Fig. 1

Representative scheme of how IL-6 trans-signaling modulates inflammation-based colorectal tumorigenesis. Under inflammatory conditions, sIL-6Rα is generated from LPDCs by TACE, which proteolytically cleaves the extracellular domain of membrane-bound IL-6Rα. Gut microbiota had a key role on the activation of TACE. IL-6 is also produced by macrophages (Mϕs) and DCs in LP and binds to sIL-6Rα. The IL-6/sIL-6Rα complex can associate with gp130 and induces IL-6 signal transduction through the phosphorylation of Stat3, termed IL-6 trans-signaling. IL-6 trans-signaling triggered in LP inputs its downstream signal into intestinal epithelial cells (IECs) and induces the expression of anti-apoptotic gene and AID and the production of reactive oxygen species (ROS), which leads to the inhibition of cell death, genetic instability and DNA damage. It is speculated that long-term accumulation of IL-6 trans-signaling finally leads to colon tumorigenesis