Interleukin 12 induces tyrosine phosphorylation and activation of STAT4 in human lymphocytes.

Abstract

Interleukin 12 (IL-12) is an important immunoregulatory cytokine whose receptor is a member of the hematopoietin receptor superfamily. Interleukin 12 (IL-12) is a monocyte/macrophage-derived cytokine (1, 2), which, through its many effects on natural killer (NK) and T lymphocytes, plays a central role in the initiation and control of cell-mediated immune responses (3,4). The receptor for IL-12 (IL-12R) is incompletely characterized, although a low-affinity subunit has recently been cloned (5). This subunit is a member of the hematopoietin receptor family, closely related to gpl3O. Like other family members, binding of IL-12 to the IL-12R induces rapid tyrosine phosphorylation of a range of intracellular substrates (6, 7). However, hematopoietin receptors do not possess intrinsic tyrosine kinase activity but instead associate with and activate members of the Janus (JAK) family of cytoplasmic protein tyrosine kinases (8-12). We have recently demonstrated that IL-12 treatment of human T and NK cells leads to the rapid tyrosine phosphorylation of both JAK2 and Tyk2 kinases, implicating these kinases in the immediate biochemical response to IL-12 (6).The biological effects of IL-12 include the rapid activation of early-response genes such as interferon y (IFN-,y) and perforin (3, 4), but the molecular mechanisms by which IL-12 might stimulate transcription are not known. A number of recent studies have identified a family of transcription factors called STATs (signal transducers and activators of transcription), which are involved in the signal-transduction cascades of many cytokines known to activate JAK kinases (8, 13-15). Originally described as mediators of IFN-induced transcription, STATs are latent cytoplasmic transcription factors that, after tyrosine phosphorylation, translocate to the nucleus and bind specific, but related, DNA sequences to promote transcription of cytokine-responsive genes (13). IFN-a induces tyrosine phosphorylation of STAT1 and STAT2, which associate with a nuclear 48-kDa DNA-binding protein to form a multiprotein transcriptional activator known as interferonstimulated gene factor 3 (16, 17). In contrast, IFN-,y promotes tyrosine phosphorylation and homodimerization of STAT1, which translocates to the nucleus and directly binds to a conserved sequence motif termed the IFN-y-activation site (18). Ligand binding to many hematopoietin receptors has now been shown to induce tyrosine phosphorylation of STAT family proteins, thereby promoting their ability to bind IFNy-activation site-related DNA sequences: the IL-6 family of cytokines activate both STAT1 and STAT3 (19,20), prolactin activates STAT1 (21) and STAT5 (22), and IL-4 activates a STAT protein designated IL-4-STAT (STAT6) (23). STAT4 is another family member with restricted distribution, being expressed mainly by myeloid cells and developing spermatogonia and also in thymus and spleen (24,25). To date, no STAT4-activating ligand has been identified.In this study we sought to determine whether STAT proteins could be identified ...

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