IL‐12 selectively regulates STAT4 via phosphatidylinositol 3‐kinase and Ras‐independent signal transduction pathways

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.