Fluoxetine inhibits NF-κB signaling in intestinal epithelial cells and ameliorates experimental colitis and colitis-associated colon cancer in mice

被引:72
作者
Koh, Seong-Joon [1 ,2 ]
Kim, Jung Mogg [3 ]
Kim, In-Kyoung [1 ,2 ]
Kim, Nayoung [1 ,2 ]
Jung, Hyun Chae [1 ,2 ]
Song, In Sung [1 ,2 ]
Kim, Joo Sung [1 ,2 ]
机构
[1] Seoul Natl Univ, Coll Med, Dept Internal Med, Seoul 110744, South Korea
[2] Seoul Natl Univ, Coll Med, Liver Res Inst, Seoul 110744, South Korea
[3] Hanyang Univ, Coll Med, Dept Microbiol, Seoul 133791, South Korea
来源
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY | 2011年 / 301卷 / 01期
关键词
INFLAMMATORY-BOWEL-DISEASE; ACUTE MURINE COLITIS; BACTEROIDES-FRAGILIS ENTEROTOXIN; SEROTONIN REUPTAKE INHIBITORS; ULCERATIVE-COLITIS; COLORECTAL-CANCER; CROHNS-DISEASE; MOUSE MODEL; IKK-BETA; ANTIDEPRESSANTS;
D O I
10.1152/ajpgi.00267.2010
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Koh S-J, Kim JM, Kim I-K, Kim N, Jung HC, Song IS, Kim JS. Fluoxetine inhibits NF-kappa B signaling in intestinal epithelial cells and ameliorates experimental colitis and colitis-associated colon cancer in mice. Am J Physiol Gastrointest Liver Physiol 301: G9-G19, 2011. First published March 24, 2010; doi:10.1152/ajpgi.00267.2010.-Although fluoxetine, a selective serotonin reuptake inhibitor, is known to demonstrate anti-inflammatory activity, little information is available on the effect of fluoxetine regarding intestinal inflammation. This study investigates the role of fluoxetine in the attenuation of acute murine colitis by suppression of the NF-kappa B pathway in intestinal epithelial cells (IEC). Fluoxetine significantly inhibited activated NF-kappa B signals and the upregulated expression of interleukin-8 (IL-8) in COLO 205 colon epithelial cells stimulated with tumor necrosis factor-alpha (TNF-alpha). Pretreatment with fluoxetine attenuated the increased I kappa B kinase (IKK) and I kappa B alpha phosphorylation induced by TNF-alpha. In a murine model, administration of fluoxetine significantly reduced the severity of dextran sulfate sodium (DSS)-induced colitis, as assessed by the disease activity index, colon length, and histology. In addition, the DSS-induced phospho-IKK activation, myeloperoxidase activity, a parameter of neutrophil accumulation, and the secretion of macrophage-inflammatory protein-2, a mouse homolog of IL-8, were significantly decreased in fluoxetine-pretreated mice. Moreover, fluoxetine significantly attenuated the development of colon cancer in mice inoculated with azoxymethane and DSS. These results indicate that fluoxetine inhibits NF-kappa B activation in IEC and that it ameliorates DSS-induced acute murine colitis and colitis-associated tumorigenesis, suggesting that fluoxetine is a potential therapeutic agent for the treatment of inflammatory bowel disease.
引用
收藏
页码:G9 / G19
页数:11
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