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 ha ve recently demonstrated that stimulation of human T and natural kille r cells with IL-12 induces tyrosine phosphorylation of the Janus famil y tyrosine kinases JAK2 and Tyk2, implicating these kinases in the imm ediate biochemical response to IL-12. Recently, transcription factors known as STATs (signal transducers and activators of transcription) ha ve been shown to be tyrosine phosphorylated and activated in response to a number of cytokines that bind hematopoietin receptors and activat e JAK kinases. In this report we demonstrate that IL-12 induces tyrosi ne phosphorylation of a recently identified STAT family member, STAT4, and show that STAT4 expression is regulated by T-cell activation. Fur thermore, we show that IL-12 stimulates formation of a DNA-binding com plex that recognizes a DNA sequence previously shown to bind STAT prot eins 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.