Thursday, July 16, 2015
Grand Hall and Gallery, Ground Floor & 1st Floor (Maritim Hotel)
Taro Watabe, MD
,
Tokyo Medical and Dental University, Tokyo, Japan
Takashi Nagaishi, MD, PhD
,
Tokyo Medical and Dental University, Tokyo, Japan
Masahiro Suzuki, MD, PhD
,
Tokyo Medical and Dental University, Tokyo, Japan
Motomi Yamazaki, PhD
,
Department of Obstetrics and Gynecology, Nihon University, Tokyo, Japan
Michio Onizawa, MD, PhD
,
Tokyo Medical and Dental University, Tokyo, Japan
Nisha Jose, MSc
,
Tokyo Medical and Dental University, Tokyo, Japan
Arisa Tokai
,
Tokyo Medical and Dental University, Tokyo, Japan
Akinori Hosoya, MD
,
Tokyo Medical and Dental University, Tokyo, Japan
Mamoru Watanabe, MD, PhD
,
Tokyo Medical and Dental University, Tokyo, Japan
Background & Aim: We previously reported up-regulation of type 2 receptor for TNF (TNFR2) in the inflamed colonic epithelia and further up-regulation in colitis-associated cancer (CAC). However, the role of TNFR2 expression in the setting of CAC has not been elucidated. We therefore analyzed TNFR2 signaling in the colonic epithelial cells.
Methods & Results: TNFR2 up-regulation was observed in a murine colonic epithelial cell line, MOC1, when stimulated with recombinant (r) IFN-γ. Epithelial NFκB-induced expression of myosin light chain kinase (MLCK) was associated with disrupted tight junction (TJ) in a rTNF dose- dependent fashion. Such MLCK up-regulation and TJ disruption in MOC1 cells were abrogated by anti-TNF mAb (MP6-XT22), TNFR2-specific siRNA or even MLCK inhibitor (ML-7). Using an animal model of CAC involving azoxymethane and dextran sodium sulfate, the colonic lamina propria was found to have pro-tumorigenic cytokine production such as IL-1β, IL-6 and MIP-2 in association with epithelial NFκB activation, TNFR2 and MLCK up-regulations and TJ disruption. Treatment with either MP6-XT22 or ML-7 restored TJ, decreased pro-tumorigenic cytokine production and reduced CAC development.
Conclusions: Epithelial TNFR2 signaling in the context of IBD may be involved in epithelial permeabilization and pro-tumorigenic cytokine production that promote CAC development.
