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*
The Wistar Institute, Philadelphia, PA 19104; and
Division of Cytokine Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892
IL-12 is a pivotal cytokine that links the innate and adaptive
immune responses. TNF-
also plays a key role in orchestrating
inflammation and immunity. The reciprocal influence of these two
inflammatory mediators on each other may have significant impact on the
cytokine balance that shapes the type and extent of immune responses.
To investigate the relationship between TNF- and IL-12 production,
we analyzed the effects of exposure of human monocyte-derived
macrophages to TNF- on LPS- or Staphylococcus
aureus-induced IL-12 production in the presence or absence of
IFN-
. TNF- is a potent inhibitor of IL-12 p40 and p70 secretion
from human macrophages induced by LPS or S. aureus.
IL-10 is not responsible for the TNF--mediated inhibition of IL-12.
TNF- selectively inhibits IL-12 p40 steady-state mRNA, but not those
of IL-12 p35, IL-1, IL-1ß, or IL-6. Nuclear run-on analysis
identified this specific inhibitory effect at the transcriptional level
for IL-12 p40 without down-regulation of the IL-12 p35 gene. The major
transcriptional factors identified to be involved in the regulation of
IL-12 p40 gene expression by LPS and IFN-, i.e., c-Rel, NF-
B p50
and p65, IFN regulatory factor-1, and ets-2, were not affected by
TNF- when examined by nuclear translocation and DNA binding. These
data demonstrate a selective negative regulation on IL-12 by TNF-,
identifying a direct negative feedback mechanism for
inflammation-induced suppression of IL-12 gene
expression.
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