TYK2 in Humans Cytokines Responses!22 Feb 2020 10:34
A Restricted Role for TYK2 Catalytic Activity in Human Cytokine Responses Revealed by Novel TYK2-Selective Inhibitors
Our studies of the role of TYK2 catalytic activity in various human cytokine signaling pathways are consistent with studies of TYK2-deficient mice, but differ from the roles for TYK2 deduced from studies of a single TYK2-deficient human patient. TYK2 deficiency results in pathway-specific impairment of immune responses in mice, characterized by a reduced ability of IFN-a to induce type I IFN-responsive genes and antiviral responses, an inability of IL-12 to induce IFN-g production from T cells and NK cells and an inability of IL-23 to induce IL-17 production from T cells.
However, the IL-10 responses of T cells and myeloid cells and the IL-6 responses of T cells remain intact in TYK2-deficient mice.
IFN-a, IL-6, IL-10, and IL-22
In humans, TYK2 deficiency has also been associated with the abrogation of IL-12 and IL-23 responses in a single patient who exhibited hyper-IgE syndrome.
However, this patient was also shown to have additional defects in type I IFN, IL-6, and IL-10 signaling, suggesting that TYK2 deficiency may affect a broader group of cytokines in humans than in mice.
Together with a lack of significant inhibitory activity of the TYK2-selective compounds in the primary cell assays and the superposition of the inhibitory curves for combined treatment with JAK1 and TYK2 selective compounds together versus treatment with the JAK1-selective compound alone, these results indicate that JAK1 kinase activity and not TYK2 kinase activity is important for these signaling events.
However, in our IFN-a, IL-6, IL-10, and IL-22 assays, we sometimes observe a partial inhibition of readouts by our TYK2-selective compounds, resulting in up to 50% inhibition of assay readouts at the highest compound concentrations. These effects occur at concentrations of the TYK2-selective compounds that are much higher than their cellular potencies against TYK2 in the TYK2 reference cell assay. This inhibition of assay readouts at very high concentrations of the TYK2-selective compounds may thus be caused by partial inhibition of JAK1 kinase activity and/or off-target effects of the compounds at these concentrations.
Results
Effects of TYK2 versus JAK2 inhibition on IL-12 and IL-23 signaling
We observed in the IL-12 assays, where there was a good correlation with TYK2 catalytic inhibition but poor correlation with JAK2 catalytic inhibition. This suggests that these aspects of IL-23 signaling may depend on both TYK2 and JAK2 catalytic activity. The contribution of JAK2 catalytic activity to IL-23–induced phospho-STAT3 and IL-17F is particularly apparent for those compounds with the highest degree of TYK2 selectivity over JAK2.
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