Dissecting the role of Tyk2 in IL-12 signaling (38.11)

Abstract Tyrosine kinase 2 (Tyk2), a member of the Jak family of non-receptor associated kinases, has been implicated in transducing signals mediated by IL-12, IL-23 and IFNα. A strain of mice (B10.Q/J) bears a missense mutation in the pseudokinase domain of Tyk2 which renders the kinase nonfunctional. These mice were initially identified by their heightened resistance to collagen-induced arthritis (CIA) and impaired response to IL-12 and type I IFNs. Following in-house confirmation of disease resistance to CIA, B10.Q/J and wild-type (WT) mice were injected with PBS, IL-12, IL-18, or IL-12+IL-18. Sera were collected at 2 and 24 hours post-injection, and levels of various polypeptide mediators were determined by multi-analyte profiling and ELISA. Compared to WT mice, the absence of functional Tyk2 in the B10.Q/J mice lead to a decrease in circulating IFNγ following IL-12+IL-18 administration. Confirmation that IFNγ output was dependent on Jak involvement was established using the Jak antagonist CP-690,550. This inhibitor was orally administered to WT mice prior to injection of IL-12+IL-18. Sera and tissues collected 2 hours following cytokine injection demonstrated reduced levels of IFNγ and phosphorylated-STAT4. Our results suggest that antagonism of Tyk2 may provide therapeutic benefit in those diseases in which disregulation of cytokines contributes to disease development.