Tyrosine kinase 2

Non-receptor tyrosine-protein kinase TYK2 is an enzyme that in humans is encoded by the TYK2 gene. TYK2 belongs to the JAK protein tyrosine kinase family and mediates the signaling of numerous antiviral and immunoregulatory cytokines (type I and type III IFNs, IL-10, IL-12, IL-22, IL-23) in immune and non-immune cells. TYK2 kinase mediates cytokine signaling by phosphorylating receptor subunits. It is also a component of the type I and type III interferon signaling pathways.

Cytokines play a central role in immunity and inflammation by regulating the survival, proliferation, differentiation and function of immune cells as well as cells of other organ systems. Therefore, targeting cytokines and their receptors is an effective means of treating such diseases.

Type I and II cytokine receptors associate with Janus family kinases (JAKs) to affect intracellular signaling. Cytokines such as interleukins, interferons, and hemopoietins activate Janus kinases that associate with their cognate receptors.

Tyk2 plays a role primarily in IL-12 and type I IFN signaling. However, in addition to IFN-α and -β and IL-12 signaling, Tyk2 also has major effects on the transduction of IL-23, IL-10, and IL-6 signaling. Because IL-6 signals through the gp-130 receptor chain, which is common to a large family of cytokines, including IL-6, IL-11, IL-27, IL-31, oncostatin M (OSM), ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, and LIF, Tyk2 may also affect signaling through these cytokines. Tyk2 is activated by IL-10. Type2 deficiency impairs the ability to generate and respond to IL-10.

A role for Tyk2 in rheumatoid arthritis is directly observed in Tyk2-deficient mice that were resistant to experimental arthritis. Moreover, these mice respond normally to IL-6 and IL-10, suggesting that Tyk2 is dispensable for mediating IL-6 and IL-10 signaling and does not play an important role in IFN-α signaling.

To what extent blocking Tyk2-induced intracellular signaling may play a role in the cytokine storm of covid-19 infection remains unresolved in such a manner (Luo W et al.2020). The most notable phenotype observed in Tyk2-deficient macrophages was the absence of nitric oxide production upon stimulation with LPS. Further elucidation of the molecular mechanisms of LPS signaling revealed that Tyk2 and IFN-β deficiency lead to resistance to LPS-induced endotoxin shock, whereas STAT1-deficient mice are susceptible.

Janus kinase (JAK) inhibitors have demonstrated clinical efficacy in psoriasis in both phase 2 and phase 3 trials and appear to be well tolerated overall (Kvist-Hansen A et al. 2020; Forman SB et al. 2020)

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