrupts both IL-12-dependent and -independent pathways of
IFN- production and that IRF-1 is a critical transcription factor
involved in the regulation of not only IL-12, but also
IL-12R.
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