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Induction of Nitric-Oxide Metabolism in Enterocytes Alleviates Colitis and Inflammation-Associated Colon Cancer.

ABSTRACT: Nitric oxide (NO) plays an established role in numerous physiological and pathological processes, but the specific cellular sources of NO in disease pathogenesis remain unclear, preventing the implementation of NO-related therapy. Argininosuccinate lyase (ASL) is the only enzyme able to produce arginine, the substrate for NO generation by nitric oxide synthase (NOS) isoforms. Here, we generated cell-specific conditional ASL knockout mice in combination with genetic and chemical colitis models. We demonstrate that NO derived from enterocytes alleviates colitis by decreasing macrophage infiltration and tissue damage, whereas immune cell-derived NO is associated with macrophage activation, resulting in increased severity of inflammation. We find that induction of endogenous NO production by enterocytes with supplements that upregulate ASL expression and complement its substrates results in improved epithelial integrity and alleviation of colitis and of inflammation-associated colon cancer.

SUBMITTER: Stettner N

PROVIDER: S-EPMC5976577 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Induction of Nitric-Oxide Metabolism in Enterocytes Alleviates Colitis and Inflammation-Associated Colon Cancer.

Stettner Noa N Rosen Chava C Bernshtein Biana B Gur-Cohen Shiri S Frug Julia J Silberman Alon A Sarver Alona A Carmel-Neiderman Narin N NN Eilam Raya R Biton Inbal I Pevsner-Fischer Meirav M Zmora Niv N Brandis Alexander A Bahar Halpern Keren K Mazkereth Ram R di Bernardo Diego D Brunetti-Pierri Nicola N Premkumar Muralidhar H MH Dank Gillian G Nagamani Sandesh C S SCS Jung Steffen S Harmelin Alon A Erez Ayelet A

Cell reports 20180501 7

Nitric oxide (NO) plays an established role in numerous physiological and pathological processes, but the specific cellular sources of NO in disease pathogenesis remain unclear, preventing the implementation of NO-related therapy. Argininosuccinate lyase (ASL) is the only enzyme able to produce arginine, the substrate for NO generation by nitric oxide synthase (NOS) isoforms. Here, we generated cell-specific conditional ASL knockout mice in combination with genetic and chemical colitis models. W ...[more]

PMID: 29768197

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Project description:Chronic inflammation is known to promote carcinogenesis; Dicer heterozygous mice are more likely to develop colitis-associated tumors. This study investigates whether Dicer is downregulated in inflamed colon tissues before malignancy occurs and whether increasing Dicer expression in inflamed colon tissues can alleviate colitis and prevent colitis-associated tumorigenesis. Methods: Gene expression in colon tissues was analyzed by immunohistochemistry, immunoblots, and real-time RT-PCR. Hydrogen peroxide or N-acetyl-L-cysteine was used to induce or alleviate oxidative stress, respectively. Mice were given azoxymethane followed by dextran sulfate sodium to induce colitis and colon tumors. Berberine, anastrozole, or pranoprofen was used to rescue Dicer expression in inflammatory colon tissues. Results: Oxidative stress repressed Dicer expression in inflamed colon tissues by inducing miR-215 expression. Decreased Dicer expression increased DNA damage and cytosolic DNA and promoted interleukin-6 expression upon hydrogen peroxide treatment. Dicer overexpression in inflamed colon tissues alleviated inflammation and repressed colitis-associated carcinogenesis. Furthermore, we found that anastrozole, berberine, and pranoprofen could promote Dicer expression and protect cells from hydrogen peroxide-induced DNA damage, thereby reducing cytosolic DNA and partially repressing interleukin-6 expression upon hydrogen peroxide treatment. Rescuing Dicer expression using anastrozole, berberine, or pranoprofen in inflamed colon tissues alleviated colitis and prevented colitis-associated tumorigenesis. Conclusions: Dicer was downregulated in inflamed colon tissues before malignancy occurred. Decreased Dicer expression further exaggerated inflammation, which may promote carcinogenesis. Anastrozole, berberine, and pranoprofen alleviated colitis and colitis-associated tumorigenesis by promoting Dicer expression. Our study provides insight into potential colitis treatment and colitis-associated colon cancer prevention strategies.

Project description:BACKGROUND:Nutrition with ammonium (NH4+) can enhance the drought tolerance of rice seedlings in comparison to nutrition with nitrate (NO3-). However, there are still no detailed studies investigating the response of nitric oxide (NO) to the different nitrogen nutrition and water regimes. To study the intrinsic mechanism underpinning this relationship, the time-dependent production of NO and its protective role in the antioxidant defense system of NH4+- or NO3--supplied rice seedlings were studied under water stress. RESULTS:An early NO burst was induced by 3?h of water stress in the roots of seedlings subjected to NH4+ treatment, but this phenomenon was not observed under NO3- treatment. Root oxidative damage induced by water stress was significantly higher for treatment with NO3- than with NH4+ due to reactive oxygen species (ROS) accumulation in the former. Inducing NO production by applying the NO donor 3?h after NO3- treatment alleviated the oxidative damage, while inhibiting the early NO burst by applying the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO) increased root oxidative damage in NH4+ treatment. Application of the nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester(L-NAME) completely suppressed NO synthesis in roots 3?h after NH4+ treatment and aggravated water stress-induced oxidative damage. Therefore, the aggravation of oxidative damage by L-NAME might have resulted from changes in the NOS-mediated early NO burst. Water stress also increased the activity of root antioxidant enzymes (catalase, superoxide dismutase, and ascorbate peroxidase). These were further induced by the NO donor but repressed by the NO scavenger and NOS inhibitor in NH4+-treated roots. CONCLUSION:These findings demonstrate that the NOS-mediated early NO burst plays an important role in alleviating oxidative damage induced by water stress by enhancing the antioxidant defenses in roots supplemented with NH4+.

Dataset Information

Induction of Nitric-Oxide Metabolism in Enterocytes Alleviates Colitis and Inflammation-Associated Colon Cancer.

Publications

Induction of Nitric-Oxide Metabolism in Enterocytes Alleviates Colitis and Inflammation-Associated Colon Cancer.

Similar Datasets

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