Interleukin 12 induces tyrosine phosphorylation and activation of STAT4 in human lymphocytes.
Interleukin 12 (IL-12) is an important immunoregulatory cytokine whose receptor is a member of the hematopoietin receptor superfamily. We have recently demonstrated that stimulation of human T and natural killer cells with IL-12 induces tyrosine phosphorylation of the Janus family tyrosine kinase JAK2 and Tyk2, implicating these kinases in the immediate biochemical response to IL-12. Recently, transcription factors known as STATs (signal transducers and activators of transcription) have been shown to be tyrosine phosphorylated and activated in response to a number of cytokines that bind hematopoietin receptors and activate JAK kinases. In this report we demonstrate that IL-12 induces tyrosine phosphorylation of a recently identified STAT family member, STAT4, and show that STAT4 expression is regulated by T-cell activation. Furthermore, we show that IL-12 stimulates formation of a DNA-binding complex that recognizes a DNA sequence previously shown to bind STAT proteins and that this complex contains STAT4. These data, and the recent demonstration of JAK phosphorylation by IL-12, identify a rapid signal-transduction pathway likely to mediate IL-12-induced gene expression.
Bacon
C M
CM
Lymphocyte Cell Biology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Petricoin
E F
EF
Ortaldo
J R
JR
Rees
R C
RC
Larner
A C
AC
Johnston
J A
JA
O'Shea
J J
JJ
D001483:Base Sequence; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D018664:Interleukin-12 / Q000494:pharmacology*; D053614:Janus Kinase 2; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D017452:Receptors, IgG / Q000235:genetics; D050797:STAT4 Transcription Factor; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D053634:TYK2 Kinase; D015534:Trans-Activators / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism*
D004268:DNA-Binding Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D017452:Receptors, IgG; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D015534:Trans-Activators; D018664:Interleukin-12; D014443:Tyrosine; D004247:DNA; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D053634:TYK2 Kinase; C070139:TYK2 protein, human