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Requires Stat1 Activation
Tularik, Inc., South San Francisco, CA 94080
IFN-
antagonizes many physiological responses mediated by IL-4,
including the inhibition of IL-4-induced IgE production. This event is
largely mediated at the level of transcription. We observed that the
IL-4 response element of the germline epsilon promoter is sufficient to
confer IFN--mediated repression onto a reporter construct. The
inhibitory effects were observed in both lymphoid and nonlymphoid cell
lines. Stat1, which is activated by IFN-, cannot recognize the
Stat6-specific IL-4 response element in the 
promoter. Hence,
competitive DNA binding does not seem to be the underlying mechanism
for the inhibitory effect. This is supported by the observation that
inhibition is not seen at early time points, but requires prolonged
IFN- treatment. IFN- stimulation results in a loss of
IL-4-induced Stat6 tyrosine phosphorylation, nuclear translocation, and
DNA binding. Using the fibrosarcoma cell line U3A, which lacks Stat1,
we demonstrated that the transcription activation function of Stat1 is
required for the IFN--mediated repression. Repression was restored
by overexpression of Stat1
, but not Stat1ß, in U3A cells.
Treatment with IFN-, but not IL-4, specifically up-regulates the
expression of SOCS-1 (silencer of cytokine signaling), a recently
characterized inhibitor of cytokine signaling pathways, such as IL-6
and IFN-. Overexpression of SOCS-1 effectively blocks IL-4-induced
Stat6 phosphorylation and transcription. This suggests that
IFN--mediated repression of IL-4-induced transcription is at least
in part mediated by SOCS-1.
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