Stat3 and Th17-mediated colitis promotes regional tumorigenesis in response to a common commensal bacterium: role of Foxp3+ Treg/Th17 balance (90.17)

Abstract

Abstract Enterotoxigenic Bacteroides fragilis (ETBF) is an inducer of inflammatory diarrheal disease with acute colitis, and may even be linked to chronic colitis and colorectal cancer in humans. The pathogenesis of ETBF can largely be attributed to the secretion of a toxin, BFT (B. fragilis toxin), which has a profound effect on the colonic microenvironment. BFT promotes cleavage of E-cadherin, activates NF-kB and Wnt/b-catenin signaling, and stimulates the secretion of pro-inflammatory cytokines, such as IL-6, IL-8, and TNF-a. The inflammation associated with ETBF is characterized by widespread colonic Stat3 activation and IL-17 cytokine secretion. In Min mice, the Th17-mediated inflammation promotes the formation of distal colon tumors, as demonstrated by reduced tumorigenesis in response to IL-17 blockade. Our research has been focused on elucidating the immunologic differences between the distal and proximal colon in an attempt to determine why tumorigenesis is so regional. We have found that the proximal colon has a greater density of Foxp3+ Tregs than the distal colon. Furthermore, preliminary data suggests that the Th17 cytokines are differentially expressed in the two regions. We propose that increased Treg density in the proximal colon restrains Th17-mediated inflammation relative to the distal colon. We are currently studying the relationship between the Treg cells and infiltrating effector cells and how that affects tumorigenesis in response to ETBF.