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-Inducing Signaling Pathways1
*
Department of Microbiology and Immunology and Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202 and Walther Cancer Institute, Indianapolis, IN 46208;
Akdeniz University Tip Fakultesi, Tibbi Biyologi, Arapsuyu, Antalya, Turkey;
Tularik, Inc., San Francisco, CA 94080; and
§
Department of Cancer Biology, Harvard School of Public Health, and Department of Medicine, Harvard Medical School, Boston, MA 02115
Stat4 is activated in response to IL-12. Most functions of IL-12,
including the induction of IFN-
, are compromised in the absence of
Stat4. Since the precise role of Stat4 in IFN- induction has not
been established, experiments were conducted to examine Stat4
activation of IFN- and other genes required for cytokine-induced
expression of IFN-. We first examined IL-12 signaling components.
Basal expression of IL-12Rß1 and IL-12Rß2 is decreased in
Stat4-deficient cells compared with that in control cells. However,
IL-12 was still capable of inducing equivalent phosphorylation of Jak2
and Tyk2 in wild-type and Stat4-deficient activated T cells. We have
further determined that other cytokine signaling pathways that induce
IFN- production are defective in the absence of Stat4. IL-18 induces
minimal IFN- production from Stat4-deficient activated T cells
compared with control cells. This is due to defective IL-18 signaling,
which results from the lack of IL-12-induced, and Stat4-dependent,
expression of the IL-18R. Following IL-12 pretreatment to induce
IL-18R, wild-type, but not Stat4-deficient, activated T cells
demonstrated IL-18-induced NF-
B DNA-binding activity. In addition,
IL-12-pretreated Stat4-deficient activated T cells have minimal IFN-
production followed by stimulation with IL-18 alone or in combination
with IL-12 compared with control cells. Thus, Stat4 activation by IL-12
is required for the function of multiple cytokine pathways that result
in induction of IFN-.
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