Role of PGE2 in bridging TLR4 signaling and intestinal tumorigenesis. A. In WT intestine, TLR4 expression is increased in chronic inflammation and PGE 2 synthesis is induced by Cox-2 induction. Produced PGE 2 stimulates the expression and release of AR and then EGFR activation either directly or through AR release. Sustained activation of this pathway results in aberrant cell proliferation and tumorigenesis. B. In the absence of TLR4, chronic intestinal inflammation does not induce tumorigenesis. C. When PGE 2 is exogenously administered to TLR4-/- mice ①, PGE 2 activates EGFR either directly ④ or through AR ②③. This may be not enough to induce tumorigenesis. However, exogenous PGE 2 induces Cox-2 production in macrophages ⑤ that causes the release of endogenous PGE 2, forming a positive feedback loop, which induces tumorigenesis ⑥.