Mechanisms of Jak/STAT Signaling in Immunity and Disease

Abstract

More than 2 decades ago, experiments on the antiviral mechanisms of interferons led to the discovery of Janus kinases (JAK) and their downstream effectors, the signal transducer of activation (STAT) proteins. This pathway has since become a paradigm for membrane to nucleus signaling and has come to explain how a broad range of soluble factors, including cytokines and hormones, mediate their diverse functions. Jak/STAT research has not only impacted basic science, particularly in the context of intercellular communication and cell-extrinsic control of gene expression, but has also become a prototype for transition from bench to bedside, culminating in the development and clinical implementation of pathway-specific therapeutics. This brief review will synthesize current understanding of Jak/STAT biology while taking stock of the lessons learned and the challenges that lie ahead.

Network pharmacology of JAK inhibitors

“…An additional level of complexity in the JAK-controlled network is that signals from most cytokines involve two different JAKs (3). It is usually unclear whether both JAKs contribute, or whether each has distinct signaling and transcriptomic consequences (for instance, by triggering parallel signaling pathways) (19,20). We addressed this question using the response of NK cells to IL-2 as a model.…”

Janus kinase inhibition lessens inflammation and ameliorates disease in murine models of hemophagocytic lymphohistiocytosis

“…10 Based on their essential roles in transmitting cytokine-induced signals, the JAKs have become a target for pharmacologic manipulation in inflammatory diseases. [11][12][13] Accordingly, studies have shown that JAK inhibition reduces the signs and symptoms of rheumatoid arthritis and ulcerative colitis, 14,15 as well as the myeloproliferative disorders. 16,17 Given the efficacy of JAK inhibition in these other conditions, we hypothesized that JAK inhibition might serve as a valid therapeutic approach in HLH.…”

IL-7–dependent STAT1 activation limits homeostatic CD4+ T cell expansion

“…Cytokines signal through STATs, and the modulation of the expression levels of these transcription factors may induce qualitative changes in the T cell response to cytokines (32,33). IL-7 is reported to signal primarily through STAT5.…”

“…Interestingly, STAT1, IFNG, IRF7, and IFNA were also noted among the top 15 best-scoring upstream regulators ( Figure 3B). To analyze the potential contribu-tion of IL-7-dependent STAT1 activation, we next compared the genes regulated upon IFN-γ stimulation (STAT1-dependent) (33). A direct comparison of the sets of DEGs for IL-7 and IFN-γ stimulation revealed a relatively small overlap in CD4 + and CD8 + naive T cells (n = 63 and n = 70 genes, respectively) ( Figure 3C, Table 2 and Supplemental Table 1; supplemental material available online with this article; https://doi.…”