Involvement of Tyrosine Kinase-2 in Both the IL-12/Th1 and IL-23/Th17 Axes In Vivo

Abstract

Tyrosine kinase-2 (Tyk2), a member of the Jak family of kinases, mediates the signals triggered by various cytokines, including type I IFNs, IL-12, and IL-23. In the current study, we investigated the in vivo involvement of Tyk2 in several IL-12/Th1– and IL-23/Th17–mediated models of experimental diseases, including methylated BSA injection-induced footpad thickness, imiquimod-induced psoriasis-like skin inflammation, and dextran sulfate sodium- or 2,4,6-trinitrobenzene sulfonic acid-induced colitis. In these disease models, Tyk2 deficiency influenced the phenotypes in immunity and/or inflammation. Our findings demonstrate a somewhat broader contribution of Tyk2 to immune systems than previously expected and suggest that Tyk2 may represent an important candidate for drug development by targeting both the IL-12/Th1 and IL-23/Th17 axes.

Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces IL-22 Signals To Protect from Acute Colitis

“…Using three mouse colitic models, our data suggest that the underlying pathomechanism in the absence of Tyk2 is rather a perturbance of the intestinal epithelial barrier involving insufficient expression of antimicrobial peptides as well as impairment in epithelial regeneration during inflammation than an imbalance of Th cell polarization. A previous study using Tyk2-deficient mice has identified the kinase as an important constituent of the Th1/Th17 axes in DSS-induced colitis and hence a promoter of the disease (42). In contrast to this study, we did not detect a significant influence of Tyk2 deletion on levels of IL-12p40 and IL-23A mRNA.…”

“…Genome-wide association studies identified Tyk2 as susceptibility locus for IBD in humans (41). During inflammation, Tyk2 2/2 mice show opposing phenotypes in that they are either protected from Th1-or Th17-driven diseases (4,5,42,43) or more prone to Th2-or Th9-dominated pathology (2, 3).…”

Genetic association and interaction between the IRF5 and TYK2 genes and systemic lupus erythematosus in the Han Chinese population

“…Thus, TYK2 may be an interesting candidate gene for SLE. A variant (rs280519) of TYK2 has been showed to be associated with susceptibility to SLE in a recent GWAS [8], which was further confirmed to be associated with increased gene expression and IFN production [9]. Furthermore, a large-scale meta-analysis has detected a significant genetic association of TYK2 SNPs (rs34536443 and rs2304256) with autoimmune and inflammatory diseases [10].…”

Immunological Consequences of JAK Inhibition: Friend or Foe?

“…Deficiency of JAK3 was first identified in severe combined immunodeficiency syndrome (SCID), associated with an almost absence of T cells and functionally defective B cells, again highlighting the importance of JAK signalling in normal immune system functioning [30]. Lastly, modelling of Tyk2 suggests activation by a range of cytokines such as type I IFNs, IL-6, IL-10 and the IL-12 and IL-23 families (reviewed in [31]) . Tyk2 functionality has been shown in murine models to be crucial for T helper 1 (Th) 1-mediated immune responses and IL-12, signalling via Tyk2, plays a pivotal role in enhancing natural killer (NK) cell cytotoxicity [31][32][33].…”

“…Lastly, modelling of Tyk2 suggests activation by a range of cytokines such as type I IFNs, IL-6, IL-10 and the IL-12 and IL-23 families (reviewed in [31]) . Tyk2 functionality has been shown in murine models to be crucial for T helper 1 (Th) 1-mediated immune responses and IL-12, signalling via Tyk2, plays a pivotal role in enhancing natural killer (NK) cell cytotoxicity [31][32][33]. As reviewed by Agnelo et al, Th1 cell differentiation also appears dependent upon a range of transcription factors, including TBET and STAT1/4, in addition to cytokines such as IL-12, IL-23 and IFN-Y; whereas, Th2 differentiation is dependent upon a number of transcription factors such as GATA-3, STAT6 and the cytokine IL-4 [34].…”