Catalytic inhibition of TYK2 exerts selective effects on human cytokine responses (174.13)

Abstract

Abstract TYK2 is a JAK family protein tyrosine kinase activated in response to multiple cytokines, including Type I IFNs, IL-6, IL-10, and IL-12/23. Genetic mutation at the tyk2 locus has been linked to broad-range immune deficiency and dysregulation in a human patient, however in murine strains that lack TYK2 expression, only select pathways are compromised. We have utilized a panel of TYK2-selective small molecule inhibitors with varying degrees of selectivity against other JAK kinases to address the requirement for TYK2 catalytic function in cytokine response pathways in human cells. Our results suggest that, similar to the effects of TYK2 deficiency in murine cells, the scope of biological processes requiring TYK2 catalytic function is much more narrow and selective in human cells than previously appreciated.