IFNgamma signaling-does it mean JAK–STAT?

Department of Pathology, NYU Cancer Institute, New York University Langone School of Medicine, New York, 10016, USA.
Cytokine & growth factor reviews (Impact Factor: 5.36). 10/2008; 19(5):383-394. DOI: 10.1016/j.cytogfr.2008.08.004


The molecular pathways involved in the cellular response to interferon (IFN)γ have been the focus of much research effort due to their importance in host defense against infection and disease, as well as its potential as a therapeutic agent. The discovery of the JAK–STAT signaling pathway greatly enhanced our understanding of the mechanism of IFNγ-mediated gene transcription. However, in recent years it has become apparent that other pathways, including MAP kinase, PI3-K, CaMKII and NF-κB, either co-operate with or act in parallel to JAK–STAT signaling to regulate the many facets of IFNγ biology in a gene- and cell type-specific manner. The complex interactions between JAK/STAT and alternate pathways and the impact of these signaling networks on the biological responses to IFNγ are beginning to be understood. This review summarizes and appraises current advances in our understanding of these complex interactions, their specificity and proposed biological outcomes.

Download full-text


Available from: David Levy, Dec 18, 2014
  • Source
    • "This Smad:p300/CBP:STAT3 complex then translocates into the nucleus, which specifies glial cell fate by transcriptional activation of astrocytic genes, such as Gfap and S100í µí»½. However, STAT3 can also be activated by different ligands, such as IFN and interleukins (Table 1)[26,363738. Activation of JAK-STAT signaling alone is insufficient to initiate gliogenesis. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Trisomy of human chromosome 21 in Down syndrome (DS) leads to several phenotypes, such as mild-to-severe intellectual disability, hypotonia, and craniofacial dysmorphisms. These are fundamental hallmarks of the disorder that affect the quality of life of most individuals with DS. Proper brain development involves meticulous regulation of various signaling pathways, and dysregulation may result in abnormal neurodevelopment. DS brain is characterized by an increased number of astrocytes with reduced number of neurons. In mouse models for DS, the pool of neural progenitor cells commits to glia rather than neuronal cell fate in the DS brain. However, the mechanism(s) and consequences of this slight neurogenic-to-gliogenic shift in DS brain are still poorly understood. To date, Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling has been proposed to be crucial in various developmental pathways, especially in promoting astrogliogenesis. Since both human and mouse models of DS brain exhibit less neurons and a higher percentage of cells with astrocytic phenotypes, understanding the role of JAK-STAT signaling in DS brain development will provide novel insight into its role in the pathogenesis of DS brain and may serve as a potential target for the development of effective therapy to improve DS cognition.
    Full-text · Article · Jan 2016
  • Source
    • "Differences with reference to IFN-γ may be explained by the expression dynamics of IFN-γ, which is only secreted by a subset of immune cells such as natural killer cells and pathogen-specific T cells. In addition, the IFNGR expression differs and therefore, these effects are not comparable to IFN-α and -λ.104,105,106 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Type-III interferons (IFN-λ, IFNL) are the most recently described family of IFNs. This family of innate cytokines are increasingly being ascribed pivotal roles in host–pathogen interactions. Herein, we will review the accumulating evidence detailing the immune biology of IFNL during viral infection, and the implications of this novel information on means to advance the development of therapies and vaccines against existing and emerging pathogens. IFNLs exert antiviral effects via induction of IFN-stimulated genes. Common single nucleotide polymorphisms (SNPs) in the IFNL3, IFNL4 and the IFNL receptor α-subunit genes have been strongly associated with IFN-α-based treatment of chronic hepatitis C virus infection. The clinical impact of these SNPs may be dependent on the status of viral infection (acute or chronic) and the potential to develop viral resistance. Another important function of IFNLs is macrophage and dendritic cell polarization, which prime helper T-cell activation and proliferation. It has been demonstrated that IFNL increase Th1- and reduce Th2-cytokines. Therefore, can such SNPs affect the IFNL signaling and thereby modulate the Th1/Th2 balance during infection? In turn, this may influence the subsequent priming of cytotoxic T cells versus antibody-secreting B cells, with implications for the breadth and durability of the host response.
    Full-text · Article · Jul 2014 · Emerging Microbes and Infections
  • Source
    • "IL-10 transgenic mice are unable to limit the growth of immunogenic tumors; however, administration of blocking IL-10 mAbs restored in vivo antitumor responses [33]. IFN-γ may exert potent antitumor effects on lung cancer and metastasis, as this cytokine boosts natural killer cell activity, induces macrophage activation and antigen presentation, and activates tumor-specific CD8+CTLs which are required for the elimination of cancer cells [34–36]. IL-10 inhibits the generation of cell-mediated antitumor immunity by inhibiting a broad array of immune parameters including antigen presentation, antigen-specific T cell proliferation, and type 1 cytokine production [37]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pathogenic mechanisms underlying the development of lung cancer are very complex and not yet entirely clarified. T lymphocytes and their immune-regulatory cytokines play a pivotal role in controlling tumor growth and metastasis. Following activation by unique cytokines, CD4+ T helper cells differentiate into Th1, Th2, Th17, and regulatory T cells (Tregs). Traditionally, research in lung cancer immunity has focused almost exclusively on Th1/Th2 cell balance. Recently, Th17 cells and Tregs represent an intriguing issue to be addressed in lung cancer pathogenesis. Tregs play an important role in the preservation of self-tolerance and modulation of overall immune responses against tumor cells. Th17 cells directly or via other proinflammatory cytokines modulate antitumor immune responses. Notably, there is a close relation between Tregs and Th17 cells. However, the possible interaction between these subsets in lung cancer remains to be elucidated. In this setting, targeting Treg/Th17 balance for therapeutic purposes may represent a useful tool for lung cancer treatment in the future. The purpose of this review is to discuss recent findings of the role of these novel populations in lung cancer immunity and to highlight the pleiotropic effects of these subsets on the development and regulation of lung cancer.
    Full-text · Article · Apr 2014 · Research Journal of Immunology
Show more