In this study here, for the first time, we provide evidence showing that ATF3 is actively involved in the IL-22-pSTAT3 signaling cascade to maintain intestinal homeostasis at the steady state and to protect against colon tissue damage during chemical-induced colitis, by a mechanism of suppressing PTP (protein tyrosine phosphatase)-mediated STAT3 inactivation. Here, ATF3 is linked to colitis.