TY - JOUR
T1 - IL-12 selectively regulates STAT4 via phosphatidylinositol 3-kinase and Ras-independent signal transduction pathways
AU - Athié-M., Verónica
AU - Flotow, Horst
AU - Hilyard, Katherine L.
AU - Cantrell, Doreen A.
PY - 2000/6/5
Y1 - 2000/6/5
N2 - IL-12 is an important immunomodulatory cytokine that induces tyrosine phosphorylation and activation of the signal transducer and activator of transcription (STAT)4. IL-12 induces sustained activation and nuclear translocation of STAT4 and this regulatory process is coupled to both tyrosine and serine phosphorylation of this molecule. IL-12-activated tyrosine kinases are the Janus kinases Jak2 and Tyk2 but little is known about IL-12 regulation of serine kinases. The object of the present study was to explore the role of mitogen-activated protein kinases (MAPK) Erk1 and Erk2 and phosphatidylinositol 3-kinase (PI3K) in STAT4 regulation. Here we show that the IL-12-induced STAT4 serine kinase is not sensitive to inhibitors of the PI3K or MAPK Erk1,2. Moreover, IL-12 activation of STAT4 in human peripheral blood-derived T cells is not accompanied by stimulation of the Ras guanine nucleotide binding cycle or stimulation of MAPK Erk1,2 or initiation of the PI3K signaling pathways. IL-12 is unable to initiate the serine phosphorylation of STAT 1 and 3. This reveals that the STAT1, 3 and 4 serine kinases are not coordinately regulated in human T cells and that IL-12 must regulate serine phosphorylation of STAT4 by a kinase network distinct to the MAPK Erk1,2 or PI3K pathways.
AB - IL-12 is an important immunomodulatory cytokine that induces tyrosine phosphorylation and activation of the signal transducer and activator of transcription (STAT)4. IL-12 induces sustained activation and nuclear translocation of STAT4 and this regulatory process is coupled to both tyrosine and serine phosphorylation of this molecule. IL-12-activated tyrosine kinases are the Janus kinases Jak2 and Tyk2 but little is known about IL-12 regulation of serine kinases. The object of the present study was to explore the role of mitogen-activated protein kinases (MAPK) Erk1 and Erk2 and phosphatidylinositol 3-kinase (PI3K) in STAT4 regulation. Here we show that the IL-12-induced STAT4 serine kinase is not sensitive to inhibitors of the PI3K or MAPK Erk1,2. Moreover, IL-12 activation of STAT4 in human peripheral blood-derived T cells is not accompanied by stimulation of the Ras guanine nucleotide binding cycle or stimulation of MAPK Erk1,2 or initiation of the PI3K signaling pathways. IL-12 is unable to initiate the serine phosphorylation of STAT 1 and 3. This reveals that the STAT1, 3 and 4 serine kinases are not coordinately regulated in human T cells and that IL-12 must regulate serine phosphorylation of STAT4 by a kinase network distinct to the MAPK Erk1,2 or PI3K pathways.
KW - IL-12
KW - Mitogen-activated protein kinase
KW - Phosphatidyl inositol 3-kinase
KW - STAT4
KW - T lymphocyte
UR - http://www.scopus.com/inward/record.url?scp=0034068634&partnerID=8YFLogxK
U2 - 10.1002/(SICI)1521-4141(200005)30:5<1425::AID-IMMU1425>3.0.CO;2-Q
DO - 10.1002/(SICI)1521-4141(200005)30:5<1425::AID-IMMU1425>3.0.CO;2-Q
M3 - Article
C2 - 10820390
AN - SCOPUS:0034068634
SN - 0014-2980
VL - 30
SP - 1425
EP - 1434
JO - European Journal of Immunology
JF - European Journal of Immunology
IS - 5
ER -