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Expression1
Department of Microbiology and Immunology, Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202; and Walther Cancer Institute, Indianapolis, IN 46208
IL-12 is a central immunoregulatory cytokine that promotes
cell-mediated immune responses and the differentiation of naive
CD4+ cells into Th1 cells. We and others have demonstrated
that the Stat4 is critical for IFN-
production by activated T cells
and Th1 cells. However, several studies have suggested that other
pathways may be involved in IL-12-stimulated IFN- expression. In
this report we demonstrate that IL-12 activates mitogen-activated
protein kinase kinase 3/6 (MKK) and p38 mitogen-activated protein
kinase (MAPK), but not p44/42 (ERK) or stress-activated protein
kinase/c-Jun N-terminal kinase MAPK. The activation of p38 MAPK is
required for normal induction of IFN- mRNA and IFN- secretion by
IL-12 in activated T cells and Th1 cells. Importantly, IL-12-stimulated
p38 MAPK effector functions occur through a Stat4-independent mechanism
and correlate with increased serine phosphorylation of activating
transcription factor-2. The requirement for p38 MAPK in IL-12 function
suggests that this pathway may be an important in vivo target for the
anti-inflammatory actions of p38 MAPK
inhibitors.
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