title: Soluble epoxide hydrolase deficiency inhibits dextran sulfate sodium-induced colitis and carcinogenesis in mice.
abstract: Soluble epoxide hydrolase (sEH) hydrolyses/inactivates anti-inflammatory epoxyeicosatrienoic acids (EETs) to their corresponding diols, and targeting sEH leads to strong anti-inflammatory effects. In the present study, using a tissue microarray and immunohistochemical approach, a significant increase of sEH expression was identified in ulcerative colitis (UC)-associated dysplasia and adenocarcinoma. The effects of deficiency in the sEH gene were determined on dextran sulfate sodium (DSS) colitis-induced carcinogenesis. The effects of EETs on lipopolysaccharide (LPS)-activated macrophages were analyzed in vitro. With extensive histopathological and immunohistochemical analyses, compared to wild-type mice, sEH(-/-) mice exhibited a significant decrease in tumor incidence (13/20 vs. 6/19, p<0.05) and a markedly reduced average tumor size (59.62±20.91 mm(3) vs. 22.42±11.22 mm(3)), and a significant number of pre-cancerous dysplasia (3±1.18 vs. 2±0.83, p<0.01). The inflammatory activity, as measured by the extent/proportion of erosion/ulceration/dense lymphoplasmacytosis (called active colitis index) in the colon, was significantly lower in sEH(-/-) mice (44.7%±24.9% vs. 20.2%±16.2%, p<0.01). The quantitative polymerase chain reaction (qPCR) assays demonstrated significantly low levels of cytokines/chemokines including monocyte chemoattractant protein (MCP-1), inducible nitric oxide synthase (iNOS), vasopressin-activated calcium-mobilizing (VCAM-1), interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α). In vitro, LPS-activated macrophages treated with 14,15-EET showed a significant reduction of LPS-triggered IL-1β and TNF-α expression. Eicosanoic acid metabolic profiling revealed a significant increase of the ratios of EETs/ dihydroeicosatrienoic acids (DHETs) and epoxyoctadecennoic acid/dihydroxyoctadecenoic acid (EpOMEs/DiHOMEs). These results indicate that sEH plays an important role in the development of colitis and in inducing carcinogenesis.
authors: Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, U.S.A.
authors: Wanying
authors: W
authors: Zhang
authors: Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, U.S.A.
authors: Haonan
authors: H
authors: Li
authors: Department of Entomology, University of California, Davis, CA, U.S.A.
authors: Hua
authors: H
authors: Dong
authors: Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, U.S.A.
authors: Jie
authors: J
authors: Liao
authors: Department of Entomology, University of California, Davis, CA, U.S.A.
authors: Bruce D
authors: BD
authors: Hammock
authors: Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, U.S.A.
authors: Guang-Yu
authors: GY
authors: Yang
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D002853:Chromatography, Liquid; D003092:Colitis / Q000139:chemically induced* / Q000201:enzymology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000201:enzymology*; D016264:Dextran Sulfate / Q000633:toxicity*; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D053719:Tandem Mass Spectrometry
chemical_list: D016264:Dextran Sulfate; D004851:Epoxide Hydrolases
keywords: Soluble epoxide hydrolase; carcinogenesis; colitis; dextran sulfate sodium; mice