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Blood, 1 September 2000, Vol. 96, No. 5, pp. 1844-1852
IMMUNOBIOLOGY
Importance of the MKK6/p38 pathway for interleukin-12-induced
STAT4 serine phosphorylation and transcriptional activity
Roberta Visconti,
Massimo Gadina,
Mario Chiariello,
Elbert H. Chen,
Louis F. Stancato,
J. Silvio Gutkind, and
John J. O'Shea
From the Lymphocyte Cell Biology Section, Arthritis and
Rheumatism Branch, National Institute of Arthritis and Musculoskeletal
and Skin Diseases; Oral and Pharyngeal Cancer Branch, National
Institute of Dental and Craniofacial Research; and Howard Hughes
Medical Institute-NIH Research Scholars Program, National Institutes of
Health, Bethesda, MD.
Interleukin-12 (IL-12) is a key immunoregulatory cytokine that
promotes Th1 differentiation and cell-mediated immune responses. The
transcription factor STAT4 (signal transducer and activator of
transcription 4) is an important element in mediating IL-12 signals, as
evidenced by the fact that STAT4 / mice display impaired
responsiveness to IL-12 and deficient Th1 differentiation. STAT4 is
inducibly phosphorylated on tyrosine and serine in response to IL-12,
but the kinase(s) responsible for the latter event is unknown. Here we
show that IL-12 induces STAT4 phosphorylation on serine 721 and that
mutation of serine 721 interferes with STAT4 transcriptional activity.
In addition, we show that mutation of tyrosine 693 abrogates
IL-12-induced STAT4 tyrosine phosphorylation and transcriptional
activity. Although the site surrounding serine 721 is an optimum
consensus sequence for mitogen-activated family of protein kinases
(MAPKs)-mediated phosphorylation, we demonstrate that IL-12 does not
induce extracellular signal-regulated kinase (ERK) or c-Jun N-terminal
kinase (JNK) activation in T and natural killer (NK) cells and that
IL-12-induced STAT4 transcriptional activity is not affected by these
kinases. Rather, we show that IL-12 induces p38 activation. Moreover,
we demonstrate that p38 and its upstream activator, MKK6,
phosphorylate STAT4 on serine 721, and are required for STAT4 full
transcriptional activity induced by IL-12, establishing the
MKK6/p38/STAT4 pathway as an important mediator of IL-12 actions.
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