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Lymphocyte Cell Biology Section, Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal Diseases, National Institutes of Health, and
Division of Cytokine Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892
IL-12 is a critical immunoregulatory cytokine that promotes
cell-mediated immune responses and the differentiation of naive
CD4+ cells to Th1 cells; however, relatively few IL-12
target genes have been identified. To better clarify the molecular
basis of IL-12 action, we set out to characterize genes up-regulated by
IL-12, first by contrasting IL-12- and IFN-
-inducible genes. We
identified several genes up-regulated by IL-12, namely, MIP-1,
MIP-1ß, IL-1RA, and IFN regulatory factor-1 (IRF-1). IRF-1 is a
transcription factor regulated by IFNs that is also essential for Th1
responses. We demonstrated that IL-12 directly up-regulates IRF-1 to
the same extent as IFN- in normal human T cells and in NK cells. We
showed that IL-12 had a direct effect on IRF-1, an effect not mediated
indirectly by the induction of IFN-
production. Furthermore, IL-2
and IL-12 synergistically induced IRF-1, whereas IFN- and IL-12 did
not. The participation of STAT4 in the regulation of IRF-1 was
demonstrated in two ways. First, STAT4 was required for the
IL-12-dependent transactivation of an IRF-1 reporter construct, and
second, STAT4 binding to the IRF-1 promoter was shown using EMSA. In
contrast to IL-12, no up-regulation of IRF-1 was found in
IL-4-stimulated cells, and IL-4 did not block IL-12-dependent
up-regulation of IRF-1. Therefore, IRF-1 may be an important
contributor to IL-12 signaling, and we speculate that the defective
IL-12 responses seen in IRF-1-/- mice might be
attributable, in part, to the absence of this transcription
factor.
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