Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces Interleukin-22 Signals to Protect from Acute Colitis

In the intestinal tract, IL-22 activates signal transducer and activator of transcription 3 (Stat3) to promote intestinal epithelial cell (IEC) homeostasis and tissue healing. The mechanism has remained obscure but we demonstrate that IL-22 acts via tyrosine kinase 2 (Tyk2), a member of the Janus kinase (Jak) family. Using a mouse model for colitis, we show that Tyk2 deficiency exacerbates inflammatory bowel disease (IBD). Colitic Tyk2^-/- mice have less phosphorylated Stat3 (pY-Stat3) in colon tissue and their IECs proliferate less efficiently. Tyk2-deficient primary IECs show reduced pY-Stat3 in response to IL-22 stimulation and expression of IL-22-Stat3 target genes is reduced in IECs from healthy and diseased Tyk2^-/- mice. Experiments with conditional Tyk2^-/- mice reveal that IEC-specific depletion of Tyk2 aggravates colitis. Disease symptoms can be alleviated by administering high doses of recombinant IL-22-Fc, indicating that Tyk2 deficiency can be rescued via the IL-22 receptor complex. The pivotal function of Tyk2 in acute colitis was confirmed in Citrobacter rodentium-induced disease. Thus, Tyk2 protects against acute colitis by amplifying inflammation-induced epithelial IL-22 signaling to Stat3.