Working model. When colitis occurs, colonic macrophages activated by invading microbes produce inflammatory cytokines, but Shp2 does not play a prominent role during this process. On the other hand, loss of Shp2 potentiates IL-10–STAT3 signaling and its dependent deactivating programs in macrophages, thus decreasing their production of inflammatory cytokines and reducing the severity of colitis. Furthermore, TNF-α has the ability to up-regulate Shp2 expression in macrophages, suggesting that IL-10 supplementation may achieve higher anti-inflammatory efficacy when used in combination with anti–TNF-α antibody.