IL-12 Induces IFN Regulating Factor-1 (IRF-1) Gene Expression in Human NK and T Cells

Abstract

IL-12 is a critical immunoregulatory cytokine that promotes cell-mediated immune responses and the differentiation of naive CD4+ cells to Th1 cells; however, relatively few IL-12 target genes have been identified. To better clarify the molecular basis of IL-12 action, we set out to characterize genes up-regulated by IL-12, first by contrasting IL-12- and IFN-α-inducible genes. We identified several genes up-regulated by IL-12, namely, MIP-1α, MIP-1β, IL-1RA, and IFN regulatory factor-1 (IRF-1). IRF-1 is a transcription factor regulated by IFNs that is also essential for Th1 responses. We demonstrated that IL-12 directly up-regulates IRF-1 to the same extent as IFN-α in normal human T cells and in NK cells. We showed that IL-12 had a direct effect on IRF-1, an effect not mediated indirectly by the induction of IFN-γ production. Furthermore, IL-2 and IL-12 synergistically induced IRF-1, whereas IFN-α and IL-12 did not. The participation of STAT4 in the regulation of IRF-1 was demonstrated in two ways. First, STAT4 was required for the IL-12-dependent transactivation of an IRF-1 reporter construct, and second, STAT4 binding to the IRF-1 promoter was shown using EMSA. In contrast to IL-12, no up-regulation of IRF-1 was found in IL-4-stimulated cells, and IL-4 did not block IL-12-dependent up-regulation of IRF-1. Therefore, IRF-1 may be an important contributor to IL-12 signaling, and we speculate that the defective IL-12 responses seen in IRF-1−/− mice might be attributable, in part, to the absence of this transcription factor.

Multicenter International Study of the Consensus Immunoscore for the Prediction of Relapse and Survival in Early-Stage Colon Cancer

“…In fact, the highest densities of adaptive immune cells were observed in the earliest tumors stages [21,47]. These indicated that adaptive immunity, including cytotoxic CD8 T-cells and helper CD4 T-cells with Th1 signature (IFNG, IL12, IRF1) [48], might arise before the carcinoma stage. We recently validated this hypothesis, showing adaptive immune infiltration, increased adaptive immunity, as well as immune escape mechanisms, including immune checkpoint, in precancer lesions [49].…”

Cold Storage Followed by Transplantation Induces Interferon-Gamma and STAT-1 in Kidney Grafts

“…STAT1 activation could induce inducible nitric-oxide synthase (iNOS), a hallmark of renal ischemia–reperfusion injury and oxidative stress. Similarly, IL-12α potentiates IFN-γ-mediated signal transduction by inducing the secretion of IFN-γ in different cell types [ 57 ]. Therefore, we evaluated the effects of 18 h CS + Tx on the expression of IFN-γ, IL-12α, iNOS, and endothelial nitric oxide synthase (eNOS) genes in renal grafts.…”

“…Subsequently, we showed that CS + Tx activates STAT1 and STAT3 factors and increases STAT1 protein levels within transplanted kidneys. Phosphorylation of STAT1 at Y701 is required for transcriptional activation of STAT1 [ 45 , 56 , 57 , 58 , 59 , 60 , 61 ], and this activation induces cell cycle/growth arrest and promotes apoptosis [ 62 , 63 , 64 , 65 , 66 ]. Similarly, phosphorylation of STAT3 at Y705 is required for transcriptional activation of STAT3 [ 61 , 67 , 68 ], and in most instances, this activation induces cell growth/proliferation that promotes cell survival [ 69 , 70 , 71 ].…”

“…Interferon-gamma (IFN-γ) is a potent activator of STAT1 [ 45 ], and in the absence of STAT1, IFN-γ exacerbates the activation/induction of STAT3 [ 100 ]. IL-12α potentiates IFN-γ-mediated signal via induction of IFN-γ secretion within different cell types [ 57 ]. As anticipated, CS + Tx induced IFN-γ and IL-12α expression in renal grafts, both of which regulate IFN-γ expression [ 101 ].…”

IRF1 regulates self-renewal and stress responsiveness to support hematopoietic stem cell maintenance

“…IRF1 has been tied to B and T lymphocyte and myeloid cell development and function (22)(23)(24)(25)(26)(27)(28)(29). Irf1 transcript levels increase during myeloid differentiation and in response to external stimuli, including viral infections, lipopolysaccharide (LPS), type I and type II IFNs, interleukin-1 (IL-1), IL-12, and granulocyte colony-stimulating factor (12,(30)(31)(32)(33)(34)(35)(36)(37). IRF1-deficient mice exhibit altered immune cell populations, with decreased numbers of peripheral blood (PB) CD8 + T and natural killer (NK) cells, concomitant with increased numbers of CD4 + T cells (28,29), and unaltered levels of red blood cells (RBCs) (38).…”