TY - JOUR
T1 - Reduction of inflammatory bowel disease-induced tumor development in IL-10 knockout mice with soluble epoxide hydrolase gene deficiency
AU - Zhang, Wanying
AU - Liao, Jie
AU - Li, Haonan
AU - Dong, Hua
AU - Bai, Han
AU - Yang, Allison
AU - Hammock, Bruce D.
AU - Yang, Guang Yu
PY - 2013/9/1
Y1 - 2013/9/1
N2 - Soluble epoxide hydrolase (sEH) quickly inactivates anti-inflammatory epoxyeicosatrienoic acids (EETs) by converting them to dihydroxyeicosatrienoic acids (DHETs). Inhibition of sEH has shown effects against inflammation, but little is studied about the role of sEH in inflammatory bowel disease (IBD) and its induced carcinogenesis. In the present study, the effect of sEH gene deficiency on the development of IBD-induced tumor development was determined in IL-10 knockout mice combined with sEH gene deficiency. Tumor development in the bowel was examined at the age of 25wk for male mice and 35wk for female mice. Compared to IL-10(-/-) mice, sEH (-/-)/IL-10(-/-) mice exhibited a significant decrease of tumor multiplicity (2±0.9tumors/mouse vs. 1±0.3tumors/mouse) and tumor size (344.55±71.73mm3 vs. 126.94±23.18mm3), as well as a marked decrease of precancerous dysplasia. The significantly lower inflammatory scores were further observed in the bowel in sEH(-/-)/IL-10(-/-) mice as compared to IL-10(-/-) mice, including parameters of inflammation-involved area (0.70±0.16 vs. 1.4±0.18), inflammation cell infiltration (1.55±0.35 vs. 2.15±0.18), and epithelial hyperplasia (0.95±0.21 vs. 1.45±0.18), as well as larger ulcer formation. qPCR and Western blotting assays demonstrated a significant downregulation of cytokines/chemokines (TNF-α, MCP-1, and IL-12, 17, and 23) and NF-κB signals. Eicosanoid acid metabolic profiling revealed a significant increase of ratios of EETs to DHETs and EpOMEs to DiOMEs. These results indicate that sEH plays an important role in IBD and its-induced carcinogenesis and could serve as a highly potential target of chemoprevention and treatment for IBD.
AB - Soluble epoxide hydrolase (sEH) quickly inactivates anti-inflammatory epoxyeicosatrienoic acids (EETs) by converting them to dihydroxyeicosatrienoic acids (DHETs). Inhibition of sEH has shown effects against inflammation, but little is studied about the role of sEH in inflammatory bowel disease (IBD) and its induced carcinogenesis. In the present study, the effect of sEH gene deficiency on the development of IBD-induced tumor development was determined in IL-10 knockout mice combined with sEH gene deficiency. Tumor development in the bowel was examined at the age of 25wk for male mice and 35wk for female mice. Compared to IL-10(-/-) mice, sEH (-/-)/IL-10(-/-) mice exhibited a significant decrease of tumor multiplicity (2±0.9tumors/mouse vs. 1±0.3tumors/mouse) and tumor size (344.55±71.73mm3 vs. 126.94±23.18mm3), as well as a marked decrease of precancerous dysplasia. The significantly lower inflammatory scores were further observed in the bowel in sEH(-/-)/IL-10(-/-) mice as compared to IL-10(-/-) mice, including parameters of inflammation-involved area (0.70±0.16 vs. 1.4±0.18), inflammation cell infiltration (1.55±0.35 vs. 2.15±0.18), and epithelial hyperplasia (0.95±0.21 vs. 1.45±0.18), as well as larger ulcer formation. qPCR and Western blotting assays demonstrated a significant downregulation of cytokines/chemokines (TNF-α, MCP-1, and IL-12, 17, and 23) and NF-κB signals. Eicosanoid acid metabolic profiling revealed a significant increase of ratios of EETs to DHETs and EpOMEs to DiOMEs. These results indicate that sEH plays an important role in IBD and its-induced carcinogenesis and could serve as a highly potential target of chemoprevention and treatment for IBD.
KW - Carcinogenesis
KW - Eicosanoid acid metabolic profiling
KW - IL-10
KW - Inflammatory bowel disease
KW - Soluble epoxide hydrolase
UR - http://www.scopus.com/inward/record.url?scp=84880752992&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84880752992&partnerID=8YFLogxK
U2 - 10.1002/mc.21918
DO - 10.1002/mc.21918
M3 - Article
C2 - 22517541
AN - SCOPUS:84880752992
VL - 52
SP - 726
EP - 738
JO - Molecular Carcinogenesis
JF - Molecular Carcinogenesis
SN - 0899-1987
IS - 9
ER -